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Journal of Clinical Oncology, Vol 22, No 7 (April 1), 2004: pp. 1253-1259 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.07.058 18F-2-Fluoro-2-Deoxy-D-Glucose Positron Emission Tomography in Staging of Locally Advanced Breast Cancer From the Departments of Nuclear Medicine and PET Research, Clinical Epidemiology and Biostatics, Surgery, and Medical Oncology, Vrije Universiteit Medical Center, Amsterdam; and Departments of Surgery and Internal Medicine, Ziekenhuis Amstelveen, Amstelveen, the Netherlands. Address reprint requests to J.J.M. van der Hoeven, MD, Vrije Universiteit University Medical Center, PET Center/Department of Nuclear Medicine, PO Box 7057, 1007 MB Amsterdam, the Netherlands; e-mail: jjho{at}zha.nl
PURPOSE: To prospectively evaluate the effect of adding whole-body 18F-2-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) to conventional screening for distant metastases in patients with locally advanced breast cancer (LABC). PATIENTS AND METHODS: All women with LABC referred for participation in the LABC Spinoza trial were considered eligible for this study. Patients were included if chest x-ray, bone scan, liver ultrasound, or computed tomography scan performed by the referring physician failed to reveal distant metastases. They underwent whole-body FDG PET scanning before therapy. Patients with subsequently proven distant metastases were switched to alternative forms of chemotherapy, hormonal therapy, or both. RESULTS: Among the 48 patients evaluated with PET, 14 had abnormal FDG uptake, and metastases were suspected in 12. After simple clinical evaluation (plain x-ray, history), 10 sites that were suggestive of abnormality remained. Further work-up revealed that four sites were metastases. Proven false positivity occurred in one patient with sarcoidosis. In the other five patients, the reason for abnormal FDG uptake (liver, lung, bone) remained unclear, and patients were treated as planned. Eleven months later, distant metastases were found in one patient at sites unrelated to the previous FDG uptake. CONCLUSION: The addition of FDG PET to the standard work-up of patients with LABC may lead to the detection of unexpected distant metastases. This may contribute to a more realistic stratification between patients with true stage III breast cancer and those who are in fact suffering from stage IV disease. Abnormal PET findings should be confirmed to prevent patients from being denied appropriate treatment.
Locally advanced breast cancer (LABC), defined as a primary tumor larger than 5 cm, inflammatory breast cancer, skin or chest wall involvement, or fixed axillary lymph node metastases, has a poor prognosis because of the high incidence of distant metastases during follow-up.1 Presently, the standard approach is neoadjuvant chemotherapy followed by mastectomy with axillary lymphadenectomy and irradiation of the chest wall. Before this treatment, an extensive battery of investigations is conducted to exclude distant metastases. Despite negative results, however, some patients quickly develop distant metastases, and for those patients, the benefit of mutilating local treatment could be questioned. Consequently, there is a need for more sophisticated staging procedures to exclude patients with metastatic disease from this aggressive treatment strategy in LABC. Studies on the use of positron emission tomography (PET) with 18F-2-fluoro-2-deoxy-D-glucose (FDG) show that FDG has affinity for breast cancer, with detection rates varying between 64% and 100%2–9 depending on size9 and aggressiveness.10,11 FDG PET has also been used for the staging of patients with breast cancer. Most studies have focused on axillary staging, with reported sensitivities of 79% to 100%.4,7,12–16 More recently, it was postulated that these detection rates might have been overestimated, because the results strongly depend on the histopathologic reference technique.17,18 The literature on the performance of FDG PET to detect distant metastases in breast cancer is limited. In patients with a high likelihood of having metastases (eg, patients with clinically suspected recurrent or metastatic disease19–21 or increasing tumor markers22), whole-body PET seems to be a promising technique. In patients presenting with smaller tumors (< 2 cm), the appearance of metastases is less than 10% in the first 2 years.23 In such patients, the risk of false positivity should not be ignored, because FDG specificity is unlikely to be greater than 90%. However, in a study of Schirmeister et al,15 seven of 117 patients with relatively small tumors (mean, 2.3 cm) were found to have distant metastases using FDG PET, with no false-positives. Conventional diagnostic procedures showed only four metastases in the same group of patients. Of course, LABC patients are clearly at a higher risk of having disseminated disease at first presentation. Therefore, the impact of performing whole-body FDG PET after conventional staging on the detection of distant metastases was studied in LABC patients considered eligible for a prospective trial of an extensive combined-modality treatment.
Patients Between August 1997 and August 2002, all LABC patients at the Vrije Universiteit University Medical Center and the community hospital Ziekenhuis Amstelveen scheduled to undergo neoadjuvant chemo-immunotherapy (Spinoza trial)24 were eligible for this prospective study. The treatment protocol included six cycles of high-dose doxorubicin/cyclophosphamide with granulocyte colony-stimulating factor/granulocyte-macrophage colony-stimulating factor, followed by mastectomy with axillary lymph node dissection and postoperative radiotherapy. Physical examination, chest x-ray (n = 48), isotope bone scan (n = 48), and ultrasonography (n = 47) or computed tomography (CT) scan (n = 1) of the liver in these patients were not indicative for the presence of distant metastases. A maximum age of 65 years was used as an eligibility criterion because of the anticipated toxicity of the treatment. Patients were required to give informed consent. Whole-body FDG PET was performed after initial work-up but before therapy. The study was approved by the ethics review committee of the Vrije Universiteit University Medical Center.
PET Imaging
Data Analysis
Statistical Analysis
Within the observation period of 5 years, 52 patients were included in the study, 22 from the university hospital and 30 from the community hospital. Logistic reasons precluded PET scanning in four patients before neoadjuvant chemotherapy. The characteristics of the 48 assessable patients at the time of PET scanning are listed in Table 1. The results of the PET reading are shown in Figure 1.
All primary tumors showed increased FDG uptake: 36 showed intense, nine showed moderate, and three showed minimal tracer accumulation. Abnormal FDG uptake outside the locoregional area was detected by the attending staff physicians in 14 patients (Table 2) and by the retrospective viewers in 12 patients. Interobserver agreement with respect to the level of suspicion was good (ICC, 0.75; 95% CI, 0.53 to 0.89).
In 12 patients, abnormal foci with at least moderate suspicion of distant metastases were seen. Two of these sites proved to be the result of recent rib fractures (patients F and N), which became clear after simple clinical evaluation (plain x-ray, history), and follow-up confirmed that these fractures healed uneventfully. Ten sites suggestive of abnormality remained. Additional investigations confirmed the presence of malignancy in four patients (8%; 95% CI, 4% to 22%). Treatment of these patients was switched from the original intervention trial to a protocol for metastatic disease after disclosure of hepatic (n = 2) and bone metastases (n = 2). Confirmation was obtained by biopsy (patient A; Fig 2) and MRI (patient C) for the patients with liver metastases and with MRI (patient B; Fig 3) and CT/biopsy (patient I) for the two patients with bone metastases.
Proven false positivity was documented in one patient with an adrenal hot spot and bilateral abnormal focal uptake in the mediastinal and hilar areas (patient J). Mediastinoscopy revealed sarcoidosis. Because this patient had a long medical history of unexplained pulmonary complaints and malaise during adolescence, the abnormal FDG uptake in the adrenal gland was clinically also interpreted as part of this disease, and prolonged follow-up (44 months) was uneventful. In four cases, no anatomic substrate was found for foci in the vertebral column (patient D and G), lung (patient H, no additional investigations), and liver (patient M, CT scan showed no focal lesions, possibly steatosis hepatis), and these patients were treated as planned. None had distant metastases after at least 35 months of follow-up. In the final patient with suspected metastasis at PET, additional MRI showed an atypical synovial growth in the recessus axillaris (patient E; Fig 4). A biopsy was not taken, because the lesion was considered benign and the patient was treated as planned, but she developed diffuse skeletal metastases 11 months later. The origin of the abnormal lesion in the recessus axillaris could not be clarified during follow-up.
Two patients had faint focal abnormalities in lung and liver, which were classified in the low suspicion category. The former proved to reflect a pulmonary infiltrate (patient L), and no substrate was found for the other (patient K). Eighteen months later, the latter patient developed bone metastases. During follow-up, four patients without suggestion of distant metastases at entry and with a normal PET scan before therapy developed metastases within 1 year after the initiation of therapy. Three had local failure as first manifestation of recurrent disease, with simultaneous malignant pleural effusion. The remaining patient had brain metastases as the first manifestation of recurrent breast cancer.
This prospective study shows that in 8% of the patients considered eligible for starting neoadjuvant therapy for locally advanced breast cancer, FDG PET correctly detected distant metastases not seen with routine investigations. Patients with disseminated breast cancer will not benefit from aggressive multimodality treatment, as clearly demonstrated in several reports.25–28 In our study, patients with proven metastases after positive PET findings switched to therapies for disseminated disease. To our knowledge, this is the first prospective study on the yield of FDG PET in staging patients with LABC. Our findings are consistent with those of Shirmeister et al,15 who performed both conventional staging and FDG PET scanning preoperatively in patients with smaller breast tumors (mean, 2.3 cm). PET upstaged three of 117 patients and also detected in all four patients the metastases that had already been shown by conventional staging techniques. Dose et al20 also concluded that FDG PET led to an upstaging, but this was a retrospective study in a heterogeneous population including patients presenting with primary tumors as well as with suspicion of or already proven metastases. Yap et al29 concluded on the base of a questionnaire sent to referring physicians of 160 patients with different stages of breast cancer that FDG PET influenced the clinical stage and management in 30% of the patients. However, only 31% of the questionnaires were returned, and the screening procedures conducted before the FDG PET were not well described. As with other diagnostic tests, PET findings may prove to be pathognomonic for disseminated disease (eg, Fig 2). Nevertheless, uneventful follow-up in patients with unconfirmed suspicious PET lesions suggests that subsequent confirmation of PET findings remains necessary. The present data illustrate that finding anatomic substrates for PET abnormalities may be complicated. Simple exchange of information between clinician, radiologist, and PET physician could solve at least some of the problems (eg, rib fractures, pulmonary infiltrates; patients F, L, and N in Table 2). Such interaction is especially needed in cases where the initial confirmatory test is negative or inconclusive. Otherwise, time-consuming and potentially ineffective diagnostic routes may be initiated. Apart from the resulting delay, the downside of such quests is that in subsequent cases clinicians erroneously may ignore potentially relevant PET findings. When starting with this indication for PET, reading the images by multiple observers may be useful. Integrated PET/CT scanners may prove to be beneficial in patients where it is difficult to define the anatomic substrate for PET abnormalities.30 Alternatively, knowledge that the mean FDG avidity of breast cancer is less than that of, for example, lung cancer,31 may tempt nuclear medicine physicians to read breast cancer scans with higher sensitivity, reasoning that metastases will also be less intense. The present data suggest that this is not advisable (patients K and L in Table 2) and that this initiates unnecessary diagnostic procedures, delay, and unnecessary anxiety to patients. In the present study, PET was used as an additional diagnostic procedure after conventional screening, so that one can only speculate about its potential as the first test. Indirect evidence resulting from comparative studies suggests that a prospective study looking at replacement of conventional tests by PET might be appropriate.15,19,20,22 This is especially relevant if PET is also to be used to monitor response to chemotherapy in patients without distant metastases.32,33 Such a study may have to stratify for the FDG avidity of the malignancy in individual patients.11,18 In conclusion, FDG PET upstages approximately 8% of patients who, on the basis of conventional diagnostic procedures, are diagnosed as suffering from LABC. This may help to select patients for new, innovative treatments that are appropriate only in the setting of LABC. Consequently, patients who are found to have distant metastases are spared from undergoing aggressive treatment that does not improve their quality of life, prognosis, or survival. However, until PET characteristics are established that are specific for disseminated disease, confirmation of PET findings remains necessary.
The authors indicated no potential conflicts of interest.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
Deceased. 
