[¹⁸F]FDG-PET/CT in prone compared to supine position for optimal axillary staging and treatment in clinically node-positive breast cancer patients with neoadjuvant systemic therapy

This retrospective cohort study included 159 women who underwent response-adjusted axillary treatment according to the MARI-protocol, of whom data have been previously published [29]. Patients with a pre-NST acquired [¹⁸F]FDG-PET/CT in supine and prone position of 18 years or older with stage II–III pathologically proven cN+ breast cancer of any subtype that underwent the MARI-procedure at the NKI between July 2014 and September 2017 were included. Exclusion criteria were history of breast cancer or a non-FDG-avid breast cancer. This study was approved by the institutional review board of the NKI.

Patients fasted for ≥ 6 h and received oral prehydration before intravenous injection of 120–400 MBq FDG according to their weight (3.5 MBq/kg). After a resting period of 60 ± 10 min, PET/CT studies were acquired using a whole-body PET/CT scanner (Gemini TF, Philips, Cleveland, OH). First, a non-contrast-enhanced low-dose CT (ldCT) scan (dose modulated, 40mAs, 2 mm slice thickness) of the thorax was performed in prone position using a mock-up coil for hanging breast imaging (Fig. 1), followed by PET acquisition (3 min per bed position, 2 mm voxel reconstruction). Subsequently, a whole-body PET (1.5 min per bed position, 4 mm voxel reconstruction) combined with ldCT scan was performed in supine position. The ldCTs were used for attenuation correction and anatomical localization. Prone and supine scans were both performed with the arms of the patient placed in identical positions above the head, to facilitate optimal imaging of the axillary nodes.

For purpose of this study, [¹⁸F]FDG-PET/CT images were retrospectively reviewed by two experienced nuclear medicine physicians with an interval of more than seven days between respective assessments of prone and supine images. The observers were blinded to clinical and other imaging results. Both observers separately assessed the total number of FDG-positive level I and II axillary lymph nodes. A lymph node was regarded as FDG-positive when the uptake was higher than the non-specific blood pool activity.

Clinical staging of the axilla at time of treatment was performed by experienced nuclear medicine physicians who assessed both prone and supine position FDG-PET/CT images. The total number of FDG-positive ALNs identified was reported. All PET/CT scans were discussed during multidisciplinary consultation prior to surgery in order to confirm correct axillary staging and treatment strategy. According to the MARI-protocol, the number of FDG-positive axillary nodes was used to stage the axilla rather than the clinical TNM classification, in which the N-classification also refers to internal mammary and peri-clavicular nodes. Patients with less than four FDG-positive axillary nodes on PET/CT were categorized as cALN<4 and patients with four or more FDG-positive nodes were categorized as cALN≥4.

A comprehensive description of the MARI-procedure and radiation safety protocols has been described previously [13]. In summary, the largest pathology proven tumor-positive axillary node (i.e., MARI-node) is marked with an ¹²⁵iodine seed under ultrasound guidance, prior to the first NST cycle. The iodine seeds used for localization of the MARI-node have an apparent activity varying from 0.2 to 1.0 MBq at time of implementation, which is lower than that for breast tumor localization (1.0–7.6 Mbq) [30, 31]. Localization and marking of breast tumor(s) were performed during the same procedure. Marking of the axilla and breast was followed by ultrasound and/or mammography to confirm adequate position of the marker(s).

After completion of NST, a gamma probe was used to localize the Iodine seed(s) and guide surgical resection. Excision of the MARI-node was performed simultaneously with surgery of the breast. An intraoperative frozen section of the MARI-node was performed in all cALN≥4 patients.

Pathological complete response (pCR) of the axilla (ypN0) was defined as the absence of vital tumor cells in all removed ALNs, irrespective of the response in the breast. All cALN<4 patients with pCR of the MARI-node (ypMARI-neg) received no further axillary treatment. Patients cALN<4 without pCR of the MARI-node (ypMARI-pos) and cALN≥4 patients with pCR of the MARI-node (ypMARI-neg) received axillary radiotherapy (levels I to IV). Patients staged cALN≥4 with residual tumor cells in the MARI-node (ypMARI-pos) received both ALND and ART.

The primary outcome was the number of patients who were upstaged or downstaged with prone position FDG-PET/CT compared to supine FDG-PET/CT. Patients could either be upstaged to cALN≥4 or downstaged to cALN<4. Secondary outcomes were differences in the number of ALNs counted as FDG-positive and interobserver agreement, assessed as the agreement on axillary staging category between the two nuclear medicine physicians on both prone and supine FDG-PET/CT images. The original axillary staging report containing both prone and supine FDG-PET/CT scan images was used as a reference standard. In addition, three-year axillary recurrence-free interval was assessed by axillary treatment and compared with observer agreement.

Six of the 159 patients analyzed were excluded due to missing prone position FDG-PET/CT, leaving 153 patients for analysis. Baseline patient characteristics are shown in Table 1. Median age was 49 years (range 22–79). The majority of patients had invasive ductal carcinoma (89%) and HR-positive/HER2-negative tumor subtype (46%). The mean number of suspect nodes identified according to axillary staging at time of treatment with combined supine and prone FDG-PET/CT images was 3.2 (range 1–14). The number of FDG-positive ALNs was cALN<4 in 108 (71%) patients and cALN≥4 in 45 (29%) patients.

After NST, pCR of the MARI-node was found in 57 (37%; 95% CI 30–45) patients. Breast pCR occurred in 42 (27%; 95% CI 21–35) patients and 39 (25%; 95% CI 19–33) patients had pCR of the breast and MARI-node (ypT0N0). Response-adjusted axillary treatment according to the MARI-protocol resulted in 36 (24%) patients receiving no further axillary treatment, 91 (59%) patients underwent ART (72 cALN<4, ypMARI-pos and 19 cALN≥4, ypMARI-neg) and 26 (17%) patients underwent ALND plus ART (Fig. 2).

Down- and upstaging with prone position compared to supine position FDG-PET/CT were evaluated for the two study observers. Irrespective of the patients scan position (i.e., prone or supine), both observers agreed on axillary staging in 124 (81%; 95% CI 74–87) patients and disagreed in 5 (3%; 95% CI 1–7). These five patients were consistently staged cALN<4 by the first observer and cALN≥4 by the second observer (Fig. 3, Table S1 [online resource 1]). In total, twenty-four (16%; 95% CI 10–22) patients were up- or downstaged at assessment of prone images by either one of the observers. Two of these patients were counted by both observers: Observers agreed on up- or downstaging with prone FDG-PET/CT in only one patient (1%; 95% CI 0–4), who was downstaged by both observers, and one patient was downstaged by observer 1 while upstaged by observer 2.

The first observer upstaged 4 patients, downstaged 5 patients and did not report a higher mean number of FDG-positive ALNs (2.8 vs. 2.8, p = 0.358). The second observer upstaged 14 patients and downstaged 3 patients and did report a higher mean number of FDG-positive ALNs (3.6 vs. 3.2, p < 0.001).

Axillary staging changed at assessment of prone scan images for the first observer in a total of 9 (6%; 95% CI 3–11) patients and for the second observer in 17 (11%; 95% CI 7–17) patients (Fig. 2). For the first observer, this change was in concordance with the original multidisciplinary determined staging category in 4 patients (3 upstaged, 1 downstaged) and in discordance in 5 patients (1 upstaged, 4 downstaged). For the second observer, the changed category was in concordance with the original report in 9 patients (6 upstaged, 3 downstaged) and in discordance in 8 patients (all upstaged).

Interobserver agreement on axillary staging was greater with FDG-PET/CT assessments in supine compared to prone position (K = 0.80 vs. K = 0.67) (Table 2). At assessment of supine position FDG-PET/CTs, a total of 141 (92%) patients were categorized in the same axillary staging group (cALN<4 or cALN≥4) and 131 (86%) patients were categorized in the same axillary staging group at assessment of prone position scans. Observer agreement was also greater using FDG-PET/CT in supine compared to prone position only when observations were compared to the original staging category based on both prone and supine FDG-PET/CT scan images together (Fleiss K = 0.78 vs. 0.74) (Table 2).

Median follow-up was 3.8 years (interquartile range [IQR] 2.9–4.6). Axillary recurrences occurred in four (3%) patients, all with synchronous other metastases, resulting in a three-year axillary recurrence-free interval of 98% (95% CI 96–100). At review of FDG-PET/CT images acquired in prone position, one of the study observers disagreed with the originally assigned staging category in one of these four patients with axillary metastases and upstaged the patient cALN≥4, which would have resulted in ART instead of no further treatment.