What is Lu PSMA (Lutetium-Prostate Specific Membrane Antigen) Therapy?

Lu177 PSMA Therapy is a treatment for patients with prostate cancer, especially those who have become refractory to conventional therapy. Lutetium PSMA therapy helps to slow down the growth of the cancer cells, reduce the size of the tumours and most importantly improve the quality of life of the patients by reducing the pain caused by the cancer.

Many prostate cancers, in particular those that have spread or become resistant to hormonal therapies, express a unique receptor on their cell surface called Prostate Specific Membrane Antigen (PSMA). When Prostate Cancer metastasizes i.e. spreads to other parts of the body, the PSMA receptor is expressed over the sites of metastases as well.

How does Lu PSMA Therapy Work?

Lutetium-177 is a radioactive substance that emits beta radiation, a destructive kind of radiation. Lutetium-177 is bound to a small peptide which attaches to the PSMA receptor expressed on the cancer cell surface. The Lutetium 177 – PSMA complex, thus attached to the prostate cancer cell, then emits killing radiation causing cell death of the cancer cell. Since the penetration of the emitted beta particle is very small, the surrounding normal cells are spared.

How is the Therapy Done?

Lu177 PSMA is administered intravenously. The patient is admitted to the hospital for 24 hours. A kidney function scan called a MAG3/EC scan is done prior to the administration of the Lu177 PSMA.

What are the Side Effects of Lu PSMA Therapy?

Lu177 PSMA is well tolerated. The most common side effects are a slightly dry mouth, fatigue and nausea. There may also be a slight fall in the white blood cells and platelets about 2 – 3 weeks after the Lu177 PSMA administration.

What is the Response Rate With Lu PSMA Therapy?

The response rates of Lu177 PSMA depend on the tumour biology of prostate cancer, the initial Gleason Score, the extent of disease and the responses to prior therapies. Typically, more than 70% of patients demonstrate a reduction in S. PSA and a shrinkage of tumours following Lu177 PSMA therapy.

When would the doctor consider using this Therapy?

Lu PSMA Therapy is a very specific therapy and is used for managing metastatic Prostate Cancer or when Prostate Cancer is no longer responsive to other types of treatment.

What are the Treatment Schedules with Lu PSMA Therapy?

Most patients undergo three-four treatment cycles at intervals of 8-12 weeks. The number of cycles and the interim duration may vary between individuals depending on the response and interim assessments.

Why should I choose the nuclear medicine therapy center at Fortis Memorial & Research Institute (FMRI), Gurugram (Haryana, India)?

The Nuclear Medicine Therapy Centre at FMRI was one of the first institutes to offer Radio-ligand Therapy with Lu PSMA, and today, the center receives patients from the country and from across the world.

Understanding Neuroendocrine Tumors and their symptoms by Dr. Ishita B Sen

Summary (10 sec read)

Neuroendocrine tumors (NETs) are hormone-secreting neoplasms causing various symptoms, especially when metastatic. Peptide Receptor Radionuclide Therapy (PRRT) is a significant advancement, using radiolabeled somatostatin analogs to target NET cells, improving progression-free survival and quality of life. PRRT is effective, well-tolerated, and complements other treatments in multidisciplinary management of advanced NETs.

Neuroendocrine tumors (NETs) are a diverse group of neoplasms arising from neuroendocrine cells dispersed throughout the body. These cells have the unique ability to produce hormones and neurotransmitters, leading to a wide array of clinical presentations. NETs can originate in various organs, and their behavior ranges from indolent to highly aggressive, especially when they become metastatic.

Understanding the classification of NETs is crucial for diagnosis and management. The primary types include:

Gastrointestinal Neuroendocrine Tumors (GI-NETs):

Origin: Digestive tract organs such as the stomach, small intestine, appendix, colon, and rectum.

Characteristics: These are the most common NETs, often presenting with nonspecific gastrointestinal symptoms.

Pancreatic Neuroendocrine Tumors (PanNETs):

Origin: Islet cells of the pancreas.

Subtypes:

Functioning PanNETs: Secrete hormones like insulin, gastrin, glucagon, and vasoactive intestinal peptide (VIP), leading to specific clinical syndromes.
Non-functioning PanNETs: Do not produce active hormones, often detected at advanced stages due to mass effects.

Pulmonary Neuroendocrine Tumors (Lung NETs):

Origin: Neuroendocrine cells in the lungs.

Subtypes: Typical carcinoids, atypical carcinoids, large cell neuroendocrine carcinoma, and small cell lung carcinoma.

Pheochromocytomas and Paragangliomas:

Origin: Adrenal medulla (pheochromocytomas) and extra-adrenal paraganglionic tissue (paragangliomas).

Characteristics: Secrete catecholamines, causing hypertension and other systemic symptoms.

Medullary Thyroid Carcinoma (MTC):

Origin: Parafollicular C cells of the thyroid gland.

Characteristics: Associated with calcitonin secretion, can be sporadic or part of genetic syndromes like Multiple Endocrine Neoplasia type 2 (MEN2).

Merkel Cell Carcinoma:

- Origin: Merkel cells in the skin.

- Characteristics: Rare, aggressive skin cancer often linked to polyomavirus infection.

Symptoms of Metastatic Neuroendocrine Tumors

When NETs metastasize, they commonly spread to the liver, bones, and lymph nodes. Metastatic NETs can produce a range of symptoms due to both tumor burden and hormonal hypersecretion.

Gastrointestinal NETs:

Carcinoid Syndrome: Occurs in about 20% of GI-NET patients with liver metastases (*Modlin et al., Lancet Oncol.*, 2008). It results from the systemic release of serotonin and other vasoactive substances.

Flushing: Sudden redness and warmth of the face and neck.

Diarrhea: Frequent, watery stools due to increased intestinal secretion.

Abdominal Cramping: Caused by enhanced gut motility.

Bronchospasm: Wheezing and difficulty breathing.

Carcinoid Heart Disease: Fibrosis of heart valves, leading to heart failure.

Pancreatic NETs:

Functioning Tumors:

Insulinomas: Excess insulin causes hypoglycemia—symptoms include confusion, weakness, and palpitations.
Gastrinomas: Overproduction of gastrin leads to Zollinger-Ellison syndrome, characterized by severe peptic ulcers and diarrhea.
Glucagonomas: Excess glucagon causes weight loss, diabetes, and necrolytic migratory erythema (a distinctive skin rash).
VIPomas: Secretion of VIP leads to watery diarrhea, hypokalemia, and achlorhydria (Verner-Morrison syndrome).
Non-functioning Tumors: Often present late with symptoms like abdominal pain or jaundice due to mass effect.

Pulmonary NETs:

Symptoms: Cough, hemoptysis, wheezing, and recurrent pneumonia.

Carcinoid Syndrome: Less common but can occur if vasoactive substances bypass pulmonary degradation.

Pheochromocytomas and Paragangliomas:

Symptoms: Persistent or episodic hypertension, headaches, sweating, palpitations, and anxiety due to catecholamine excess.

Medullary Thyroid Carcinoma:

Symptoms: Neck mass, dysphagia, hoarseness, and elevated calcitonin levels leading to diarrhea and flushing.

Importance of Early Detection: As emphasized by Wells et al., early diagnosis improves outcomes (*Wells SA Jr et al., Thyroid*, 2015).

Peptide Receptor Radionuclide Therapy (PRRT)

A significant advancement in treating metastatic NETs is Peptide Receptor Radionuclide Therapy (PRRT).

Mechanism of PRRT

PRRT involves administering a radiolabeled somatostatin analog, such as Lutetium-177 DOTATATE. NET cells often overexpress somatostatin receptors, particularly subtype 2 (SSTR2). The therapy works by:

Targeted Delivery: The radiolabeled peptide binds specifically to SSTR2 on tumor cells.
Radiation Emission: Once bound, it emits beta radiation, inducing DNA damage and cell death in the tumor.
Minimal Impact on Healthy Tissue: Due to the targeted nature, surrounding normal cells are largely spared.

Efficacy of PRRT

Clinical studies, including the NETTER-1 trial published in *The New England Journal of Medicine*, have demonstrated PRRT's effectiveness. Patients receiving Lutetium-177 DOTATATE showed:

Improved Progression-Free Survival: Significant delay in tumor progression compared to those receiving high-dose octreotide.

Symptom Relief: Reduction in hormone-related symptoms, enhancing quality of life.

Tumor Regression: In some cases, substantial reduction in tumor size was observed.

PRRT is particularly beneficial for patients who have exhausted conventional therapies. It offers a new avenue for managing advanced NETs, especially those expressing high levels of somatostatin receptors.

Safety Profile

PRRT is generally well-tolerated. Common side effects include:

Transient Nausea and Vomiting: Usually mild and manageable.

Hematological Toxicity: Temporary decreases in blood cell counts, necessitating monitoring.

Renal Function: Kidneys are at risk due to radiopeptide excretion; co-infusion of amino acids helps protect renal tissue.

Long-Term Risks: Rare cases of myelodysplastic syndrome or leukemia have been reported, underscoring the need for long-term follow-up.

Integration into Multidisciplinary Care

The management of metastatic NETs requires a collaborative approach. PRRT fits into this paradigm by:

- Complementing Other Therapies: Can be used alongside surgery, somatostatin analogs, and targeted therapies like everolimus and sunitinib.

- Personalized Treatment Planning: Selection for PRRT depends on factors like receptor expression, renal function, and overall health status.

References:

- Modlin IM, et al. "Gastroenteropancreatic neuroendocrine tumours." *Lancet Oncol.* 2008.

- Wells SA Jr, et al. "Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma." *Thyroid.* 2015.

- Strosberg J, et al. "Phase 3 trial of 177Lu-Dotatate for midgut neuroendocrine tumors." *N Engl J Med.* 2017.

Also Read

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Frequently Asked Questions

What are Neuroendocrine Tumors (NETs)?

NETs are a diverse group of tumors arising from neuroendocrine cells dispersed throughout the body. These cells produce hormones and neurotransmitters, leading to various clinical symptoms.
Where do NETs commonly originate?

NETs can originate in multiple organs, including the gastrointestinal tract, pancreas, lungs, adrenal glands, thyroid gland, and skin.
What are the primary types of NETs?

The main types include:
- Gastrointestinal Neuroendocrine Tumors (GI-NETs): Found in the stomach, small intestine, appendix, colon, and rectum.
- Pancreatic Neuroendocrine Tumors (PanNETs): Originating from the islet cells of the pancreas.
- Pulmonary Neuroendocrine Tumors (Lung NETs): Arising from neuroendocrine cells in the lungs.
- Pheochromocytomas and Paragangliomas: Found in the adrenal medulla and extra-adrenal paraganglionic tissue.
- Medullary Thyroid Carcinoma (MTC): Originating from parafollicular C cells of the thyroid gland.
- Merkel Cell Carcinoma: A rare, aggressive skin cancer from Merkel cells.
Can PRRT be repeated or combined with other treatments?

PRRT can sometimes be repeated and may be combined with other treatments based on individual patient needs and response.
What follow-up is necessary after PRRT?

Regular monitoring of blood counts and renal function is essential, along with long-term follow-up to detect any delayed side effects.
Is PRRT available worldwide?

PRRT is available in many countries but may be limited to specialized centers with the necessary facilities and expertise in nuclear medicine.
What symptoms do metastatic NETs cause?

Symptoms vary but can include flushing, diarrhea, abdominal cramping, wheezing, heart valve issues, hypoglycemia, severe peptic ulcers, weight loss, hypertension, headaches, sweating, palpitations, neck masses, and skin rashes.
What is Carcinoid Syndrome?

A condition occurring in about 20% of GI-NET patients with liver metastases, caused by systemic release of serotonin and other substances. Symptoms include flushing, diarrhea, abdominal cramping, bronchospasm, and heart valve fibrosis.
How do Pancreatic NETs present clinically?

Functioning PanNETs: Secrete hormones like insulin, gastrin, glucagon, and VIP, causing specific syndromes such as hypoglycemia or severe ulcers.

Non-functioning PanNETs: Do not produce active hormones and often present late with mass effect symptoms like abdominal pain.
What are Pheochromocytomas and Paragangliomas?

Tumors that secrete catecholamines, leading to symptoms like persistent or episodic hypertension, headaches, sweating, palpitations, and anxiety.
What is Peptide Receptor Radionuclide Therapy (PRRT)?

PRRT is a targeted molecular therapy for treating metastatic NETs. It uses radiolabeled somatostatin analogs to deliver radiation directly to tumor cells, minimizing damage to healthy tissues.
How does PRRT work?

The therapy involves:

Targeted Delivery: Radiolabeled peptides bind to somatostatin receptors on tumor cells.

Radiation Emission: Bound peptides emit beta radiation, causing DNA damage and cell death.

Selective Action: Healthy tissues are largely spared due to the specificity for tumor receptors.
What are the benefits of PRRT for NET patients?

PRRT has shown to:
- Improve progression-free survival.
- Reduce hormone-related symptoms.
- Cause tumor regression in some cases.
- Enhance the overall quality of life.
What are the common side effects of PRRT?

Side effects are generally mild and may include:
- Transient nausea and vomiting.
- Temporary decreases in blood cell counts (hematological toxicity).
- Potential impacts on renal function, mitigated by amino acid co-infusion.
- Rare long-term risks like myelodysplastic syndrome or leukemia.
Who is a candidate for PRRT?

Patients with advanced metastatic NETs that overexpress somatostatin receptors and who have limited options with conventional therapies may be considered for PRRT.
How does PRRT fit into a multidisciplinary treatment plan?

PRRT complements other therapies such as surgery, somatostatin analogs, and targeted medications like everolimus and sunitinib, allowing for personalized treatment strategies.
What is the role of somatostatin receptors in NET treatment?

Many NETs overexpress somatostatin receptor subtype 2 (SSTR2), which PRRT targets, enabling selective delivery of radiation to tumor cells.
What is Carcinoid Heart Disease?

A condition resulting from long-term exposure to high levels of serotonin, leading to fibrosis of heart valves and potential heart failure in NET patients.
What precautions are taken to protect the kidneys during PRRT?

An infusion of amino acids is administered alongside PRRT to protect renal tissue from radiation exposure during radiopeptide excretion.
What is the success rate of PRRT in treating NETs?

Clinical trials have demonstrated significant improvements in progression-free survival and symptom management, though individual responses may vary.
How does PRRT improve the quality of life for NET patients?

By targeting and reducing tumor burden and alleviating hormone-related symptoms, PRRT can significantly enhance patient well-being and daily functioning.
What are the limitations of PRRT?

Not all NET patients are suitable candidates; effectiveness depends on somatostatin receptor expression, and there are potential risks requiring careful patient selection and monitoring.
What are the long-term outcomes for patients treated with PRRT?

Long-term outcomes are generally positive, with many patients experiencing prolonged disease control and symptom relief, but ongoing research continues to evaluate extended benefits and risks.
Are there alternative treatments if PRRT is not suitable?

Alternatives include surgical resection, systemic therapies like chemotherapy, targeted therapies, and symptomatic management with medications.
How important is early detection of NETs?

Early detection can improve treatment outcomes and may allow for surgical removal before metastasis, emphasizing the need for awareness of NET symptoms.

Consult Dr Ishita B Sen

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