F-18 fluoro-deoxy-glucose and F-18 sodium fluoride cocktail PET/CT scan in patients with breast cancer having equivocal bone SPECT/CT.

INTRODUCTION: Although single-photon emission computed tomography (SPECT)/computed tomography (CT) plays a major role in the characterization of equivocal lesions on bone scintigraphy, it remains equivocal in a fraction of these patients. We evaluated the additional value of cocktail F-18 sodium fluoride (18F-NaF) and F-18 fluorodeoxyglucose (18F-FDG) co-injection positron emission tomography (PET) (cocktail PET) in these patients.
MATERIALS AND METHODS: Fifteen breast cancer patients, who had equivocal findings on the whole body bone scan (WBS) and SPECT/CT, were subjected to a cocktail PET/CT scan. The cocktail PET/CT was performed by co-administration of 18F-FDG and 18F-NaF in a ratio of about 2.4, with the total administered activity kept at approximately 10 mCi.
RESULTS: Of the 15 patients, seven were with locally advanced breast cancer (LABC) and the other eight were referred because of suspicion of recurrent disease on follow-up. Of the seven patients with LABC, the cocktail PET scan was positive for all the lesions suspicious on WBS and SPECT/CT. Additionally, it showed uptake in the primary tumor and ipsilateral axillary lymph nodes as well as identified additional osseous, lymph nodal, and solid organ metastases in these patients. Similarly, of the eight patients studied for suspicion of recurrence, the cocktail PET scan was found to be positive in seven patients. In three patients, additional osseous lesions were noted.
CONCLUSION: The cocktail PET/CT scan can characterize almost all the suspicious equivocal lesions on the bone scan and SPECT/CT. The distinct advantage of identifying lymph nodal and solid organ metastases allows it to be considered as a useful imaging modality in patients with equivocal bone SPECT/CT.

INTRODUCTION

The proven role of fluorodeoxyglucose positron emission tomography/computed tomography (F-18 FDG PET/CT) in a variety of cancers has changed the practice of oncology.[1] It has been seen to perform much better than the conventional imaging modalities in the initial staging of a variety of FDG avid cancers. The utility of the FDG PET/CT in the evaluation of patients with malignancy is fast expanding. Breast cancer is the most common cancer in women, excluding non-melanoma skin cancers.[2] As per the national comprehensive cancer network (NCCN) guidelines, although the FDG PET/CT is not indicated in the early stage of breast cancer (Stage I, II, and operable stage III disease), it is helpful when standard imaging studies are equivocal or suspicious, especially in the setting of LABC or metastatic staging.[3] FDG PET/CT is also useful in identifying unsuspected regional lymph nodal disease or distant metastases in LABC, when used in addition to standard staging studies.[4] In the evaluation of bone metastases (BM), although FDG PET tends to be superior in the detection of osteolytic lesions, it is inferior in the detection of osteoblastic lesions.[5] FDG PET and whole body bone scintigraphy (WBS) play a complementary role in detecting bone marrow (BM) involvement from breast cancer.

Whole body MDP bone scintigraphy (WBS) is a routinely performed investigation for the evaluation of BM in patients with advanced breast cancers or suspicious clinical symptoms, and when alkaline phosphatase is elevated. WBS is a highly sensitive investigation for the identification of BM. However, equivocal lesions also occur with WBS. Single photon emission computed tomography/computed tomography (SPECT/CT) has been shown to be a useful investigation in the characterization of lesions equivocal on WBS. However, SPECT/CT also remains equivocal in a fraction of these patients. PET/CT with F-18 sodium fluoride (18F-NaF) is an alternative to WBS in the evaluation of BM. It is reported to be more sensitive than WBS in the detection of BM.[5] We evaluated the additional value of 18F-NaF and F-18 fluorodeoxyglucose (FDG) co-injection PET (cocktail PET) as a one-stop shop for patients who had equivocal findings on WBS and SPECT/CT.

MATERIALS AND METHODS

This prospective study was conducted in patients with breast cancer referred for WBS. The patient population included those with LABC and suspected recurrence. Informed consent was obtained prior to the study. The status of breast tumor and axillary nodes on clinical examination were recorded. Clinical details of trauma, surgery, and bone pain were also recorded. The study was approved by the departmental review committee.

Whole body bone scintigraphy and single-photon emission computed tomography/computed tomography

All the patients underwent WBS three hours after intravenous injection of approximately 740 MBq (20 mCi) of Tc99m-methylene diphosphonate (MDP). Images were acquired in both anterior and posterior views under a dual-headed gamma camera fitted with low energy high resolution (LEHR) collimators. Patients with normal WBS or definitely abnormal findings were excluded. Patients having equivocal findings on WBS were further subjected to SPECT/CT in a hybrid scanner (Infinia Hawkeye 4, GE healthcare, Milwaukee, USA). SPECT images of the involved area were acquired in a step-and-shoot method in a 64 × 64 matrix, covering 360 degrees in 60 views, with 30 seconds per view. Following the SPECT acquisition, CT was acquired in a helical mode and the tube current was 2.5 mA. Patients whose SPECT/CT findings were suggestive of metastases or degenerative changes were excluded. Patients who had equivocal findings on SPECT/CT were subjected to cocktail PET within two weeks of WBS.

18F-NaF + 18F-FDG cocktail positron emission tomography procedure

Cocktail PET was performed after co-administration of F-18 FDG and 18F-NaF. They were injected in a ratio of 2.4, with the total injected activity being kept at approximately 370 MBq (10 mCi). The images were acquired in 3-D mode at two minutes per bed position, 60 minutes after the injection of radiotracers in the PET/CT scanner (Discovery STE-16, GE healthcare, Milwaukee, USA). The acquired data was reconstructed using an iterative algorithm (two iterations and 20 subsets). The findings of CT and fused PET/CT were recorded.

Pathological confirmation was performed when a single abnormal lesion was noted in the cocktail PET scan. In the presence of multiple sites of abnormality, the following were considered as evidence of metastases:

Enlarged lymph nodes with intense FDG uptake (lymph nodal metastases)

Unequivocal CT findings of lytic, sclerotic or mixed lytic sclerotic lesions in the bones (BM)

Multiple FDG avid space-occupying lesions with morphology consistent with metastases in the solid organs (solid organ metastases)

FDG avid mass lesion in the brain with disproportionate cerebral edema (brain metastases)

FDG avid pulmonary nodules with morphology consistent with metastases (lung metastases).

The findings of cocktail PET were compared with the previous imaging studies, if available. New radiological abnormalities, with features consistent with metastases, were also considered metastatic. Fractures, osteophytes, and degenerative changes were considered as benign. The findings of cocktail PET were considered equivocal if the abnormality could not be classified as either benign or malignant. No attempt was made to separate the sites of uptake as those due to 18F-NaF or those due to 18F-FDG uptake.

RESULTS

Fifteen histologically proven breast cancer patients were eligible for inclusion into this study. All the patients had equivocal findings on WBS and SPECT/CT. All the patients underwent the cocktail PET as per protocol. The mean injected activity during cocktail PET was 401 MBq (10.84 mCi); and the 18F-FDG/18F-NaF ratio was 2.4.

Of the 15 patients, seven were of LABC and referred for WBS at the initial diagnosis. All these patients had a T4 tumor and ipsilateral axillary lymph nodal involvement on clinical examination. The other eight patients had undergone mastectomy and chemotherapy and were referred because of suspicion of recurrent disease.

Of the seven patients with LABC, the WBS and SPECT/CT showed a single abnormal focus in six patients (sternum in two, vertebrae in three, rib in one) and one had two abnormal foci (sternum and acromion process of the scapula), which were equivocal for bone metastases. All the lesions noted in WBS were positive on cocktail PET scan. Additionally, the cocktail PET showed uptake in the primary tumor and ipsilateral axillary lymph nodes in all these patients. The cocktail PET identified additional osseous, lymph nodal, and solid organ metastases in these patients, the details of which are presented in Table 1. Based on the morphology of the lesions and patterns of involvement, all these lesions were classified as metastatic. Figures 1 and 2 depicts two such patient in whom cocktail PET/CT scan not only helped in characterizing equivocal lesions seen on conventional bone scan but also showed several additional lesions indicating widespread metastases.

Table 1

WBS and Cocktail PET/CT findings of patient with locally advanced breast cancer

Figure 1

Whole body bone scan of a patient with LABC in anterior (a) and posterior (b) views showing an equivocal lesion in the L4 vertebra, which could not be characterized further with SPECT/CT. Maximum intensity projection (MIP) image of cocktail PET / CT (c) shows intense tracer uptake in the L4 vertebra. Several additional lesions indicating widespread metastases are also noted

Figure 2

Whole body bone scan in anterior (a) and posterior (b) views of a breast cancer patient on follow up showing an equivocal lesion in the L5 vertebra. Maximum intensity projection (MIP) image of cocktail PET/CT (c) shows intense tracer uptake in the L5 vertebra, along with multiple liver metastases, mediastinal lymph nodal metastases, and a brain metastases

Of the eight patients studied for suspicion of recurrence, WBS and SPECT/CT showed a single abnormal focus in six patients (sternum in two, vertebra in four). Two patients had two abnormal foci on WBS and SPECT/CT (fourth rib and L5 vertebra in one and two contiguous ribs in the other patient). All the lesions noted in WBS were positive on the cocktail PET scan also. In three patients, additional osseous lesions were noted. The additional findings on cocktail PET in these patients are presented in Table 2. The findings of cocktail PET were considered as indicating metastases in seven patients and benign (rib fracture) in one patient. Figure 3 shows whole body bone scan and cocktail PET/CT scan findings in a patient on follow up. Several other lesions were also noticed in addition to the characterization of an equivocal lesion in the D12 vertebra.

Table 2

WBS and cocktail PET/CT findings in breast cancer patient with suspicion of metastatic disease

Figure 3

Whole body bone scan in anterior (a) and posterior (b) views of a breast cancer patient on follow-up, showing an equivocal lesion in the D12 vertebra. Maximum intensity projection (MIP) image of a cocktail PET/CT (c) and fused transaxial images (d) shows intense tracer uptake in the transverse process of the D12 vertebra. FDG uptake was also noted in the chest wall, bilateral axillary lymph nodes, and mediastinal lymph nodes. Additional osseous lesions were also noted in the pelvis, vertebrae, and scapula

DISCUSSION

Breast cancer is the most common non-skin cancer and the second-leading cause of cancer death in women.[6] Positron emission tomography imaging may play a significant role in defining the extent of the disease, to monitor the response and predict tumor behavior in these patients. Axillary node metastasis is the most important prognostic factor in early stage breast cancer patients and the extent of axillary disease influences the choice of the therapeutic regimen for patients. FDG PET for axillary staging has shown a sensitivity of 57 to 100% and a specificity of 66 to 100%.[78] Lymphatic spread of the tumor to the internal mammary (IM) nodes occurs in up to 25% of the patients at the time of initial diagnosis and possibly more commonly in recurrent cancer.[9] FDG uptake in the IM nodes indicates a poorer prognosis and treatment failure.[10] Neoplastic spread to the mediastinal nodes is also common in patients with advanced disease. However, IM nodes and mediastinal nodes are rarely sampled. FDG-PET/CT is significantly more accurate in the evaluation of IM and mediastinal lymph nodal involvement.[1112] The skeleton is the most common site of distant metastasis in breast cancer. Purely lytic lesions or metastases confined to the marrow cavity may be difficult to detect on WBS because of a lack of sufficient osteoblastic response. In a study of breast cancer patients with known skeletal metastases who underwent both bone scintigraphy and FDG-PET, it was noted that FDG PET detected more lesions than bone scintigraphy, except in a subgroup of patients with osteoblastic metastases.[13] FDG is more likely to detect metastases at an earlier stage than WBS, when still confined to the bone marrow, before an osteoblastic reaction that can be visualized on WBS occurs. In osteolytic metastases, FDG uptake is higher because of the presence of a larger amount of tumor cells with a high glycolytic rate.[13] Hence, WBS and FDG PET/CT play a complementary role and do not substitute each other in the evaluation of BM.

The addition of SPECT improves the diagnostic accuracy of WBS. SPECT enables accurate localization of tracer activity, especially in complex skeletal structures. Hybrid SPECT/CT further improves the sensitivity and specificity of WBS. CT can assist in the diagnosis of benign skeletal findings, including osteophytes or degenerative changes and hemangiomas or cysts, which cause an abnormal tracer activity on WBS. The uptake of F18 is approximately two-fold higher and its blood clearance is significantly faster compared with the Technetium-labeled agents used for WBS. This results in an increased bone-to-background ratio. In addition, PET offers high sensitivity and high resolution, and is therefore, able to perform a highly accurate whole-body screening for metastases. 18F also has higher sensitivity for the detection of bone metastases compared to WBS.[5]

The cocktail PET scan performed after co-injection of 18F-NaF and 18F-FDG has several potential advantages. The high sensitivity of FDG for identifying soft tissue metastases, bone marrow metastases, and osteolytic BM is combined with the high sensitivity of 18F-NaF for identifying early BM and osteoblastic BM. The radiation exposure can be reduced by avoiding two separate studies. Hoegerle et al.,[13] reported the use of combined 18F-NaF and 18F-FDG administration for PET more than a decade ago, when the PET/CT was not available. Skeletal 18F-NaF uptake was used as a surrogate for anatomic localization of abnormal 18F-FDG in the absence of fused PET/CT. In recent times, a cocktail PET/CT scan has been tried and found to be a feasible method for the detection of metastases.[1415]

In a recently published study, the clinical usefulness of a combined 18F- FDG/18F-NaF PET/CT was compared with a separate 18F - FDG only PET/CT scan.[16] In 34% of the patients, a greater number of lesions were detected using the cocktail scan compared to 18F- FDG only PET/CT. The authors concluded that the cocktail PET/CT scan has increased sensitivity for detection of osseous lesions compared to the 18F- FDG only PET/CT scan. They administered approximately 15 mCi of 18F- FDG and 5 mCi of 18F-NaF. In our study, the total administered activity was approximately 10 mCi with good diagnostic images. In a subgroup of breast cancer patients, in this study, 9/34 (26%) patients showed more number of skeletal lesions in the 18F- FDG/18F-NaF PET/CT compared to the F18 FDG only PET/CT scan.

The cocktail PET/CT is better suited for breast cancer patients in contrast to prostate cancer, which predominantly causes sclerotic BM, whereas, BM from breast cancer can be lytic, sclerotic or mixed lytic sclerotic. Addition of 18F-NaF to 18F-FDG helps to identify sclerotic BM, which is usually missed on 18F - FDG PET/CT alone. Hence, the high sensitivity of 18F-FDG in detecting soft tissue and nodal involvement is combined with the high sensitivity of 18F-NaF in detecting sclerotic BM.

The addition of cocktail PET/CT in our patients helped in the characterization of equivocal lesions on WBS and hybrid SPECT/CT. Furthermore, several additional sites of metastases were also identified. Metastases to the contralateral axillary lymph nodes were identified in 13% (2/15), internal mammary lymph nodal involvement in 13% (2/15), supraclavicular lymph nodal involvement in 20% (3/15), and mediastinal and/or intra-abdominal lymph nodal involvement in 40% (6/15) patients. Additional sites of BM were identified in 60% (9/15) of the patients. Solid organ metastases were noted in 40% (6/15) of the patients. Hence, in a patient with equivocal findings on WBS and SPECT/CT imaging, cocktail PET imaging may be considered as a ‘one-stop shop’ imaging modality for both characterizing the equivocal lesions and also for evaluation of the extent of the disease. The mean activity injected in our study was 10.84 mCi, similar to the activity used in routine 18F-FDG PET/CT. This suggests that it is possible to perform a cocktail PET scan without any additional radiation exposure to the patient.

Limitations of the study

Our study was conducted in a small number of patients. In many patients, the equivocal findings on WBS were characterized by SPECT/CT imaging. These patients were excluded from our study. A strict inclusion criterion was one of the reasons for the small number of patients in our study. All the sites of abnormalities were not subjected to pathological confirmation. Although it is a significant limitation of the study, we felt that in the presence of multiple metastases, pathological confirmation from individual sites was not warranted. No attempt was made to separate the sites of uptake as those due to 18F-NaF or those due to 18F-FDG uptake. Although it is known that 18F-FDG uptake carries a prognostic significance, we felt that trying to differentiate the sites of uptake as those due to either of the tracers was not going to have any significant impact on the clinical management of the patient.

CONCLUSION

The cocktail PET/CT has a significant impact on the evaluation of breast cancer patients, who have equivocal findings on a bone scan and SPECT/CT. The cocktail PET/CT scan could characterize the equivocal lesions in all our patients. It also identified significant additional metastatic disease in the lymph nodes, bone, and solid organs. The distinct advantage of evaluating the extent of the disease throughout the body will allow cocktail PET/CT to be considered as a useful imaging modality in patients with equivocal bone SPECT/CT.