18F-choline-PET-CT vs Ultrasonography and 99-technetium Sestamibi Scintigraphy in Preoperative Localization for pHPT - A Randomized Trial

1 Improving precision in parathyroid surgery 18F-choline-PET-CT vs ultrasonography and 99-technetium sestamibi scintigraphy in preoperative localization for pHPT - A randomized trial Martin Almquist, 2022-03-08 Purpose and aims The purpose of the present open, single-center, prospective, randomized, clinical study is to investigate whether precision imaging with [18F]fluoromethyl-dimethyl-2-hydroxyethylammonium (18F-choline) positron-emission-tomography - computed-tomography, 18F-ch-PETCT, is superior to conventional imaging in localizing diseased parathyroid glands in primary hyperparathyroidism, pHPT. Our overall objective is to improve precision in parathyroid surgery, increase cure rates, minimize complications and shorten operation times. State-of-the-art Primary hyperparathyroidism (pHPT) is a common endocrine disorder, causing kidney stones, renal insufficiency, and osteoporosis, which increases the risk of fractures, especially hip fractures, which carry a substantial mortality risk (1). PHPT is caused by increased production of parathyroid hormone (PTH) in one or several enlarged parathyroid glands. Surgical removal of the pathologic gland(s) cures the disease (2). Successful preoperative localization of such glands limits the surgical dissection, increases the cure rate, minimizes complications, and decreases operation time (3). However, there is no perfect imaging method, which in all patients correctly identifies each and every pathologic gland (4). Commonly used imaging methods are neck ultrasonography and 99-technetium sestamibi scintigraphy (5). In patients with inconclusive imaging, multiphase four-dimensional computed tomography, 4DCT, can further help localize diseased parathyroids (6). The rate of inconclusive or negative studies is high (5). The current first-line imaging strategy with ultrasound and scintigraphy causes up to a half of patients to undergo no less than three localization procedures, adding to costs and inconvenience for patients. Replacing the current strategy with one modality might thus be beneficial for patients and cost-effective for the health care system. Imaging with [18F]fluoromethyl-dimethyl-2-hydroxyethyl-ammonium- PET-CT, 18F-ch-PET-CT, previously used for detection and staging in prostate cancer, might more precisely localize parathyroid glands than ultrasound and scintigraphy (7). However, 18F-ch-PET-CT is also more expensive than ultrasound and sestamibi scintigraphy, and not available at all centers. Hence, 18F-ch-PET-CT has mostly been used as a second-line method, for instance in patients with inconclusive ultrasound and/or scintigraphy, or in patients with persistent disease after previous parathyroid surgery (7). Significance and scientific novelty 18F-choline-PET-CT has not been used as the first-line modality in localizing parathyroid glands, and there has been no randomized trial comparing its efficacy to conventional imaging in this setting. A randomized trial would yield solid evidence and its results would be both novel and clinically important. 2 Preliminary and previous results Between 1st January 2017 and 31st December 2020, a total of 241 patients with first-time, nonhereditary pHPT were operated on at the Department of Surgery at Skåne University Hospital, Lund. Out of these, 225 patients (93 %) underwent ultrasonography, and 223 patients (92 %) underwent 99-technetium sestamibi scintigraphy. Ultrasound was inconclusive in 39 % of 225 patients, and sestamibi scintigraphy was inconclusive in 47 % of 223 patients. Hence, 116 patients (48 % of all patients) also underwent 4DCT. 4DCT was inconclusive in 28 % of patients.

Thus, a total of 42 (17 % of all patients) had inconclusive results in all three investigations. In patients with localized disease, the cure rate was 95 %; in patients where all three examinations were inconclusive, the cure rate was only 81 %. Thus, precision in preoperative localization is needed. At the Department of Clinical Physiology and Nuclear Medicine, Skåne University Hospital, 18Fch- PET-CT has been used in 5,500 patients between 2008 and 2019 for imaging of prostate cancer. No adverse reactions were reported. An on-site cyclotron, PETtrace 880, GE Healthcare, is used to produce the radiotracer [18F]fluoromethyl-dimethyl-2-hydroxyethylammonium.

Project description Theory and methods This is a non-blinded, single-center, prospective, randomized, clinical study comparing 18F-ch- PET-CT to 99-technetium sestamibi scintigraphy and ultrasonography for localizing parathyroid glands in primary hyperparathyroidism. Inclusion and exclusion criteria Adult patients with primary hyperparathyroidism referred to the Department of Surgery at Skåne University Hospital, Lund, deemed candidates for surgery by the attending surgeon, using criteria specified in clinical national and international guidelines, patient preferences, and surgeon judgment of indication and operability, are invited to participate. Invited patients are given oral and written information. After signed informed consent, patients are randomized to either 18F-ch-PET-CT or ultrasound and scintigraphy. Allocation is open, since blinding is not possible, neither for providers nor for patients. Patients with previous parathyroid or thyroid surgery, or with the need for concurrent thyroid surgery, or with lithium therapy, hereditary parathyroid disease, such as multiple endocrine neoplasia type 1, MEN1, or with severe renal insufficiency, are not eligible. Outcomes Since cure rates are high, even after negative imaging, 18F-ch-PET-CT might only increase cure rates slightly. However, more precise preoperative localization with 18F-ch-PET-CT should decrease operation time, facilitating surgical planning, with similar or higher cure rates than conventional imaging with ultrasound, scintigraphy, and (in half of the patients) 4DCT.

The primary outcome, therefore, is operation time, measured from incision to the last suture.

Secondary outcomes are cure rates, defined as normocalcemia without treatment with calcium or vitamin D at first follow-up, one month postoperatively; rates of complications such as damage to the recurrent laryngeal nerve and hypocalcemia; rates of persistent disease, i.e.