Peptide receptor radionuclide therapy (PRRT) using somatostatin analogues

What is Peptide Receptor Radionuclide Therapy (PRRT) with ¹⁷⁷Lu-DOTATATE?

Peptide Receptor Radionuclide Therapy (PRRT) with ¹⁷⁷Lu-DOTATATE is a targeted radiation treatment of neuroendocrine tumors (NETs) that uses somatostatin receptors on the surface of cancerous cells to deliver the radiopharmaceuticals and directly destroy the tumor and metastases with minimal damage to the surrounding healthy tissue.

NETs are rare and very different in nature, most commonly arising in the gastroenteropancreatic (GEP) tract. Basically, NETs grow in cells that make hormones, that’s why they are called neuroendocrine. These tumors and their metastases have been shown to possess an abundance of, or overexpress in medical jargon, somatostatin receptors on their cell membrane. Somatostatin (chemically a peptide) is a natural hormone circulating in the body produced principally by the nervous and digestive systems. Modern medicine uses synthetic somatostatin analogues (SSAs), such as DOTATOC and DOTATATE, to deliver radioactive material to the cell, for both diagnostic and treatment purposes. Hence the blend name of this medical field – theranostics, i.e. the combination of therapy and diagnostics of the target.

How does the diagnostics work?

For this purpose, for example, DOTATATE is combined with the radioactive substance, or radionuclide, gallium 68 (⁶⁸Ga), thus creating a special type of radiopharmaceutical called a radiopeptide. Thereafter these radiopeptides are administered intravenously to the patient and a PET/CT scan is performed, which allows to detect the locations where the substance has accumulated and thus to indicate the location of tumors and metastases clearly and accurately.

Accurate staging of NET is essential for optimizing the treatment. Surgery is mostly the only possible curative approach, if the primary tumor hasn’t metastasized yet. Metastases are unfortunately very common. Moreover, since NETs cause little to no symptoms at initial stages, they are often discovered at a later stage with metastases already present. The PET/CT scan can detect up to 50% more cancer foci than "normal" imaging. Therefore, ⁶⁸Ga-DOTATATE PET/CT can help determine which patients will benefit from surgery. This PET/CT scan is also necessary to assess whether PRRT is applicable, as its success depends on the presence (or expression in medical parlance) of somatostatin receptors. Hence, it is possible to determine already before the therapy whether it will really have an effect of all existing tumor foci.

In 2018 National Comprehensive Cancer Network (NCCN) added ⁶⁸Ga-DOTATATE PET/CT to its guidelines as an appropriate evaluation tool along with site-specific anatomic imaging (CT, MRI, or endoscopic ultrasound). The Society of Nuclear Medicine and Molecular Imaging (SNMMI) established it as the preferred imaging modality for initial diagnosis, selection of patients for PRRT, and localization of unknown primary tumors.

How does the treatment work?

For PRRT, the somatostatin analogue is combined with another radionuclide: beta emitter Lutetium 177 (¹⁷⁷Lu). Radiopeptides are injected intravenously and set off to independently seek their goal - cancer cells. After binding to cancer cells, the emitters begin to destroy them. The fact that the radiation radius of lutetium is very localized (mean penetration radius of lutetium into the surrounding tissues is 0,3 mm) significantly reduces the collateral damage that often accompanies traditional radiation treatment.

Another beta emitter yttrium 90 (⁹⁰Y) used to be applied for bulkier tumors, due to its higher radiation and deeper tissue penetration, but it didn’t demonstrate superior results compared to ¹⁷⁷Lu. This treatment remains very personalized. So the doctor will advise which emitter, in what quantity or in which combination to use depending on your specific case.

Procedure

The procedure itself takes about 15-20 minutes and is preceded and followed by an infusion of an amino acid solution, which protects the kidneys from damage. Radiopeptides are intravenously administered to the patient. For supportive purposes, to lessen the strain on the kidneys, you should drink plenty of fluids before and after therapy. You can leave the clinic immediately after the therapy. We will inform you in detail in advance as to the specific radiation precautions.

The usually recommended treatment course consists of 4 sessions with an 8-week interval in-between accompanied by a ⁶⁸Ga DOTATATE-PET/CT 6 to 7 weeks after the fourth session to evaluate the efficacy. An interim evaluation with PET/CT is eventually necessary. Further treatments afterwards are possible.

Types of neuroendocrine tumors

Classification

NETs vary in aggressiveness and are graded from G1 to G3 based on:

morphological differentiation,
the level of the nuclear protein Ki-67 (Ki-67 proliferation index), associated with cellular proliferation, and
mitotic count.

The degree of morphological differentiation describes how much cancer cells look like healthy cells when viewed under a microscope.

The cells are well differentiated when they look more like healthy cells.
The cells are poorly differentiated when they look less like healthy cells.

Mitotic count and Ki-67 are both markers of how fast the tumor cells grow and divide.

To determine the mitotic count, dividing cells contained in a specific amount of space are counted under a microscope.

Ki-67 is a protein in cells that increases as they prepare to divide. The Ki-67 index is an indicator of how quickly the cancerous cells are multiplying. If there are many cells with Ki-67 in a limited area, it means that the cells are dividing rapidly.

Grade 1 (low-grade tumor): mitotic count < 2, Ki-67 index <3%. These cells divide at a low rate and therefore grow slowly.

Grade 2 (intermediate-grade tumor): mitotic count 2 to 20, Ki-67 index 3 to 20%. These cells divide at an intermediate rate.

Grade 3 (high-grade tumor): mitotic count >20, Ki-67 index > 20%. These cells divide at a fast rate and therefore grow quickly. Grade 3 NET can further be divided into grade 3 NET with a behavior closer to well-differentiated NET, and grade 3 neuroendocrine carcinoma, with a more aggressive behavior.

Inoperable (e.g. metastatic) well-differentiated G1 and G2 tumors and G3 NET with high expression of somatostatin receptors can potentially be treated with targeted molecular therapy PRRT.

NETs most commonly arise in the gastroenteropancreatic tract and lungs (pulmonary carcinoids), but also affect other organs. NETs themselves can release different types of hormones, what can affect how the patient feels. They can cause diarrhea, hot flushes, itching, etc.

Pancreas:

Insulinomas produce extra insulin, the hormone that controls blood sugar levels, and cause hypoglycemia or low blood sugar.

Glucagonomas conversely make glucagon, a hormone that raises blood sugar level.

Gastrinomas make the hormone gastrin, which helps digest food, but can cause gastric ulcerations.

Somatostatinomas produce extra somatostatin what affects how the body produces other hormones.

VIPomas make a hormone called vasoactive intestinal peptides (VIP) that triggers the release of other hormones, and cause massive diarrhea.

Thyroid gland:

Medullary thyroid carcinoma is a NET of the parafollicular or C cells of the thyroid gland and secretes extra amounts of a hormone called calcitonin, whose role in the body is to regulate the transfer of calcium from bone tissue to the blood.

Adrenal glands:

Pheochromocytomas grow from hormone-producing cells called chromaffin cells found in the adrenal glands. They release hormones known as catecholamines, such as adrenaline, controlling heart rate, metabolism, and blood pressure.

Paragangliomas form near certain blood vessels and nerves outside of the adrenal glands. This type of NET can also secrete catecholamines such as adrenaline, responsible for the fight-or-flight response. It can consequently cause high blood pressure, a rapid heartbeat, sweating, headache and tremors.

Neuroblastomas form in immature nerve tissue (neuroblasts) in the adrenal glands, neck, chest, or spinal cord. A neuroblastoma may also release hormones and can cause diarrhea, fever, high blood pressure, fast heart rate, flushing or redness of skin, sweating.