Eur Radiol DOI 10.1007/s00330-015-3630-6
BREAST
18
F-FDG PET/CT for initial staging in breast cancer patients – Is there a relevant impact on treatment planning compared to conventional staging modalities?
J. Krammer & A. Schnitzer & C. G. Kaiser & K. A. Buesing & E. Sperk & J. Brade & S. Wasgindt & M. Suetterlin & S. O. Schoenberg & E. J. Sutton & K. Wasser
Received: 17 September 2014 / Revised: 13 December 2014 / Accepted: 21 January 2015 # European Society of Radiology 2015
Abstract Objective To evaluate the impact of whole-body 18 F-FDG PET/CT on initial staging of breast cancer in comparison to conventional staging modalities. Methods This study included 102 breast cancer patients, 101 patients were eligible for evaluation. Preoperative whole-body staging with PET/CT was performed in patients with clinical stage≥T2 tumours or positive local lymph nodes (n=91). Postoperative PET/CT was performed in patients without these criteria but positive sentinel lymph node biopsy (n=10). All patients underwent PET/CT and a conventional staging J. Krammer (*) : A. Schnitzer : C. G. Kaiser : K. A. Buesing : S. O. Schoenberg : K. Wasser Institute of Clinical Radiology and Nuclear Medicine, University Medical Centre Mannheim, Medical Faculty Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany e-mail: [email protected] E. Sperk Department of Radiation Oncology, University Medical Centre Mannheim, Medical Faculty Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany J. Brade Institute of Medical Statistics, Biomathematics and Data Processing, Medical Faculty Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany S. Wasgindt : M. Suetterlin Department of Gynaecology and Obstetrics, University Medical Centre Mannheim, Medical Faculty Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany E. J. Sutton Department of Radiology, Memorial Sloan-Kettering Cancer Center, Evelyn H. Lauder Breast Center, 300 East 66th Street, New York 10065, NY, USA
algorithm, which included bone scan, chest X-ray and abdominal ultrasound. PET/CT findings were compared to conventional staging and the impact on therapeutic management was evaluated. Results PET/CT led to an upgrade of the N or M stage in overall 19 patients (19 %) and newly identified manifestation of breast cancer in two patients (2 %). PET/CT findings caused a change in treatment of 11 patients (11 %). This is within the range of recent studies, all applying conventional inclusion criteria based on the initial T and N status. Conclusions PET/CT has a relevant impact on initial staging and treatment of breast cancer when compared to conventional modalities. Further studies should assess inclusion criteria beyond the conventional T and N status, e.g. tumour grading and receptor status. Key Points • PET/CT may be relevant in staging breast cancer patients at higher risk for metastases • PET/CT may modify the N and M stage in multiple patients • PET/CT may impact treatment planning in breast cancer patients Keywords PET/CT . Breast Cancer . Staging . Treatment . Conventional Imaging
Introduction Breast cancer tumour stage at initial diagnosis determines prognosis and directs treatment planning. Current staging gu id elin es rec om m en d c lini ca l ex ami nat ion an d multimodality imaging, which includes conventional
Eur Radiol
mammography, ultrasound of the breast and ultrasound of the axillary fossae for local staging. Chest X-ray or chest computed tomography, bone scan and ultrasound of the liver to evaluate for distant metastases should be considered in patients with intermediate or high risk breast cancer [1, 2]. The availability of combined 18 F-2-Fluoro-2-deoxy-Dglucose (18 F-FDG) positron emission tomography and computed tomography (PET/CT) as a whole body imaging method is increasing, as is its role in oncologic imaging, treatment, and management [3]. Multiple studies evaluated the use of PET/CT for initial breast cancer staging in different groups [4–8], but its clinical significance remains the subject of discussion. This is mainly based on a lack of studies clearly showing its impact on the overall survival or at least on therapeutic management [9]. The purpose of this study is to prospectively assess the impact of whole body 18 F-FDG PET/CT on initial staging of breast cancer in comparison to conventional modalities and the associated changes in management as it pertains to current clinical guidelines. A systematic review of literature is provided and the study is discussed in the context of current literature.
First, all included patients received a guideline-based staging for metastases in the routine setting of our hospital, which included abdominal ultrasound, chest X-ray, and bone scan [1]. Afterwards, PET/CT was obtained. One preoperatively included patient had to be excluded from the study due to motion artefacts on PET/CT. One hundred and one patients were eligible for evaluation. PET/CT images were interpreted in consensus by two physicians, one board-certified in radiology and nuclear medicine with ten years experience in oncologic imaging and one nuclear medicine resident. Conventional imaging and PET/CT were evaluated independently from each, which meant, i.e., that both physicians were blinded to the diagnostic results of the other staging modality. Finally, an expert group of the tumour board (consisting of a radiologist, gynaecologist, radiation oncologist and nuclear medicine specialist) considered findings from PET/CT, conventional imaging, and results from additional diagnostic procedures in consensus to define the clinically relevant tumour stage and compose therapeutic strategies. Then the benefit of PET/CT and its effect on therapeutic management was determined. PET/CT technique and image analysis
Material and methods This prospective study was approved by our country’s Federal Radiation Commission and the Institutional Review Board. Data analysis was performed in accordance with the Health Insurance Portability and Accountability Act (HIPAA) and the Declaration of Helsinki. All participants gave their informed written consent. Patients with biopsy-proven first diagnosis of invasive breast cancer were considered between 04/2010 and 03/2013 in consensus by a gynaecological and radiological member of our interdisciplinary breast care centre. For evaluation of the primary tumour all patients received a routine assessment at our breast centre including clinical examination, mammography, and ultrasound of the breast and local lymph nodes. Additional magnetic resonance imaging (MRI) of the breast was preoperatively performed in a subset of patients (lobular invasive carcinoma, prior to neo-adjuvant chemotherapy or insufficient evaluation on mammography and ultrasound). Patients with clinical tumour stage≥T2 or positive lymph nodes were included preoperatively. Clinical node negative patients with stage T1 tumours were included postoperatively, if following sentinel lymph node biopsy (SLNB), they were positive for malignant cells. Patients with further malignancies, insulindependent diabetes or current pregnancy in their history as well as patients in their lactation period were not included. Overall, 102 women met the criteria. Three of them had a known synchronous contralateral breast cancer. Ninety-two patients were included preoperatively, ten patients postoperatively.
All patients were imaged on a Siemens Biograph PET/CT system (Siemens Healthcare Sector) applying 5.0 mm spatial resolution in 3-D mode and an acquisition time of 3 min per bed position. Low dose CT scan without iodinated contrast material was acquired (50 mAs, 120 kV, 2 mm). Whole-body imaging was performed 60 min after the administration of maximal 350 MBq (median 330 range 199–350 MBq) of 18 F-FDG including the skull and proximal extremities with arms positioned above the head. Patients were instructed to fast for a minimum of 6 h before starting the examination. Blood samples collected before the injection of the radioactive tracer ensured blood glucose levels in the normal range (60–110 mg/dL). Images were interpreted at a workstation equipped with fusion software, able to display CT, PET, and PET/CT images (MMWP, VE31A; Siemens Medical Solutions). The extent and intensity of the FDG uptake patterns were assessed and correlated to the anatomy and morphology on CT images. The uptake of FDG was further quantified by measuring the SUVmax normalized to patient body weight. Following our standard reading procedures, PET/CT was first analysed visually. Afterwards, SUVmax values were measured in a region of interest. Although a general cut off value of SUVmax was not set, lesions were considered as malignant if the SUVmax definitely exceeded the physiological uptake of an anatomic structure or organ [10, 11]. Final interpretation was based on both the functional and morphological/anatomical information. N stage was upgraded, if local lymph node involvement was newly diagnosed or if unknown lymph node involvement beyond the axillary region (periclavicular or internal
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mammary lymph nodes) was found. A downgrading of the N could be considered, if positive lymph nodes on conventional imaging were not seen on PET/CT. The M stage was upgraded in case distant metastases were newly diagnosed on PET/CT and could be downgraded if distant metastases on conventional imaging were not confirmed by PET/CT.
Reference standard Based on clinical practice, different methods were used to establish the extent of disease. In principle, a final work-up was only required in case a lesion was unclear on imaging and a definite diagnosis was essential for staging and treatment planning. Unclear distant lesions were verified by means of biopsy or additional imaging (n=8). Axillary lymph node involvement was proved via SLNB or axillary lymph node dissection (ALND) resulting in 70 patients with histologically proven axillary lymph node metastases. If histopathology of lymph nodes was not available, i.e., a palliative approach without any surgery (n=4) or localization periclavicular or in the internal mammary chain (n=15), the N stage was re-evaluated based on clinical findings, ultrasound, and PET/CT. Nodes were classified as malignant, if typical and conclusive findings were made. They could be fixed masses within a clinical exam or lymph nodes with a size>10 mm, round shape, and resolved fatty hilum on imaging [12]. Additionally, a SUVmax clearly exceeding the expected physiological uptake of lymph nodes on PET/CT was seen as a reliable criterion for nodal involvement [13, 14]. Using this approach, further biopsy or fine needle aspiration of lymph nodes was considered as unnecessary in these patients. Additionally, one year after obtaining PET/CT staging, medical records were checked to determine the patient disease status, i.e., the occurrence of distant metastases.
Results One hundred and one women with a mean age of 54± 10 years were included. The TNM stage prior to wholebody staging with PET/CT imaging is shown in Table 1. The corresponding tumour histopathology is displayed in Table 2. Overall, 75 of 101 patients had a local or distant metastatic disease. The lesion-based performance of PET/ CT and conventional imaging in detecting these metastases are itemized in Table 3. The final N and/or M stage was upgraded due to PET/CT in overall for 19 (19 %) patients. A final downgrading of the N and/or M stage was not initiated by PET/CT findings. Although the local tumour disease of the breast was no initial point of interest in a whole body PET/CT setting, unknown synchronous breast cancer was detected with PET/CT in two patients. Finally, the TNM stage was upgraded in 20 (20 %) patients. Overall PET/CT findings led to a significant change of therapeutic management in 11 (11 %) patients, ten included preoperatively and one postoperatively. Findings and treatment changes are described in detail below and summarized in Table 4.
Table 1 Patients initial staging prior to PET/CT (N=104 tumours in 101 patients)* Stage
TNM
Preoperative cTNM (n=91)
IA IB IIA
T1N0M0 T0N1miM0 T0N1M0 T1N1M0 T2N0M0 T2N1M0 T3N0M0 T0N2M0 T1N2M0 T2N2M0 T3N1M0 T3N2M0 T4N0M0 T4N1M0 T4N2M0 AnyTN3M0 AnyTAnyNM1
0 0 0 4 43 23 0 0 0 2 2 2 1 3 1 0 10
IIB
Statistics
IIIA
Frequencies and percentages were used to summarize categorical variables. Medians and ranges were used to summarize continuous variables. IIIB
Review of literature Literature search was carried out on May 25, 2014 via PubMed with the items PET/CT, breast cancer, staging, management, and treatment. Retrospective as well as prospective studies of the last ten years evaluating the impact of PET/CT (not PET only) on treatment planning were included. Results were verified via the Cochrane Library.
IIIC IV
Postoperative pTNcM (n=10)
5
2 1
1 1
*Initial clinical TN stage of 91 preoperatively and pathological TN stage of ten postoperatively included patients, M stage based on conventional imaging including abdominal ultrasound, chest x-ray, and bone scan prior to whole body imaging with PET/CT. Three of 101 patients had a known contralateral carcinoma
Eur Radiol Table 2 Histopathology of tumors (N=104 tumors in 101 patients)
Patient Number (%) Histology Ductal Lobular Mixed Other
80 (77) 15 (14) 4 (4) 4 (4)
Unknown Histological Grade 1 2 3 Unknown Hormone Receptor Estrogen Pos Neg Progesterone Pos Neg Her2/neu status Pos Neg
1(1) 5 (5) 48 (46) 45 (43) 6 (6)
67 (64) 37 (36) 56 (54) 48 (46) 56 (54) 48 (46)
Local disease and local lymph node metastases In one patient (No. 1 from Table 4) PET/CT revealed an additional contralateral breast cancer. In a second patient (No. 2 from Table 4) a multicentric carcinoma was seen by PET/CT. Histology confirmed both findings. Overall, 74 patients had positive local lymph nodes. Seventy-one out of 91 preoperatively included patients had axillary lymph node metastases. Histopathological proof was available in 67 of the node positive patients. In four patients with extensive disease, histopathology was not available due
Table 3 Lesion-based performance of PET/CT and conventional imaging in the detection of metastases
Locoregional LN* Lung/Pleura Liver Bone Adrenal gland Distant LN Soft tissue * LN = Lymph node
Number of patients with metastases
Detected by PET/CT
Detected by conventional imaging
74 5 5 13 3 6 2
60 5 5 13 3 6 2
53 1 4 11 0 0 0
to a palliative approach without surgery. They were classified as positive based on obvious findings on clinical examination and imaging. Fifteen patients (14 included preoperatively, one included postoperatively) had an involvement of periclavicular or internal mammary lymph nodes. PET/CT correctly identified local lymph node involvement in 60 patients including 56 with axillary lymph node metastases. There was no patient with a false positive nuclide uptake of local lymph nodes on PET/CT. The resulting sensitivity, specificity, positive predictive value, and negative predictive value of PET/CT for axillary lymph node involvement was 78 %, 100 %, 100 % and 57 %. The N stage was upgraded by PET/CT in 18 (18 %) patients. In seven of these patients local lymph node involvement was initially seen on preoperative PET/CT with negative conventional diagnostics. In 11 patients PET/CT showed additional localizations of local lymph node metastases compared to conventional diagnostics (Fig. 1). This led to a change in treatment of six of the patients (No.1, 3–7 from Table 4), five with an extension of the radiation field, and one with a re-resection of the axillary fossa. One patient with histopathologically proven axillary lymph node metastases had positive findings on ultrasound (>1 cm in size, round shape, resolved fatty hilum) but no pathologic nuclide uptake on PET/CT. Due to the explicit findings on ultrasound, a downgrading based on PET/CT or a separate lymph node biopsy was not considered in this patient after final re-evaluation. This was the only case with a true positive lymph node finding on conventional imaging but false negative finding on PET/CT. Distant metastases Sixteen patients had distant metastases. Three of them had a conventional staging without pathologic findings and PET/CT initially revealed distant metastases in the following localizations. The first patient (No. 8 from Table 4) had bone metastases and a pleural carcinomatosis. In the second patient (No. 9 from Table 4) mediastinal, hilar, and abdominal paraaortal lymph node metastases as well as metastases of the adrenal gland and lung were detected. The third patient showed metastases of the adrenal gland, lung, mediastinal and hilar lymph nodes as well as bones (No. 11 from Table 4 and Fig. 2). In all three patients findings led to corresponding changes in disease management. In nine patients distant metastases were already described in conventional staging, but PET/CT showed additional sites (bone, lung) leading to a change in treatment plan in one of these patients (No. 10 from Table 4). There was no patient with distant metastases, not detected by PET/CT but by conventional methods. All 85 patients with a negative PET/CT for distant metastases remained disease free over one year resulting in a negative predictive value for distant metastases of 100 %.
Internal mammary LN Mediastinal/hilar LN Bone, lung and adrenal gland metastases
* LN = Lymph node
11
10
9
4 5 6 7 8
Remaining axillary LN after SLNB and ALND (postoperative Staging) Internal mammary LN Internal mammary LN Internal mammary LN Internal mammary LN Internal mammary LN Bone metastasis Pleural carcinomatosis Mediastinal, hilar and abdominal paraaortal LN Adrenal gland and pulmonary metastases Further bone metastases (femur, acetabulum with fracture risk)
3
T4N2M0
Left: T2N1M0 Right: T1N0M0 T2N0M1
T1N0M0 (pT2pN2)M0 T4N1M0 T3N3M0 T4N1M1 T2N1M0 T2N2M0
T2N0M0
Further ipsilateral carcinoma
2
Change of management
T4N3M1
Left: T2N1M1 Right: T1N0M1 T2N0M1
Immediate radiation therapy of the proximal femur and acetabulum prior to radiation therapy of other bone metastases and surgery No radiation or surgery, palliative approach with systemic chemotherapy
Palliative approach with systemic chemotherapy
Extended field of radiation therapy, therapy of the contralateral carcinoma Extended surgery with ablatio mammae, no breast conserving therapy (pT2pN2)M0 Re-resection of the axillary fossa in order to reduce the tumor Further axillary LN metastases load before radiotherapy T4N3M0 Extended field of radiation therapy T3N3(+internal mammary)M0 Extended field of radiation therapy T4N3M1 Extended field of radiation therapy T2N3M0 Extended field of radiation therapy T2N3M1 Palliative chemotherapy with bisphosphonate therapy
Right: T2N1M0
Internal mammary LN* Contralateral carcinoma
1
Right: T2N3M0 Left: T1N0M0 T2N0M0
TNM conventional TNM PET/CT
Change of management in N=11 out of 101 patients
Patient number Additional positive PET/CT findings
Table 4
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Discussion
Fig. 1 A 56-year-old woman with right-sided ductal invasive carcinoma. On ultrasound multiple metastatic lymph nodes in the right axilla were described. On PET/CT an enlarged, round shaped internal mammary lymph node with pathologic nuclide uptake was seen (arrow) resulting in an upgrade of the N stage and adaption of the radiation field
Fig. 2 A 60-year-old woman with right-sided inflammatory breast cancer and positive axillary lymph nodes on ultrasound. a: On bone scan the joint-related increase of radiotracer uptake of the feet and knees, thoracic and lumbar spine and acromioclavicular and sternoclavicular joints was assigned to degenerative processes. The moderate uptake of the right breast could be correlated to inflammatory
Accurately determining the extent of breast cancer disease at diagnosis is important as it defines oncologic treatment and management. The clinical role of PET/CT for initial staging of breast cancer remains controversial, and the guideline recommendations are still rather conservative. In this study we demonstrated that PET/CT for initial staging was superior to a conventional staging algorithm. PET/CT detected local and distant metastases not seen on the conventional imaging modalities leading to an upgrade of the N and/or M stage in 19/ 101 (19 %) patients. PET/CT findings caused a change in the disease management of 11/101 (11 %) patients. In four patients treatment planning was modified because of distant metastases diagnosed on PET/CT. One patient underwent extended surgery with ablatio mammae based on a secondary ipsilateral breast cancer. Six patients received a modified
breast cancer. No metastases were registered. b: PET/CT revealed pathologic nuclide uptake of the spine (not joint-related) and pelvic bone, right adrenal gland and mediastinal and hilar lymph nodes (arrows). Abdominal ultrasound and X-ray did not show any suspect lesions (not shown)
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treatment because of an upgraded local N status including one patient with a re-resection of the axillary fossa. Specifically, five patient’s radiation fields were extended to include the supraclavicular and internal mammary lymph nodes. This is clinically important as patients with N3 disease (i.e., additional extra-axillary lymph node involvement) have a less than 50 % overall survival rate in five years [15]. As a result, radiation therapy is recommended for stage>N2a as it improves disease-free and overall survival [16, 17]. PET/CT is reported to have a high specificity and positive predictive value for the detection of metastatic axillary lymph nodes [13, 14] and some authors suggest to proceed directly to ALND without SLNB in case of positive findings [18]. Our findings are in line with these studies, as there was no patient with a false positive nuclide uptake of local lymph nodes on PET/CT. However, in our study only six out of 18 patients with an increased N stage based on PET/CT findings had a change in treatment. This is based on the fact that PET/CT could not be defined as a gold standard in this study setting. According to current clinical guidelines, patients with positive axillary lymph node findings on PET/CT, but negative findings on clinical examination and ultrasound (n= 12) still proceeded to SLNB in our study protocol. Thus, the following therapeutic decisions were based on the histological results of the SLNB and could not be counted as change of treatment due to PET/CT findings. The role of PET/CT in determining the surgical management of the axillary region is still the subject of discussion and requires further research. In our opinion, it is rather of clinical importance to use imaging for the identification of metastatic axillary lymph nodes with an advanced metastatic involvement. Those lymph nodes have a high risk of an inadequate nuclide uptake on lymphscintigraphy and could, therefore, have a negative effect on the success of SLNB. Consequently, positive axillary lymph nodes newly detected on PET/CT should be reconsidered with dedicated ultrasound for signs of an advanced metastatic involvement (round shape, resolved fatty hilum, low echogenicity) prior to SLNB. In our experience, lymph nodes positive on PET/CT that are morphologically negative on ultrasound demonstrate normal nuclide uptake on lymphscintigraphy. In addition, the one case with a false negative axillary lymph node on PET/CT and a right positive finding on ultrasound underlines the importance of a routine axillary ultrasound. In our opinion, axillary ultrasound should still be the method of choice for preoperative planning, if SLNB will be performed for lymph node staging. The power of PET/CT should rather be seen in the detection of unexpected extra-axillary regional lymph node involvement. Even though PET/CT mammography was not performed in this study, PET/CT changed the local tumour staging in two patients. It identifies multicentric disease in one patient and a contralateral breast cancer in another patient leading to the corresponding changes in disease management. This
underlines the approach of other authors suggesting a Bone stop shop imaging protocol^ such as whole body PET/CT combined with PET/CT mammography or PET/MRI [6, 19], that results in simultaneous local and distant staging of breast cancer. A review of the literature identified eight studies assessing the clinical impact of PET/CT for initial staging of breast cancer (Table 5). Five studies were prospective, while three were retrospective. In these studies, PET/CT findings resulted in a treatment modification in 8–18 % of patients [6, 20–26]. Our study demonstrated an 11 % change in treatment, which is in the range. The study by Cochet et al., was comparable in terms of size and inclusion criteria (stage≥T2 patients), and they demonstrated a change of management in 13 %. However, they reported a 37 % change of initial N and M stage due to PET/CT findings, which is much higher than in our study [20]. Remarkably, regarding the local N staging, Cochet et al., described a downstaging in 22 out of 47 patients due to PET/ CT findings, which is nearly half of the patients. Two patients were described to have false negative axillary lymph nodes on PET/CT. With just one patient in our study, who turned out to have a false negative axillary lymph node on PET/CT, our findings are comparable. However, a correct downstaging based on PET/CT findings was not observed in any of the included patients in our study. The reason for this discrepancy is difficult to address, especially as the authors of the cited publication do not state whether a dedicated ultrasound of the local lymph nodes was performed besides physical examination, ultrasound of the breast and optional CT of the chest. It has to be assumed that different conventional findings determined the initial N stage in the two studies. Overall, the available studies vary regarding the size (range 39 to 154 patients), inclusion criteria (T and N stage) and use of conventional imaging modalities. In our study we ensured a consistent conventional imaging algorithm in all patients as adapted from the national guidelines. In contrast, in the study by Sen et al., almost 40 % of the patients included did not undergo any imaging for initial distant staging, while the other 60 % underwent abdominal ultrasound, chest X-ray, and CT of the chest and abdomen [21]. Bernsdorf et al., did not perform abdominal imaging or bone scans on any patients. Although this might indicate a high number of undetected distant metastases on PET/CT, it only changed the treatment in 8 % of patients [24]. Overall, considering the various study designs, the range of findings that resulted in treatment changes remained relatively consistent in the literature. All the studies demonstrated the value of PET/CT for staging and treatment planning of breast cancer. Especially in terms of distant metastases, neither our study nor other cited studies described cases with positive conventional imaging but negative findings on PET/CT. In all studies PET/CT showed additional sites of metastases and newly detected distant metastases (including extra-axillary regional nodes) in multiple patients.
77
106
Sen et al. (2013) [21], retrospective
Riegger et al. (2012) [23], retrospective
Groheux et al. (2008) [25], prospective
39
Bernsdorf et al. (2012) 103 [24], prospective Koolen et al. (2011) 154 [26], prospective Garami et al. (2011) 115 [22], prospective Heusner et al. (2008) 40 [6], retrospective
142
Cochet et al. (2014) [20], prospective
WB PET approximately 60 min after FDG injection; full-dose CT with contrast
WB PET approximately 60 min after FDG injection; low-dose CT without contrast
Whole body (WB) PET approximately 60 min after FDG injection; low-dose CT without contrast
PET/CT imaging
Mammography and/or breast and axillary ultrasound, bone scan, abdominal ultrasound and/or CT, X-rays and/or CT of the chest Mammography, breast and axillary ultrasound, abdominal ultrasound, CT of the chest and abdomen, bone scan Mammography (+/− breast MRI), breast and axillary ultrasound, chest X-ray, bone scan and liver ultrasound (+/− CT Abdomen) Mammography, breast and axillary ultrasound, chest X-ray, blood samples Chest X-ray, abdomen ultrasound, bone scan
Conventional imaging
WB PET approximately 60 min after FDG injection; full-dose CT with contrast Stage II and III WB PET approximately 60 min after FDG injection; low-dose CT without contrast Tumors
BREAST
18
F-FDG PET/CT for initial staging in breast cancer patients – Is there a relevant impact on treatment planning compared to conventional staging modalities?
J. Krammer & A. Schnitzer & C. G. Kaiser & K. A. Buesing & E. Sperk & J. Brade & S. Wasgindt & M. Suetterlin & S. O. Schoenberg & E. J. Sutton & K. Wasser
Received: 17 September 2014 / Revised: 13 December 2014 / Accepted: 21 January 2015 # European Society of Radiology 2015
Abstract Objective To evaluate the impact of whole-body 18 F-FDG PET/CT on initial staging of breast cancer in comparison to conventional staging modalities. Methods This study included 102 breast cancer patients, 101 patients were eligible for evaluation. Preoperative whole-body staging with PET/CT was performed in patients with clinical stage≥T2 tumours or positive local lymph nodes (n=91). Postoperative PET/CT was performed in patients without these criteria but positive sentinel lymph node biopsy (n=10). All patients underwent PET/CT and a conventional staging J. Krammer (*) : A. Schnitzer : C. G. Kaiser : K. A. Buesing : S. O. Schoenberg : K. Wasser Institute of Clinical Radiology and Nuclear Medicine, University Medical Centre Mannheim, Medical Faculty Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany e-mail: [email protected] E. Sperk Department of Radiation Oncology, University Medical Centre Mannheim, Medical Faculty Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany J. Brade Institute of Medical Statistics, Biomathematics and Data Processing, Medical Faculty Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany S. Wasgindt : M. Suetterlin Department of Gynaecology and Obstetrics, University Medical Centre Mannheim, Medical Faculty Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany E. J. Sutton Department of Radiology, Memorial Sloan-Kettering Cancer Center, Evelyn H. Lauder Breast Center, 300 East 66th Street, New York 10065, NY, USA
algorithm, which included bone scan, chest X-ray and abdominal ultrasound. PET/CT findings were compared to conventional staging and the impact on therapeutic management was evaluated. Results PET/CT led to an upgrade of the N or M stage in overall 19 patients (19 %) and newly identified manifestation of breast cancer in two patients (2 %). PET/CT findings caused a change in treatment of 11 patients (11 %). This is within the range of recent studies, all applying conventional inclusion criteria based on the initial T and N status. Conclusions PET/CT has a relevant impact on initial staging and treatment of breast cancer when compared to conventional modalities. Further studies should assess inclusion criteria beyond the conventional T and N status, e.g. tumour grading and receptor status. Key Points • PET/CT may be relevant in staging breast cancer patients at higher risk for metastases • PET/CT may modify the N and M stage in multiple patients • PET/CT may impact treatment planning in breast cancer patients Keywords PET/CT . Breast Cancer . Staging . Treatment . Conventional Imaging
Introduction Breast cancer tumour stage at initial diagnosis determines prognosis and directs treatment planning. Current staging gu id elin es rec om m en d c lini ca l ex ami nat ion an d multimodality imaging, which includes conventional
Eur Radiol
mammography, ultrasound of the breast and ultrasound of the axillary fossae for local staging. Chest X-ray or chest computed tomography, bone scan and ultrasound of the liver to evaluate for distant metastases should be considered in patients with intermediate or high risk breast cancer [1, 2]. The availability of combined 18 F-2-Fluoro-2-deoxy-Dglucose (18 F-FDG) positron emission tomography and computed tomography (PET/CT) as a whole body imaging method is increasing, as is its role in oncologic imaging, treatment, and management [3]. Multiple studies evaluated the use of PET/CT for initial breast cancer staging in different groups [4–8], but its clinical significance remains the subject of discussion. This is mainly based on a lack of studies clearly showing its impact on the overall survival or at least on therapeutic management [9]. The purpose of this study is to prospectively assess the impact of whole body 18 F-FDG PET/CT on initial staging of breast cancer in comparison to conventional modalities and the associated changes in management as it pertains to current clinical guidelines. A systematic review of literature is provided and the study is discussed in the context of current literature.
First, all included patients received a guideline-based staging for metastases in the routine setting of our hospital, which included abdominal ultrasound, chest X-ray, and bone scan [1]. Afterwards, PET/CT was obtained. One preoperatively included patient had to be excluded from the study due to motion artefacts on PET/CT. One hundred and one patients were eligible for evaluation. PET/CT images were interpreted in consensus by two physicians, one board-certified in radiology and nuclear medicine with ten years experience in oncologic imaging and one nuclear medicine resident. Conventional imaging and PET/CT were evaluated independently from each, which meant, i.e., that both physicians were blinded to the diagnostic results of the other staging modality. Finally, an expert group of the tumour board (consisting of a radiologist, gynaecologist, radiation oncologist and nuclear medicine specialist) considered findings from PET/CT, conventional imaging, and results from additional diagnostic procedures in consensus to define the clinically relevant tumour stage and compose therapeutic strategies. Then the benefit of PET/CT and its effect on therapeutic management was determined. PET/CT technique and image analysis
Material and methods This prospective study was approved by our country’s Federal Radiation Commission and the Institutional Review Board. Data analysis was performed in accordance with the Health Insurance Portability and Accountability Act (HIPAA) and the Declaration of Helsinki. All participants gave their informed written consent. Patients with biopsy-proven first diagnosis of invasive breast cancer were considered between 04/2010 and 03/2013 in consensus by a gynaecological and radiological member of our interdisciplinary breast care centre. For evaluation of the primary tumour all patients received a routine assessment at our breast centre including clinical examination, mammography, and ultrasound of the breast and local lymph nodes. Additional magnetic resonance imaging (MRI) of the breast was preoperatively performed in a subset of patients (lobular invasive carcinoma, prior to neo-adjuvant chemotherapy or insufficient evaluation on mammography and ultrasound). Patients with clinical tumour stage≥T2 or positive lymph nodes were included preoperatively. Clinical node negative patients with stage T1 tumours were included postoperatively, if following sentinel lymph node biopsy (SLNB), they were positive for malignant cells. Patients with further malignancies, insulindependent diabetes or current pregnancy in their history as well as patients in their lactation period were not included. Overall, 102 women met the criteria. Three of them had a known synchronous contralateral breast cancer. Ninety-two patients were included preoperatively, ten patients postoperatively.
All patients were imaged on a Siemens Biograph PET/CT system (Siemens Healthcare Sector) applying 5.0 mm spatial resolution in 3-D mode and an acquisition time of 3 min per bed position. Low dose CT scan without iodinated contrast material was acquired (50 mAs, 120 kV, 2 mm). Whole-body imaging was performed 60 min after the administration of maximal 350 MBq (median 330 range 199–350 MBq) of 18 F-FDG including the skull and proximal extremities with arms positioned above the head. Patients were instructed to fast for a minimum of 6 h before starting the examination. Blood samples collected before the injection of the radioactive tracer ensured blood glucose levels in the normal range (60–110 mg/dL). Images were interpreted at a workstation equipped with fusion software, able to display CT, PET, and PET/CT images (MMWP, VE31A; Siemens Medical Solutions). The extent and intensity of the FDG uptake patterns were assessed and correlated to the anatomy and morphology on CT images. The uptake of FDG was further quantified by measuring the SUVmax normalized to patient body weight. Following our standard reading procedures, PET/CT was first analysed visually. Afterwards, SUVmax values were measured in a region of interest. Although a general cut off value of SUVmax was not set, lesions were considered as malignant if the SUVmax definitely exceeded the physiological uptake of an anatomic structure or organ [10, 11]. Final interpretation was based on both the functional and morphological/anatomical information. N stage was upgraded, if local lymph node involvement was newly diagnosed or if unknown lymph node involvement beyond the axillary region (periclavicular or internal
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mammary lymph nodes) was found. A downgrading of the N could be considered, if positive lymph nodes on conventional imaging were not seen on PET/CT. The M stage was upgraded in case distant metastases were newly diagnosed on PET/CT and could be downgraded if distant metastases on conventional imaging were not confirmed by PET/CT.
Reference standard Based on clinical practice, different methods were used to establish the extent of disease. In principle, a final work-up was only required in case a lesion was unclear on imaging and a definite diagnosis was essential for staging and treatment planning. Unclear distant lesions were verified by means of biopsy or additional imaging (n=8). Axillary lymph node involvement was proved via SLNB or axillary lymph node dissection (ALND) resulting in 70 patients with histologically proven axillary lymph node metastases. If histopathology of lymph nodes was not available, i.e., a palliative approach without any surgery (n=4) or localization periclavicular or in the internal mammary chain (n=15), the N stage was re-evaluated based on clinical findings, ultrasound, and PET/CT. Nodes were classified as malignant, if typical and conclusive findings were made. They could be fixed masses within a clinical exam or lymph nodes with a size>10 mm, round shape, and resolved fatty hilum on imaging [12]. Additionally, a SUVmax clearly exceeding the expected physiological uptake of lymph nodes on PET/CT was seen as a reliable criterion for nodal involvement [13, 14]. Using this approach, further biopsy or fine needle aspiration of lymph nodes was considered as unnecessary in these patients. Additionally, one year after obtaining PET/CT staging, medical records were checked to determine the patient disease status, i.e., the occurrence of distant metastases.
Results One hundred and one women with a mean age of 54± 10 years were included. The TNM stage prior to wholebody staging with PET/CT imaging is shown in Table 1. The corresponding tumour histopathology is displayed in Table 2. Overall, 75 of 101 patients had a local or distant metastatic disease. The lesion-based performance of PET/ CT and conventional imaging in detecting these metastases are itemized in Table 3. The final N and/or M stage was upgraded due to PET/CT in overall for 19 (19 %) patients. A final downgrading of the N and/or M stage was not initiated by PET/CT findings. Although the local tumour disease of the breast was no initial point of interest in a whole body PET/CT setting, unknown synchronous breast cancer was detected with PET/CT in two patients. Finally, the TNM stage was upgraded in 20 (20 %) patients. Overall PET/CT findings led to a significant change of therapeutic management in 11 (11 %) patients, ten included preoperatively and one postoperatively. Findings and treatment changes are described in detail below and summarized in Table 4.
Table 1 Patients initial staging prior to PET/CT (N=104 tumours in 101 patients)* Stage
TNM
Preoperative cTNM (n=91)
IA IB IIA
T1N0M0 T0N1miM0 T0N1M0 T1N1M0 T2N0M0 T2N1M0 T3N0M0 T0N2M0 T1N2M0 T2N2M0 T3N1M0 T3N2M0 T4N0M0 T4N1M0 T4N2M0 AnyTN3M0 AnyTAnyNM1
0 0 0 4 43 23 0 0 0 2 2 2 1 3 1 0 10
IIB
Statistics
IIIA
Frequencies and percentages were used to summarize categorical variables. Medians and ranges were used to summarize continuous variables. IIIB
Review of literature Literature search was carried out on May 25, 2014 via PubMed with the items PET/CT, breast cancer, staging, management, and treatment. Retrospective as well as prospective studies of the last ten years evaluating the impact of PET/CT (not PET only) on treatment planning were included. Results were verified via the Cochrane Library.
IIIC IV
Postoperative pTNcM (n=10)
5
2 1
1 1
*Initial clinical TN stage of 91 preoperatively and pathological TN stage of ten postoperatively included patients, M stage based on conventional imaging including abdominal ultrasound, chest x-ray, and bone scan prior to whole body imaging with PET/CT. Three of 101 patients had a known contralateral carcinoma
Eur Radiol Table 2 Histopathology of tumors (N=104 tumors in 101 patients)
Patient Number (%) Histology Ductal Lobular Mixed Other
80 (77) 15 (14) 4 (4) 4 (4)
Unknown Histological Grade 1 2 3 Unknown Hormone Receptor Estrogen Pos Neg Progesterone Pos Neg Her2/neu status Pos Neg
1(1) 5 (5) 48 (46) 45 (43) 6 (6)
67 (64) 37 (36) 56 (54) 48 (46) 56 (54) 48 (46)
Local disease and local lymph node metastases In one patient (No. 1 from Table 4) PET/CT revealed an additional contralateral breast cancer. In a second patient (No. 2 from Table 4) a multicentric carcinoma was seen by PET/CT. Histology confirmed both findings. Overall, 74 patients had positive local lymph nodes. Seventy-one out of 91 preoperatively included patients had axillary lymph node metastases. Histopathological proof was available in 67 of the node positive patients. In four patients with extensive disease, histopathology was not available due
Table 3 Lesion-based performance of PET/CT and conventional imaging in the detection of metastases
Locoregional LN* Lung/Pleura Liver Bone Adrenal gland Distant LN Soft tissue * LN = Lymph node
Number of patients with metastases
Detected by PET/CT
Detected by conventional imaging
74 5 5 13 3 6 2
60 5 5 13 3 6 2
53 1 4 11 0 0 0
to a palliative approach without surgery. They were classified as positive based on obvious findings on clinical examination and imaging. Fifteen patients (14 included preoperatively, one included postoperatively) had an involvement of periclavicular or internal mammary lymph nodes. PET/CT correctly identified local lymph node involvement in 60 patients including 56 with axillary lymph node metastases. There was no patient with a false positive nuclide uptake of local lymph nodes on PET/CT. The resulting sensitivity, specificity, positive predictive value, and negative predictive value of PET/CT for axillary lymph node involvement was 78 %, 100 %, 100 % and 57 %. The N stage was upgraded by PET/CT in 18 (18 %) patients. In seven of these patients local lymph node involvement was initially seen on preoperative PET/CT with negative conventional diagnostics. In 11 patients PET/CT showed additional localizations of local lymph node metastases compared to conventional diagnostics (Fig. 1). This led to a change in treatment of six of the patients (No.1, 3–7 from Table 4), five with an extension of the radiation field, and one with a re-resection of the axillary fossa. One patient with histopathologically proven axillary lymph node metastases had positive findings on ultrasound (>1 cm in size, round shape, resolved fatty hilum) but no pathologic nuclide uptake on PET/CT. Due to the explicit findings on ultrasound, a downgrading based on PET/CT or a separate lymph node biopsy was not considered in this patient after final re-evaluation. This was the only case with a true positive lymph node finding on conventional imaging but false negative finding on PET/CT. Distant metastases Sixteen patients had distant metastases. Three of them had a conventional staging without pathologic findings and PET/CT initially revealed distant metastases in the following localizations. The first patient (No. 8 from Table 4) had bone metastases and a pleural carcinomatosis. In the second patient (No. 9 from Table 4) mediastinal, hilar, and abdominal paraaortal lymph node metastases as well as metastases of the adrenal gland and lung were detected. The third patient showed metastases of the adrenal gland, lung, mediastinal and hilar lymph nodes as well as bones (No. 11 from Table 4 and Fig. 2). In all three patients findings led to corresponding changes in disease management. In nine patients distant metastases were already described in conventional staging, but PET/CT showed additional sites (bone, lung) leading to a change in treatment plan in one of these patients (No. 10 from Table 4). There was no patient with distant metastases, not detected by PET/CT but by conventional methods. All 85 patients with a negative PET/CT for distant metastases remained disease free over one year resulting in a negative predictive value for distant metastases of 100 %.
Internal mammary LN Mediastinal/hilar LN Bone, lung and adrenal gland metastases
* LN = Lymph node
11
10
9
4 5 6 7 8
Remaining axillary LN after SLNB and ALND (postoperative Staging) Internal mammary LN Internal mammary LN Internal mammary LN Internal mammary LN Internal mammary LN Bone metastasis Pleural carcinomatosis Mediastinal, hilar and abdominal paraaortal LN Adrenal gland and pulmonary metastases Further bone metastases (femur, acetabulum with fracture risk)
3
T4N2M0
Left: T2N1M0 Right: T1N0M0 T2N0M1
T1N0M0 (pT2pN2)M0 T4N1M0 T3N3M0 T4N1M1 T2N1M0 T2N2M0
T2N0M0
Further ipsilateral carcinoma
2
Change of management
T4N3M1
Left: T2N1M1 Right: T1N0M1 T2N0M1
Immediate radiation therapy of the proximal femur and acetabulum prior to radiation therapy of other bone metastases and surgery No radiation or surgery, palliative approach with systemic chemotherapy
Palliative approach with systemic chemotherapy
Extended field of radiation therapy, therapy of the contralateral carcinoma Extended surgery with ablatio mammae, no breast conserving therapy (pT2pN2)M0 Re-resection of the axillary fossa in order to reduce the tumor Further axillary LN metastases load before radiotherapy T4N3M0 Extended field of radiation therapy T3N3(+internal mammary)M0 Extended field of radiation therapy T4N3M1 Extended field of radiation therapy T2N3M0 Extended field of radiation therapy T2N3M1 Palliative chemotherapy with bisphosphonate therapy
Right: T2N1M0
Internal mammary LN* Contralateral carcinoma
1
Right: T2N3M0 Left: T1N0M0 T2N0M0
TNM conventional TNM PET/CT
Change of management in N=11 out of 101 patients
Patient number Additional positive PET/CT findings
Table 4
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Discussion
Fig. 1 A 56-year-old woman with right-sided ductal invasive carcinoma. On ultrasound multiple metastatic lymph nodes in the right axilla were described. On PET/CT an enlarged, round shaped internal mammary lymph node with pathologic nuclide uptake was seen (arrow) resulting in an upgrade of the N stage and adaption of the radiation field
Fig. 2 A 60-year-old woman with right-sided inflammatory breast cancer and positive axillary lymph nodes on ultrasound. a: On bone scan the joint-related increase of radiotracer uptake of the feet and knees, thoracic and lumbar spine and acromioclavicular and sternoclavicular joints was assigned to degenerative processes. The moderate uptake of the right breast could be correlated to inflammatory
Accurately determining the extent of breast cancer disease at diagnosis is important as it defines oncologic treatment and management. The clinical role of PET/CT for initial staging of breast cancer remains controversial, and the guideline recommendations are still rather conservative. In this study we demonstrated that PET/CT for initial staging was superior to a conventional staging algorithm. PET/CT detected local and distant metastases not seen on the conventional imaging modalities leading to an upgrade of the N and/or M stage in 19/ 101 (19 %) patients. PET/CT findings caused a change in the disease management of 11/101 (11 %) patients. In four patients treatment planning was modified because of distant metastases diagnosed on PET/CT. One patient underwent extended surgery with ablatio mammae based on a secondary ipsilateral breast cancer. Six patients received a modified
breast cancer. No metastases were registered. b: PET/CT revealed pathologic nuclide uptake of the spine (not joint-related) and pelvic bone, right adrenal gland and mediastinal and hilar lymph nodes (arrows). Abdominal ultrasound and X-ray did not show any suspect lesions (not shown)
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treatment because of an upgraded local N status including one patient with a re-resection of the axillary fossa. Specifically, five patient’s radiation fields were extended to include the supraclavicular and internal mammary lymph nodes. This is clinically important as patients with N3 disease (i.e., additional extra-axillary lymph node involvement) have a less than 50 % overall survival rate in five years [15]. As a result, radiation therapy is recommended for stage>N2a as it improves disease-free and overall survival [16, 17]. PET/CT is reported to have a high specificity and positive predictive value for the detection of metastatic axillary lymph nodes [13, 14] and some authors suggest to proceed directly to ALND without SLNB in case of positive findings [18]. Our findings are in line with these studies, as there was no patient with a false positive nuclide uptake of local lymph nodes on PET/CT. However, in our study only six out of 18 patients with an increased N stage based on PET/CT findings had a change in treatment. This is based on the fact that PET/CT could not be defined as a gold standard in this study setting. According to current clinical guidelines, patients with positive axillary lymph node findings on PET/CT, but negative findings on clinical examination and ultrasound (n= 12) still proceeded to SLNB in our study protocol. Thus, the following therapeutic decisions were based on the histological results of the SLNB and could not be counted as change of treatment due to PET/CT findings. The role of PET/CT in determining the surgical management of the axillary region is still the subject of discussion and requires further research. In our opinion, it is rather of clinical importance to use imaging for the identification of metastatic axillary lymph nodes with an advanced metastatic involvement. Those lymph nodes have a high risk of an inadequate nuclide uptake on lymphscintigraphy and could, therefore, have a negative effect on the success of SLNB. Consequently, positive axillary lymph nodes newly detected on PET/CT should be reconsidered with dedicated ultrasound for signs of an advanced metastatic involvement (round shape, resolved fatty hilum, low echogenicity) prior to SLNB. In our experience, lymph nodes positive on PET/CT that are morphologically negative on ultrasound demonstrate normal nuclide uptake on lymphscintigraphy. In addition, the one case with a false negative axillary lymph node on PET/CT and a right positive finding on ultrasound underlines the importance of a routine axillary ultrasound. In our opinion, axillary ultrasound should still be the method of choice for preoperative planning, if SLNB will be performed for lymph node staging. The power of PET/CT should rather be seen in the detection of unexpected extra-axillary regional lymph node involvement. Even though PET/CT mammography was not performed in this study, PET/CT changed the local tumour staging in two patients. It identifies multicentric disease in one patient and a contralateral breast cancer in another patient leading to the corresponding changes in disease management. This
underlines the approach of other authors suggesting a Bone stop shop imaging protocol^ such as whole body PET/CT combined with PET/CT mammography or PET/MRI [6, 19], that results in simultaneous local and distant staging of breast cancer. A review of the literature identified eight studies assessing the clinical impact of PET/CT for initial staging of breast cancer (Table 5). Five studies were prospective, while three were retrospective. In these studies, PET/CT findings resulted in a treatment modification in 8–18 % of patients [6, 20–26]. Our study demonstrated an 11 % change in treatment, which is in the range. The study by Cochet et al., was comparable in terms of size and inclusion criteria (stage≥T2 patients), and they demonstrated a change of management in 13 %. However, they reported a 37 % change of initial N and M stage due to PET/CT findings, which is much higher than in our study [20]. Remarkably, regarding the local N staging, Cochet et al., described a downstaging in 22 out of 47 patients due to PET/ CT findings, which is nearly half of the patients. Two patients were described to have false negative axillary lymph nodes on PET/CT. With just one patient in our study, who turned out to have a false negative axillary lymph node on PET/CT, our findings are comparable. However, a correct downstaging based on PET/CT findings was not observed in any of the included patients in our study. The reason for this discrepancy is difficult to address, especially as the authors of the cited publication do not state whether a dedicated ultrasound of the local lymph nodes was performed besides physical examination, ultrasound of the breast and optional CT of the chest. It has to be assumed that different conventional findings determined the initial N stage in the two studies. Overall, the available studies vary regarding the size (range 39 to 154 patients), inclusion criteria (T and N stage) and use of conventional imaging modalities. In our study we ensured a consistent conventional imaging algorithm in all patients as adapted from the national guidelines. In contrast, in the study by Sen et al., almost 40 % of the patients included did not undergo any imaging for initial distant staging, while the other 60 % underwent abdominal ultrasound, chest X-ray, and CT of the chest and abdomen [21]. Bernsdorf et al., did not perform abdominal imaging or bone scans on any patients. Although this might indicate a high number of undetected distant metastases on PET/CT, it only changed the treatment in 8 % of patients [24]. Overall, considering the various study designs, the range of findings that resulted in treatment changes remained relatively consistent in the literature. All the studies demonstrated the value of PET/CT for staging and treatment planning of breast cancer. Especially in terms of distant metastases, neither our study nor other cited studies described cases with positive conventional imaging but negative findings on PET/CT. In all studies PET/CT showed additional sites of metastases and newly detected distant metastases (including extra-axillary regional nodes) in multiple patients.
77
106
Sen et al. (2013) [21], retrospective
Riegger et al. (2012) [23], retrospective
Groheux et al. (2008) [25], prospective
39
Bernsdorf et al. (2012) 103 [24], prospective Koolen et al. (2011) 154 [26], prospective Garami et al. (2011) 115 [22], prospective Heusner et al. (2008) 40 [6], retrospective
142
Cochet et al. (2014) [20], prospective
WB PET approximately 60 min after FDG injection; full-dose CT with contrast
WB PET approximately 60 min after FDG injection; low-dose CT without contrast
Whole body (WB) PET approximately 60 min after FDG injection; low-dose CT without contrast
PET/CT imaging
Mammography and/or breast and axillary ultrasound, bone scan, abdominal ultrasound and/or CT, X-rays and/or CT of the chest Mammography, breast and axillary ultrasound, abdominal ultrasound, CT of the chest and abdomen, bone scan Mammography (+/− breast MRI), breast and axillary ultrasound, chest X-ray, bone scan and liver ultrasound (+/− CT Abdomen) Mammography, breast and axillary ultrasound, chest X-ray, blood samples Chest X-ray, abdomen ultrasound, bone scan
Conventional imaging
WB PET approximately 60 min after FDG injection; full-dose CT with contrast Stage II and III WB PET approximately 60 min after FDG injection; low-dose CT without contrast Tumors
