Neuroendocrine Tumor Treatment in India | PRRT and Nuclear Medicine

1. 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.

2. WHAT IS PSMA?

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.

PSMA is an excellent target for both Radionuclide Imaging & Therapy of Prostate Cancer for several reasons:

It is expressed in practically all Prostate Cancers in all stages of the disease
It gets upregulated in hormonerefractory or metastatic disease
It is an integral cell membrane protein and not released into circulation
The PSMA is internalised after Antibody Binding (Receptor-mediated Endocytosis)

3. 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.

4. 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. The patient is usually hydrated by intravenous fluids before and after the administration of the Lu177 PSMA over a period of 24 hours.

5. 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. Usually, these side effects are mild and transient and recover spontaneously without any active treatment. The chances of serious or life-threatening complications are extremely rare

6. 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. Nearly all patients demonstrate a reduction in pain and an improvement in global health by the second dose of therapy.

7. 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.

The therapy is offered to patients of Advanced Castration-resistant Metastatic Prostate Cancer with evidence of tumour progression are eligible for this therapy. Cancer progression may manifest as :

Rising Serum PSA levels
Increase in the size or number of the metastatic lesions on CT/MRI or Ga68 PSMA scans
Increasing pain or other worsening symptoms due to the disease
Lu177 PSMA Therapy cannot be given to patients in case of
Severe renal insufficiency
Severe haematological compromise

8. 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. The average dose of Lu PSMA Therapy administered is in the range of 5.5-11GBq per treatment and the doses are based on pre-treatment dosimetry (Dosimetry is the measurement, calculation and assessment of the ionising radiation dose absorbed by the human body).

For treatment, the patient is admitted in the hospital in a Specialised High Dose Radioisotope Therapy Unit for monitoring and radiation protection.

9. WHY SHOULD I CHOSE THE NUCLEAR MEDICINE THERAPY CENTRE 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. All cases are discussed in a multidisciplinary tumor board and an entire team of specialists from different specialties actually looks after the patient. The patient outcomes of the center are at par with the best centers of the world.

10. WHAT IS TARGETED ALPHA PSMA THERAPY?

Targeted Alpha PSMA Therapy is a targeted, selective internal cellular level radiotherapy to control advanced prostrate and cancer. Targeted Alpha PSMA Therapy uses alpha-emitting radioisotopes like Actinium 225 and is a safe, effective therapy with very minimal side-effects. Being highly selective, targeted alpha therapy, often called Magic Bullet therapy has the potential to revolutionize the way metastatic prostate cancer is treated in the future.

The Nuclear Oncology Experts Team operating out of Fortis Memorial & Research Institute (FMRI), Gurugram, Haryana, India was the pioneer of this therapy in India and Asia. The centre is currently the only centre performing this therapy in India on a regular basis.

11. WHAT ARE THE SIDE-EFFECTS OF TARGETED ALPHA PSMA THERAPY?

The most common side-effect of Targeted Alpha PSMA Therapy is dry mouth (Xerostomia), While some patients may find it distressing, most patients do not report a very significant impact on their lifestyle due to the xerostomia.

There is usually no bone marrow suppression, nor any damage to the kidney or liver functions due to targeted Alpha PSMA therapy.

12. WHERE IS THE AC225 SOURCED FROM?

The Actinium 225 is sourced from Mssrs ITG Germany. The product is approved by the European Medicines Association as well as the Indian Pharmacopia. The highly purified peptides are sourced from ABX Germany. The labelling of Actinium 225 with the peptide is done in house using Good Manufacturing Techniques. The highest standards of quality assurance are maintained at every level.

13. WHAT ARE THE BENEFITS FROM TARGETED ALPHA PSMA THERAPY?

After completing almost 50 treatment cycles at the centre, the Nuclear Oncology Experts Team is extremely excited with the initial results. With each therapy cycle, most of the patients who have undertaken the treatment have experienced a remarkable improvement in their quality of life with reduced symptoms and pain. Apart from this, the team has also seen an associated biochemical response with a fall in serum PSA levels, indicating a reduction in total tumour burden in the body. Most patients also show a prolonged duration of response with a few patients being in near-complete biochemical and clinical remission for over a year. They continue in clinical remission and as more time goes by the impact of Ac225 PSMA Therapy on the overall survival of patients would become clearer.

The team has performed Ga68 PSMA scans before the next due cycles to monitor radiological responses and have witnessed some encouraging results – nearly 70% tumour reduction in a single cycle in some patients.

14. WHAT IS PRRT AND HOW DOES IT WORK?

PRRT - Peptide Receptor Radionuclide Therapy, also known as Radioisotope Therapy, is a molecular therapy that is used to treat a specific type of cancer called Neuroendocrine Carcinoma or NETs (Neuroendocrine Tumours).

In PRRT, a cell-targeting protein (or peptide) is combined with a small amount of radioactive material, or radionuclide, creating a special type of radiopharmaceutical called a Radiopeptide. When this radiopeptide is injected into the patient’s bloodstream, it travels to and binds itself to the neuroendocrine tumour cells and delivers a high dose of radiation to cancer.

In PRRT, Yttrium 90 (Y-90) and Lutetium 177 (Lu-177) are the most commonly used radionuclides.

15. WHAT CONDITIONS ARE TREATED WITH PRRT?

PRRT or Peptide Receptor Radionuclide Therapy may be used to treat patients with Neuroendocrine Tumours (NETs) including:

Carcinoids
Islet Cell Carcinoma of the Pancreas
Small Cell Carcinoma of the Lung
Pheochromocytoma (a rare tumour that forms in the adrenal glands)
Gastro-enteropancreatic (stomach, intestines, and pancreas) Neuroendocrine Tumours, and
Rare Thyroid Cancers that are unresponsive to treatment with radioiodine.

16. WHEN WOULD THE DOCTOR CONSIDER USING THIS THERAPY?

Doctors might consider this therapy as an option for patients who

have advanced and/ or progressive Neuroendocrine Tumours.
are not candidates for surgery.
have symptoms that do not respond to other medical therapies.

17. WHAT IS THE MAIN GOAL OF PRRT?

The main goals of PRRT are:

To provide symptom relief,
To stop or slow down the tumour progression, and
To improve overall survival

18. WHAT ARE THE ADVERSE EFFECTS OF THE THERAPY?

While the administration of the PRRT is well tolerated, some patients might experience nausea and vomiting during the amino acid infusion that is managed with anti-nausea medication.

19. HOW IS PRRT PERFORMED?

Depending on the type of cancer being treated and the medical facility performing the procedure, patients may need to undergo up to 10 PRRT sessions (usually there would be around four-six sessions) spaced two to three months apart.

The procedure may be done an outpatient procedure or may require a few days of hospital stay depending upon the type of radionuclide being used.

Each PRRT session begins with an Amino Acid Solution delivered intravenously. This is done to protect the patient’s kidneys from the effects of radiation. The radiopeptide is then injected into the patient and that is followed by an additional Amino Acid Solution. The session lasts for approximately four hours.

In some cases, Molecular Imaging Scans may be taken during and following the treatment process to see where the injected radiopeptide has traveled in the body.

20. WHAT ARE THE ADVANTAGES OF PRRT?

PRRT and other such molecular therapies offer a more personalised cancer treatment as the radiopharmaceuticals can be tailored to the unique biological characteristics of the patient and the molecular properties of the tumour.
PRRT is also considered a targeted therapy as the radiopeptides are highly selective in their ability to damage the neuroendocrine tumour cells while limiting radiation exposure to the healthy tissues.
Also, since PRRT can target the neuroendocrine tumour cells while not affecting the healthy tissues, it has milder adverse effects as compared to chemotherapy.

While PRRT is a treatment option that is extremely effective in controlling Advanced Progressive Neuroendocrine Tumours, it is not a curative procedure. However, it has shown to help relieve symptoms and slow the progression of the disease.

21. HOW SAFE IS PRRT?

PRRT, like any other therapy, has some adverse effects and risks. It is advised that patients discuss the risks and benefits of PRRT with the Specialist Doctors at the centre. The doctors at the centre will determine whether the therapy is right for the patient given the patient’s medical history. It is also advised that the patients should inform the team of any prior therapies as it can play a role in determining the correct therapy and dosage.

22. WHAT IS TARGETED ALPHA PRRT THERAPY?

Alpha PRRT is based on the use of specific peptides and monoclonal antibodies, labelled with alpha-emitting radionuclides like Actinium (Ac225) or Bismuth(Bi213) or Lead(Pb212). The conjugated molecules target the cancer cells through the specific receptors which are located on the surface of the cancer cells and can selectively bind to these receptors. Once attached, these alpha-emitting radiomolecules destroy the cells by delivering radiation which kills the cells. Alpha particles have a high energy in the range of 5-9 MeV and at the same time a very short path length in human tissue below 0.1 mm, corresponding to less than 10 cell diameters. Consequently, the use of alpha emitters allows the specific targeting and killing of individual malignant cells, while minimizing the toxicity to surrounding healthy tissue.

23. HOW IS ALPHA PRRT BETTER THAN CONVENTIONAL PRRT

Targeted alpha PRRT has the potential to overcome many of the limitations of conventional Lu177 PRRT. As the alpha particles are more energetic than the B particles used in conventional PRRT, the alpha particles induce damage such as double-stranded DNA breaks and base chemical modifications. Unlike the damage caused by the beta particles, the kind of damage caused by the alpha particles is difficult to repair by the cancer cell, leading to more rapid cell death. Targeted alpha therapy thus has the ability to overcome the radioresistance to beta particles therapy. Also since the range of the alpha emitters is in millimeters in tissue, the surrounding normal tissue is unaffected by alpha emitters. Targeted alpha therapy often called the magic bullet therapy thus is an excellent alternative to treat patients of Neuroendocrine Tumours, especially those who either do not respond to Lu177 PRRTtor have become resistant to conventional PRRT

24. SO IS TARGETED ALPHA PRRT AVAILABLE FOR PATIENTS?

Currently the Nuclear Medicine Therapy Unit at Fortis Memorial Research Institute, Gurugram is the only centre offering targeted Alpha PRRT in India. Targeted Alpha PRRT is available to patients as a salvage therapy with due consent under the Paragraph 37 of the Helsinki Declaration of Therapies of unproven efficacy. What this means is that though there are small studies which prove the efficacy of targeted Alpha PRRT, the quantum of studies is still too small to prescribe Targeted Alpha PRRT as a standard conventional therapy. Nevertheless in patients who have exhausted or are ineligible for conventional therapies and the treating physician as well as the patient is convinced that the patient may benefit from this therapy, Alpha PRRT is offered as an option. The patient’s clinical condition, prior treatments and responses as well as the current clinical situation are meticulously scrutinised by a multidisciplinary tumour board before considering a patient for alpha PRRT. Alpha PRRT is not offered as a clinical trial.

25. HOW IS IT DONE?

Just like Conventional PRRT, targeted alpha PRRT is administered as an intravenous infusion. The patient is admitted in the hospital in a special high dose therapy unit. An intravenous cannula is placed in the forearm. A special amino acid infusion is administered prior to the Alpha PRRT infusion to protect the kidneys. An anti emetic injection is administered as some patients experience nausea due to the amino acid infusion. The alpha PRRT drug is administered over a period of 20 mins.

26. WHAT ARE THE ADVERSE EFFECTS?

Targeted Alpha PRRT is very well tolerated. Some patients experience some nausea during the infusion and for a few days after the treatment. Usually the nausea is mild an controlled by taking standard anti nausea medicine. There are some reports of delayed mild derangement of renal function though there are no reports of any patient going into permanent renal failure. There is also practically no haematological toxicity noted.

27. HOW ARE THE CLINICAL OUTCOMES OF ALPHA PRRT

Alpha PRRT is administered with a palliative intent. The aim of the treatments is to achieve disease stabilisation with an attempt to improve the progression free survival. In our experience with alpha PRRT over the past two years nearly 75 – 80% patients demonstrate disease stabilisation with most patients reporting a significant improvement in the quality of their lives. There is alleviation of pain, diarrhea with an improvement in the general well being of most patients. Studies have shown durable response with responses continuing for over 30 months after therapy.

28. WHAT IS IODINE MIBG THERAPY?

MIBG is short for Meta Iodo Benzyl Guanidine. High dose Iodine MIBG Therapy is a novel form of treatment for refractory high risk advanced neuroblastoma, a cancerous tumour that begins in nerve tissue of infants and very young children.

29. HOW DOES THE TREATMENT WORK?

MIBG concentrates in neuroblastoma cells and can be combined with radioactive iodine (I-131) to deliver targeted radiation therapy to the tumour cells. The beta emitting isotope, I-131, is used to deliver targeted radiation to neuroblastoma cells. The I-131 MIBG is absorbed by tumour cells, which are killed by radiation emitted by the radioactive I-131. While this therapy destroys the tumour cells, it spares the normal, healthy tissue.

There has been extensive research done with this type of treatment for patients with advanced neuroblastomas. Studies have shown that 30-40% of children with relapsed neuroblastoma respond to MIBG Therapy, and this makes it one of the most active agents for relapsed disease. While this therapy doesn’t cure neuroblastoma, the I-131 MIBG allows patients to gain control of their disease and provide the possibility of prolonged disease stabilisation.

30. WHAT ARE THE POTENTIAL RISKS AND ADVERSE EFFECTS OF I-131 MIBG?

Most of the adverse effects of I-131 MIBG are mild and the therapy is overall well tolerated.

LIKELY ADVERSE EFFECTS (Happens to 21-100 children out of every 100 children)

Decrease in the number of red and white blood cells and platelets made in the bone marrow. The patient may need blood and platelet transfusions and sometimes stem cell infusions are necessary.
Nausea
Dry mouth
Salivary gland irritation

LESS LIKELY ADVERSE EFFECTS (Happens to 5-20 children out of every 100 children)

Decrease function of the thyroid gland. This causes tiredness, weight gain, and constipation. Lifetime treatment with a medicine to supplement the thyroid gland may be needed.
Not being able to get pregnant or father a child.
High or low blood pressure during or after the I-131 MIBG infusion.
Thinning of hair.
Vomiting
Infection due to low white blood cells.
Fatigue due to low red blood cells.
Bleeding/ bruising due to low platelets.
Loss of appetite.

RARE ADVERSE EFFECTS (Happens to less than five children out of every 100 children)

Pain in the salivary glands or mouth.
Decreased function of the adrenal gland. This affects the activity level & growth, causes tiredness, weight changes, and blood pressure changes. The patient may need to take medicine to supplement the adrenal gland.
Decreased heart function.
Inflation of the liver – some of the radioactive I-131 MIBG is taken up by the liver and there is a possible risk of future liver damage.
A second cancer (such as, leukaemia) that is different from the kind of cancer which the patient has now.
Trouble breathing due to infection or damage to the lung (overactive thyroid gland).

The patient will need oral medication (Lugol’s Iodine) to prevent thyroid damage from the radioactive iodine contained in the I-131 MIBG compound. This medication will need to be taken before the treatment begins and will continue for a total of three weeks.

31. HOW IS I-131 MIBG THERAPY ADMINSTERED?

On the scheduled day of the therapy, the patient is admitted to a special room called the Nuclear Medicine Therapy Room or the Radioisotope Therapy Isolation Room. The I-131 MIBG is given through IV canula or by a central venous catheter over three to four hours. And, if required, IV fluids for hydration and other medications may be given.

Most of the I-131 MIBG accumulates in the neuroblastoma cells and the rest is excreted through the urine. Special precaution needs to be taken as this urine is radioactive. Other bodily wastes like saliva are radioactive as well. This makes the people around the patient vulnerable to radiation exposure. Speak to your doctor regarding precautions and safety measures that need to be taken.

The Radioisotope Therapy Isolation Room

Since the caregivers and other attending the patient receiving the I-131 MIBG Therapy are vulnerable to radiation exposure, the patient is admitted to a special high-dose radioisotope therapy isolation room.

The isolation room is a specially constructed room with lead lined walls and floors. Lead minimises the possibility of radiation exposure. The patient’s bed is also surrounded by portable lead sheets. The caregivers are always required to stay behind these lead shields.

The patient’s urine and other bodily wastes are also radioactive. These effluents are discarded through lead-lined pipes and are collected in a specially constructed decay tank submerged underground where they are stored till it’s safe to be released into the sewers.

The waste disposal bins are also lead-lined. The waste, such as soiled linen, diapers etc. are collected daily and taken to a specialised waste storage facility where it’s kept for a period of three months post which the waste can be disposed of as normal medical waste. A Radiation Safety Officer is responsible for monitoring the radiation levels on a daily basis.

32. WHAT IS THE ROLE OF CAREGIVER DURING AND AFTER THE I-131 MIBG THERAPY?

As a caregiver, the parents will need to play a very important role in providing day-to-day care and support:

Assisting the child with bathing and hygiene needs such as brushing teeth.
Giving all oral medications to the child.
Providing the child with an emesis basin when the child feels nauseous.
Helping the child with bathroom needs.

The team of doctors and the radiation safety personnel at the centre will work closely with the parents and help them with taking care of the child.

33. WHAT IS TRANSARTERIAL RADIOEMBOLISATION?

Transarterial Radioembolisation (TARE) consists of the delivering particles loaded with a radioactive compound directly into the liver. This is done by placing these particles super selectively into the artery supplying the liver. The hepatic artery is accessed through an angiography catheter inserted per cutaneously through a puncture in the groin. Radioactive compounds such as yttrium-90 microspheres or iodine131 or rhenium188 labelled Lipiodol may then be injected through this catheter, into the tumour in the liver.

34. WHO ARE THE PATIENTS WHO MAY BENEFIT FROM TARE?

TARE is used in the treatment of primary and metastatic HCC and cholangiocarcinoma. TARE in combination with chemotherapy is also a very effective therapy in the treatment of colon cancer with secondaries in the liver.

35. IS TARE THE SAME AS TACE?

TACE is Transarterial Chemoembolisation where chemotherapy loaded particles into the liver. TACE is effective only in small liver tumours or where there are only one or two secondaries in the liver while TARE can be used even in situations where there is a large tumour in the liver or multiple tumours in the liver. While TACE is less expensive than TARE, the post procedure side effects of TACE may be slightly more severe than TARE.

36. WHAT ARE THE SIDE EFFECTS OF TARE?

Typically TARE is well tolerated. There may be some transient pain in the upper abdomen. In very few cases where there is extensive liver involvement there may be a worsening of the liver function tests and in rare instances an acute liver failure. However complications are extremely rare, with the incidence of serious complications being less than 1%.

37. WHY SHOULD I CHOOSE FMRI FOR THE PROCEDURE?

Having an experience of more than 14 years, the team at FMRI is adept at performing TARE procedures with response and complication rates at par with the best centres of the world. Also due to the vibrant technological support to the team, they have access to both Y90 Sirspheres as well as I-131 lipiodol. While Y90 Sirspheres is commercially available, is imported from Australia. Iodine 131 lipiodol is labelled in house using extremely strict quality assurance protocols. While the efficacy and adverse effects of both tracers is similar, Iodine 131 lipiodol is far cheaper than Y90 Sirspheres. Iodine Lipiodol is available at very select centres across the world, FMRI being one of them, as it requires a high degree of technical expertise to label and administer.

38. WHAT ABOUT RESPONSE RATES OF TARE?

Response rates depend of multiple factors, whether the tumours are primary cancers of the liver or secondaries from another cancer. How big are the tumours, how much of the liver is involved by the tumour, the tumour biology and the general condition of the patient. Treatments are personalised based on all these factors. Each case is discussed in a multidisciplinary tumour board consisting of medical oncologists, radiation oncologists and surgeons to ensure that best clinical practice protocols are followed.

39. HOW IS THE PROCEDURE DONE?

The interventional radiologist and the Nuclear Medicine Expert first study the triple phase CT scan of the patient to ascertain feasibility of performing TARE. Then the patient is admitted for a day or in the day care for a hepatic angiography. Hepatic angiography involves inserting an angiographic catheter through a puncture in the groin to visualise the arterian anatomy of the patients liver. Some vessels may also need coiling to ensure that the radioactive particles are delivered specifically to site of the tumour and do not run off into the other organs due to any errant vessels. The interventional radiologist while doing the angiography injects a radioactive substance called Tc99m MAA which helps him simulate the exact distribution of the TARE particles in the liver even before the actual injection of TARE particle. The patient is subsequently discharged from the hospital while the interventional radiologist and the nuclear medicine expert study the patients images to plan the procedure and calculate the dose which needs to be delivered. It typically takes about a week to order the dose. In a second round the patient is admitted again, an angiography catheter is again placed in the liver artery and this time the actual TARE pharmaceutical is injected. The TARE particle finds its way to the tumours in the liver and get trapped there, emitting radiation to the tumour and killing it slowly.

40. WHAT HAPPENS AFTER THE PROCEDURE?

The patient usually needs to stay in the hospital for 2-3 days after the TARE procedure, primarily because the radioactive material administered to the patient renders the patient radioactive for some time and he needs to be kept in relative isolation to protect the attendants and the general population from uneccesary radiation exposure.

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