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© 2000 American Society for Clinical Oncology Positron Emission Tomography Using [18F]Fluorodeoxyglucose for Monitoring Primary Chemotherapy in Breast CancerByFrom the Departments of GynecologyNuclear Medicine, and Pathology, Technische Universität München, Munich, and Department of Gynecology, University Hospital Eppendorf, Hamburg, Germany. Address reprint requests to Marcus Schelling, MD, Department of Gynecology, Klinikum rechts der Isar, Technische Universität München, Ismaningerstr 22, 81675 München, Germany.
PURPOSE: To address the role of positron emission tomography (PET) using [18F]fluorodeoxyglucose (FDG) to monitor primary (neoadjuvant) chemotherapy in patients with locally advanced breast cancer. PATIENTS AND METHODS: Quantification of regional FDG uptake of the breast acquired after the first and second courses of chemotherapy was compared with the baseline scan in 22 patients with a total of 24 breast carcinomas. To evaluate the predictive value of PET imaging, histopathologic response after completion of chemotherapy classified as gross residual disease (GRD) or minimal residual disease (MRD) served as the gold standard. RESULTS: Significant differences in tracer uptake between nonresponding tumors (GRD) and responding lesions (MRD) were observed (P < .05) as early as after the first course of chemotherapy. Tracer uptake showed little change in tumors with GRD found later in pathologic analysis but decreased sharply to the background level in most tumors with MRD. After the first course, all responders were correctly identified (sensitivity 100%, specificity 85%) by a standardized uptake value decrease below 55% of the baseline scan. At this threshold, histopathologic response could be predicted with an accuracy of 88% and 91% after the first and second courses of therapy, respectively. CONCLUSION: This study demonstrates that in patients with advanced breast cancer undergoing primary chemotherapy, FDG-PET differentiates responders from nonresponders early in the course of therapy. This may help improve patient management by avoiding ineffective chemotherapy and supporting the decision to continue dose-intensive preoperative chemotherapy in responding patients.
MORE THAN 20 YEARS ago, primary (neoadjuvant) chemotherapy was introduced for the preoperative treatment of inflammatory breast cancer. Results demonstrated that use of primary chemotherapy increased survival rates compared with primary operative treatment.1 This success resulted in increasing application of preoperative chemotherapy, even in patients presenting with noninflammatory locally advanced breast cancer. An important advantage of primary chemotherapy is that it increases the rate of breast-conserving surgery by preoperatively reducing tumor volume.2,3 However, it still needs to be determined whether preoperative chemotherapy also provides a prognostic benefit compared with primary tumor resection followed by adjuvant chemotherapy.4-6 Recent studies have shown the prognostic relevance of histopathologic response among patients receiving primary chemotherapy.7,8 Patients with minimal residual disease (MRD) had significantly higher disease-free and overall survival rates compared with patients with gross residual disease (GRD). In contrast to the clinically assessed response of approximately 70% in most studies, the partial or complete regression in histopathologic tissue analysis is only 20% to 30%.9 Patients with a clinical response but GRD in pathology seem to benefit predominantly from breast conservation rather than from an improved prognosis. Since clinical response does not necessarily reflect histopathologic response, it is not possible to accurately determine the therapeutic effect until definitive breast surgery. Considering the side effects of primary chemotherapy, there is clearly a need for early therapy monitoring to identify nonresponding patients. Anatomical imaging procedures, including mammography, ultrasonography, and magnetic resonance imaging, have been used for measuring tumor size to derive response to therapy.10-13 However, general restrictions of these imaging procedures include the limited accuracy and reproducibility in determining tumor size and the delay between initiation of therapy and tumor shrinkage.14 Moreover, in patients with residual masses after therapy, anatomical imaging does not distinguish viable tumor tissue from fibrotic scar tissue.10,11 Currently, histopathologic analysis is necessary to accurately assess response to therapy. For distant metastases, therapy monitoring is even more difficult because histopathologic tissue examination is often not possible. Imaging metabolic pathways offers an alternative method to visualize therapeutic effects. Malignant transformation of cells is frequently associated with increased metabolic activity.15 Positron emission tomography (PET) using the radiolabeled glucose analog 2-(fluorine-18)-fluoro-2-deoxy-D-glucose (FDG) enables three-dimensional visualization of regional glucose metabolism within the body. After cellular uptake via glucose transporters, glucose and FDG are phosphorylated by intracellular hexokinase; however, FDG-6-phosphate is trapped and is no longer a substrate for glycolysis, glycogen synthesis, or the pentose phosphate pathways.16 Therefore, FDG-PET imaging has been proposed to improve diagnostic strategies in cancer patients by identification of primary tumors and distant metastases.17,18 Metabolic imaging by PET has been shown to be potentially valuable for staging of different tumor types, including breast cancer.19-23 Assessment of therapy response should be possible at earlier time points compared with anatomical imaging because changes in tumor metabolism precede a reduction of tumor size. Presently, there are only a few studies available that report on small patient populations and therapy monitoring of breast cancer with PET.24-27 Nevertheless, these studies suggest that quantification of tumor glucose metabolism is highly accurate for monitoring the effects of chemotherapy. The aim of this study was to prospectively use FDG-PET imaging in patients with locally advanced breast cancer to monitor response to preoperative chemotherapy. Regional FDG uptake after the first and second courses of chemotherapy was compared with the baseline scan in order to differentiate responding from nonresponding patients using histopathologic response as the gold standard.
Patients Women who presented with newly diagnosed locally advanced breast cancer (> 3 cm in diameter) were scheduled to undergo preoperative chemotherapy according to a study protocol. Patients were asked to participate in this study but were not included if they had had prior surgery of the breast, chemotherapy, or radiation therapy within the last 3 months. Patients were not studied if they were pregnant, had known diabetes, or were younger than 18 years. Details of the study were explained by a physician, and written informed consent was obtained from all patients. The study protocol was approved by the local ethical committee of the Technische Universität München. PET scanning of the breast was performed in 22 patients with a total of 24 histologically proven breast carcinomas (two patients had bilateral breast cancer). All patients underwent core needle biopsy of the breast after the baseline PET study. The chemotherapeutic regimen consisted of epirubicin 90 mg/m2 and cyclophosphamide 600 mg/m2 (n = 17) or epirubicin 90 mg/m2 and paclitaxel 175 mg/m2 (n = 5) given on a single day. Surgery was performed after three courses of treatment (n = 6) and four courses of treatment (n = 15). One patient underwent surgery after the second course of chemotherapy because of progressive disease. After completion of primary chemotherapy, 11 patients underwent breast-conserving surgery and the remaining 11 patients (with 13 breast carcinomas) underwent mastectomy. In all patients, standardized postoperative chemotherapy with cyclophosphamide, methotrexate, and fluorouracil was administered. Patients who underwent breast-conserving surgery received additional radiotherapy. Patient characteristics are listed in Table 1.
PET Imaging FDG of high specific activity was produced with a standard technique using a method modified from the synthesis of Hamacher et al.28 Whole-body PET scanners (ECAT 951R/31 and ECAT EXACT; Siemens CTI, Knoxville, TN) were used, providing an axial field of view of 10.5 and 15.8 cm, resulting in 31 and 47 transverse slices with a thickness of 3.4 mm. Transmission scans were performed with germanium-68 rod sources. Emission data corrected for random events, dead time, and attenuation were reconstructed with filtered backprojection (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. The resulting in-plane image resolution of transaxial images was approximately 8 mm full width half maximum with an axial resolution of approximately 5 mm full width half maximum. Patients were fasted for at least 6 hours before PET imaging. Their serum glucose levels were measured (mean, 95 ± 15 mg/dL) before the intravenous administration of 280 to 400 MBq (approximately 10 mCi) of FDG. All patients were studied in the prone position with both arms at their sides. In all patients, emission scans of the breast, acquired in one bed position, were obtained from 45 to 60 minutes after tracer injection followed by the transmission scan. The time difference in acquiring emission scans between baseline and follow-up scans was 2.3 ± 3.4 minutes (mean ± SD) in all patients. Twenty-two patients underwent a total of 56 PET scans. Baseline scans were performed in all patients before core biopsy and initiation of chemotherapy (median, 7 days; range, 1 to 20 days). In 14 patients (16 breast tumors), a second PET scan was performed after the first course (median, 10 days; range, 3 to 16 days) and in 20 patients (22 breast tumors), after the second course (median, 9 days; range, 5 to 23 days) of chemotherapy.
Image Analysis
Assessment of Therapy Response For the assessment of histopathologic response, lumpectomy (n = 11) and mastectomy (n = 13) specimens were cut in slices measuring 0.5 cm and evaluated for the presence or absence of macroscopic tumor. Complete tumors or the area of the tumor was taken for histologic examination. Additionally, routine blocks from the remaining breast tissue were examined. 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. Histopathologic tumor classification was performed according to the tumor-node-metastasis staging system of the International Union Against Cancer.30 All sections were studied under a microscope independently by two experienced pathologists (J.N. and M.W.). Histopathologic tumor regression served as the gold standard for the evaluation of therapy response with PET. Response was classified as proposed by Honkoop et al8 by separating tumors into two major groups of regression, namely GRD (group A) and MRD (group B). MRD comprised tumors with only scattered small foci of tumor cells (pMRD; subgroup B1) and those with a complete histopathologic response (pCR; subgroup B2). GRD comprised tumors showing macroscopically residual tumor or microscopically extensive infiltration. Because patients with GRD may still benefit from primary chemotherapy by breast conservation, tumors with GRD were subdivided into two groups depending on clinical response: cNC or cPD tumors (group A1) and cPR and cCR tumors (group A2).
Statistical Analysis
Clinical and Histopathologic Therapy Response After completion of chemotherapy, 17 (71%) of 24 breast carcinomas showed GRD (group A) and seven (29%) of 24 showed MRD (group B) in pathology. Six breast carcinomas (25%) showed no evidence of clinical or histopathologic regression (group A1). All patients in this group underwent mastectomy. Eleven breast carcinomas (46%) showed a clinical response although they were diagnosed with GRD (group A2). Breast-conserving therapy was possible in five patients in this group. Among patients with MRD (seven tumors), all except one had a cPR or cCR. Four of the tumors had pMRD (group B1) and three had a pCR (group B2). In one patient described above with MRD but cNC, mastectomy was necessary due to extensive residual ductal carcinoma-in-situ; all other patients underwent breast-conserving surgery. A summary of the clinical and pathologic responses is given in Table 2 and Fig 1.
PET Monitoring of Therapy Response Comparing SUVs calculated for maximum and average activity values within an ROI showed a good correlation (r = .97). Therefore, we used the SUV based on the maximum activity within the tumor normalized to blood glucose at time of tracer injection for the following statistical analysis. Follow-up studies after the first and second courses of chemotherapy were related to the baseline study, which served as the 100% reference value. Table 3 and Fig 2 summarize the changes in tracer uptake expressed as SUV. After the first course of chemotherapy, there was already a clear difference between tumors that had no response (group A) and tumors that showed a response in final pathology (group B). The difference increased after the second course and was statistically significant (P < .05) at both time points. In a more detailed analysis (Fig 2), group A1 (no clinical or histopathologic response) was characterized by only a small decrease of SUVs after the first course (to 83% of baseline) followed by an increase above the level of the baseline study (104%) after the second course. In tumors with clinical response but GRD (group A2), the PET signal decreased to 72% and 76% (not significant) of the baseline study after the first and second courses, respectively. In a comparison of tumors with MRD (group B1) and a pCR (group B2), SUVs decreased sharply to the level of the background activity of surrounding breast tissue in most patients. Therefore, it was not possible to differentiate the decrease in SUV between groups B1 and B2.
Prediction of Histopathologic Response by PET The changes in FDG uptake in breast carcinomas during chemotherapy, expressed as SUVs, showed significant differences (P < .05) between GRD (group A) and MRD (group B). To determine a threshold for optimal differentiation between responders and nonresponders, receiver operating characteristic analysis showed the highest accuracy using a decrease of the SUV to a level below 55% of the baseline study. At this threshold, three of three responders that were studied after the first course of therapy were correctly identified. On the other hand, two of 13 nonresponding tumors were included, resulting in a specificity of 85%. At the defined threshold, histopathologic response was predicted with an accuracy of 88%. After the second course of chemotherapy, five of six histopathologic responding tumors and one of 16 nonresponding tumors showed a decrease below the threshold (55% of baseline), resulting in a sensitivity of 83% and a specificity of 94% (Fig 3). Therefore, accuracy at the defined threshold increased to 91% after the second course of therapy.
The higher rate of breast-conserving surgery is an important advantage of preoperative chemotherapy for locally advanced breast cancer.2,3 Additionally, it has been shown that after completion of primary chemotherapy, patients with MRD by pathology have a better prognosis compared with those with GRD.7,8 This prospective study demonstrates that metabolic imaging by PET using radiolabeled FDG allows noninvasive differentiation between MRD and GRD groups as early as after the first course of chemotherapy. In nonresponding patients, the glucose metabolism of breast carcinomas showed little change, whereas the PET signal in responders decreased to the background level in most patients. Regional accumulation of radiolabeled FDG in tissue reflects exogenous glucose consumption.31 PET enables visualization of increased glucose metabolism of malignant tissue, and in vitro data suggest that FDG uptake predominantly reflects the number of viable tumor cells.32 FDG-PET has previously been used to assess therapy response. Wahl et al24 studied 11 women with newly diagnosed primary breast cancer undergoing chemohormonotherapy. The imaging protocol consisted of a baseline scan followed by PET scans during three cycles of treatment. There was a rapid and significant decrease in tumor glucose metabolism in the responding patients but no significant decrease in nonresponding patients. The decrease in metabolism preceded the reduction in tumor size, which was assessed clinically and radiographically. Bassa et al26 studied 13 patients undergoing primary chemotherapy and 14 patients about to undergo surgery. They found a reduction of FDG uptake in breast carcinomas at the midpoint of chemotherapy. In addition, preoperative PET scans showed a good correlation with pathology findings at surgery. Using FDG and carbon-11 methionine, Jansson et al25 studied 16 patients; PET showed a significant decrease in tracer uptake after the first course of therapy in eight of 12 patients with a clinical response after completion of chemotherapy. They concluded that therapy response could be determined earlier with PET than with any other method of conventional therapy evaluation. We compared the results from PET imaging with clinical response to primary chemotherapy and, more importantly, with histopathologic response using distinct criteria (GRD and MRD) that had been previously identified to provide prognostic information.8 The clinical response was comparable to that reported by other groups. Seventeen (71%) of 24 breast carcinomas showed a decrease in tumor size after completion of chemotherapy. Of this group, breast-conserving surgery was possible in 11 patients. Results from PET imaging allowed for estimation of histopathologic response early after the initiation of therapy. Kuerer et al33 found a survival rate of almost 90% at 5 years in patients with a pCR. In a recent editorial of the Journal of Clinical Oncology, McMasters and Hunt34 emphasized the need to identify these patients before definitive breast cancer surgery. Our study showed a significant decrease of glucose metabolism in responding breast carcinomas after the first course of chemotherapy (Fig 4). The accuracy in predicting the histopathologic response was 88% and increased to 91% after the second course of chemotherapy. One patient with MRD in pathology showed no change in FDG uptake after the second course of therapy. Surgery resulted in mastectomy due to extensive residual ductal carcinoma-in-situ. The most likely explanation for this PET result is that the predominant contribution to FDG uptake was derived from the in situ component, which is known to be less affected by chemotherapy.
The threshold determined after the first course of chemotherapy (decrease below 55% of baseline) for differentiation between responders and nonresponders included two tumors with GRD in histopathology. In one patient, the tumor showed an initial decrease of tracer uptake to 47% of baseline after the first course followed by a subsequent increase to 68% of baseline. This may be explained by tumor inhomogeneity consisting of clones with different chemosensitivities. In the other patient, the tumor showed a continual decrease of tracer uptake during chemotherapy and an excellent clinical response, but there was viable tumor in a residual mass of 1.8 cm in diameter. This patient may have benefited from an additional course of chemotherapy. There was a noticeable difference in tracer uptake over time in patients with GRD depending on clinical response (Fig 2), although the change was not significant. Patients with a clinical response showed a more pronounced decrease of tumor glucose metabolism. These patients can still benefit from preoperative chemotherapy by breast conservation. The clinical response and the decision for breast-conserving surgery are mainly dependent on the reduction in tumor size, which was not addressed by the PET analysis in this study. Metabolic imaging with PET was found to enable monitoring during chemotherapy. Additionally, it reflected the response to therapy later in pathology. Assessment of chemosensitivity would support the decision to continue dose-intensive preoperative chemotherapy in responding patients because this group benefits from an improved prognosis. By identifying nonresponding patients, PET can help to avoid ineffective therapy and, therefore, reduce toxic side effects in these patients. Furthermore, the number of patients who develop metastases under ineffective chemotherapy and the time delay until definitive surgery may be reduced. If the predictive value of PET imaging can be confirmed in larger patient populations, PET may also aid in the decision to apply an alternative chemotherapeutic regimen early in the course of chemotherapy in nonresponding patients. Some limitations of the presented study have to be considered. The number of patients studied was relatively small; therefore, determination of cutoff values to accurately differentiate between responders and nonresponders was limited. Sixteen of 24 tumors were studied after the first course and 22 after the second course of chemotherapy. PET imaging was not possible in some patients because of poor clinical condition resulting from side effects of chemotherapy. Of note, the optimal threshold to differentiate between responder and nonresponder needs to be confirmed in an independent patient population. Imaging with PET is highly sensitive and is able to detect radiolabeled tracers in nanomolar concentrations. However, the resolution of currently available PET scanners is approximately 6 to 8 mm, which does not allow measurement of regional glucose metabolism on a microscopic level. Therefore, after the second course of chemotherapy, PET could not differentiate between patients with microscopic residual tumor (group B1) and those with a complete response (group B2). Assessment of tumor metabolism during chemotherapy provides different information compared with histopathology obtained several weeks later. Therefore, response to therapy assessed by PET may provide independent prognostic information. To address the questions raised above, a multicenter study was conducted including PET scanning after completion of chemotherapy and before surgery to directly compare the PET signal with residual viable tumor in pathology. The results of this study have demonstrated the predictive value of metabolic imaging by PET in the early assessment of response to primary chemotherapy in locally advanced breast cancer. Earlier assessment may also have implications in the palliative situation, where direct histopathologic assessment of the response to chemotherapy is not possible. Monitoring breast cancer patients with PET may provide information to alter chemotherapeutic regimens early in the course of therapy if firstline treatment is ineffective.
The authors gratefully acknowledge the effort of the cyclotron and radiochemistry staff. Furthermore, they appreciate the excellent technical support of the PET technicians and the editorial help of Jodi Neverve in the preparation of the manuscript.
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ABSTRACT
INTRODUCTION
55% of the baseline. Accuracy 88% and 91%, sensitivity 100% and 83%, specificity 85% and 94% after the first (n = 16) and second (n = 22) courses of therapy, respectively.
