LUTETIUM-177 DOTA-TATE THERAPY
Indication
Lu-177 DOTA-TATE therapy is indicated for the treatment of neuroendocrine tumors where other treatment options such as surgery or chemotherapy are inappropriate or ineffective.
What is the Lutetium-177 DODA-TATE ?
Neuroendocrine tumors (NET); They are rare cancers that can occur anywhere in the body, especially in the intestine, pancreas and lungs. This heterogeneous group of malignancies is often accompanied by overexpression of somatostatin receptors (SSTR).
Theranostic is a new and emerging field in the medical world. It is based on the realization of imaging and treatment on a single system, allowing the specific treatment and follow-up of treatment simultaneously.
In Neuroendocrine tumors, Ga-68 DOTA-TATE PET / CT can visualize tumoral tissues with high sensitivity, and Lu-177 DOTA-TATE can perform specific and targeted treatment of tumoral tissues. This is a very successful and new method for theranostic applications.
How does Lutetium-177 DODA-TATE Treat?
Radiolabelled somatostatin analogs bind to somatostatin receptors, with the highest affinity for SSTR type 2, and internalize after binding to somatostatin receptor-expressing cells, including somatostatin receptor-positive malignant tumors.
While NETs can be imaged using Gallium-68 labeled somatostatin analogs (Ga-68 DOTA-TATE etc.), they can also be treated with analogs labeled with beta radiation emitting radionuclides such as Lutetium-177 (Lu-177 DOTA-TATE etc.).
Lu-177 DOTA-TATE therapy can also be referred to by different names such as “targeted radionuclide therapy”, “peptide receptor radionuclide therapy (PRRT)” “somatostatin receptor radioligand therapy”.
Labeled peptides are administered to patients intravenously. Peptides that bind to the surface of neuroendocrine tumors with DOTA-TATE, and Lutetium-177 directly apply a high dose of local radiotherapy to the tumor. Beta radiation of lutetium-177 induces cellular damage by creating free radicals in somatostatin receptor positive cells and neighboring cells.
The purpose of Lu-177 DOTA-TATE therapy is to slow or stop tumor growth and reduce some of the symptoms caused by the tumor. Lu-177 DOTA-TATE treatment usually consists of four cycles administered 8 to 12 weeks apart.
The NETTER-1 study showed a longer progression-free survival in midgut NET patients treated with 4 cycles of Lu-177 DOTA-TATE at 8-week intervals, and enabled Lu-177 DOTA-TATE therapy to be approved in NET patients.
Who is Lutetium-177 DOTA-TATE Treatment applied?
Lu-177 DOTA-TATE is a highly specific treatment modality approved by the FDA for NETs patients. The treatment is conventionally applied as 4 cycles at 8-week intervals.
Lu-177 DOTA-TATE is primarily used in the treatment of NETs patients where other treatment options such as surgery or chemotherapy are inappropriate or ineffective.
Studies show that Lu-177 DOTA-TATE can improve life expectancy and quality, alleviate symptoms and complaints in NET patients.
When this treatment is considered, Ga-68 DOTA-TATE PET/CT scan should be performed in order to determine the positivity of somatostatin receptors in tumors and metastases and to evaluate the suitability of the patients for this treatment.
Is Lutetium-177 DOTA-TATE Treatment safe?
NET patients receiving Lu-177 DOTA-TATE treatment experience minimal and less severe long-term side effects compared to other cancer treatments.
The radiation used in this treatment is designed to directly damage and kill cancer cells. Since most of Lu-177 DOTA-TATE goes to tumor tissue, damage to healthy tissues is minimal.
However, as radiation can affect the kidney and bone marrow, patients are followed up with post-treatment blood tests.
Side effects related to treatment can be examined under two headings :
- Treatment-related possible side effects
Nausea: Usually only on the day of treatment.
Tumoral inflammation: It can cause an increase in pain, which can be seen in patients with tumors in the bone, liver or pancreas. This condition usually resolves within 72 hours of treatment. Low-dose steroid (dexamethasone) can be used to help reduce this. However, it would be beneficial to take regular pain medications more regularly.
Increase in symptoms: It can cause a temporary increase in the intensity of daily symptoms such as flushing, sweating, palpitations, or wheezing, and an increased frequency of existing diarrhea. This picture usually stabilizes within 24-48 hours. The dose of antidiarrheal medication used may need to be increased.
Temoparary Hair Loss : May be seen in some patients, returns to normal after Lu-177 DOTA-TATE treatment is completed..
Weakness: It can be felt for several weeks after each course of treatment..
2. Radiation dosage related side effects
Although healthy normal cells show a very low amount of Lu-177 DOTA-TATE uptake compared to tumor tissue, the side effects of radiation can also damage these cells. Radiation can also partially affect non-tumor parts of the body, especially the bone marrow and kidneys. This may cause discomfort or be more susceptible to infection a few weeks after treatment. Therefore, patients will need to have regular blood tests after each course of treatment. Secondary myelodysplastic syndrome and leukemia have been reported, although rarely.
Lutetium-177 DOTA-TATE and pregnancy
Since Lu-177 DOTA-TATE therapy contains radiation, it cannot be applied during pregnancy. Pregnancy testing is requested from all women of fertile age to rule out pregnancy before starting each course of Lu-177 DOTA-TATE. Both men and women are advised not to have children or become pregnant during their treatment and for at least six months after completing the treatment. During this time, reliable contraceptive methods should be used.
Preparation before Lutetium-177 DOTA-TATE Treatment
Evaluation of patient eligibility
The patients with NETs should be evaluated by the multidisciplinary NET committee, including oncology and Nuclear Medicine Specialists, in terms of the decision of suitability for Lu-177 DOTA-TATE treatment and the right timing. Potential treatment candidates must undergo a Ga-68 DOTA-TATE PET/CT scan to demonstrate the presence of adequate SSTR. Traditionally, a higher level of Ga-68 DOTA-TATE uptake in lesions than liver involvement is considered an eligibility condition for Lu-177 DOTA-TATE therapy. The blood tests listed below should be checked shortly before treatment planning, typically 2 weeks before each cycle.
BUN (blood urea nitrogen)
Creatinine
GFR (glomerular filtration rate)
Serum Albumin
ALP (alkaline phosphatase)
AST (aspartate aminotransferase)
ALT (alanine aminotransferase)
Total bilirubin
White blood cell count
Hemoglobin (HGB)
Platelet count
Recommended laboratory threshold values for Lu-177 DOTA-TATE therapy
|
Lab testing |
Acceptable value before first treatment |
|
Hemoglobin |
> 8 g/dL |
|
White blood cell count |
> 2.000 /mm3 |
|
Platelet count |
> 70.000 /mm3 |
|
GFR |
> 50 mL/min |
|
Total bilirubin |
≤ 3 X upper limit of normal |
|
Serum albumin |
> 3.0 g/dL |
Somatostatin Analog (SSA) Therapy
SSAs are often used in the treatment of NETs patients and are typically administered in a long-acting depot form (Sandostatin LAR, etc.) every 4 weeks.
It is recommended that Lu-177 DOTA-TATE therapy be scheduled at least 4 weeks after the last long-acting SSA treatment to avoid interference with SSTR binding. For this purpose, applying the Lu-177 DOTA-TATE treatment course in the days just before the long acting SSA injection can be a practical solution. In symptomatic patients using short-acting SSAs, this treatment should be stopped at least 24 hours before Lu-177 DOTA-TATE administration. Subsequent SSA doses can be administered within a few hours after completion of Lu-177 DOTA-TATE treatment.
Although it is recommended that patients use SSAs for up to 18 months after Lu-177 DOTA-TATE treatment, there are no clear data to support or refute this recommendation.
How does Lutetium-177 DOTA-TATE treatment process progress?
Patient preparation
Preferably, two separate vascular accesses are opened in both antecubital fossa, one for the administration of Lu-177 DOTA-TATE infusion and the other for the administration of amino acid solution. If this is not possible, the two infusions can be given on the same line.
Although the central venous catheter can be used for premedication and amino acid solution administration, the use of a peripheral intravenous line is recommended for Lu-177 DOTA-TATE. During the infusion of both agents, the patency of the vascular access should be closely monitored in terms of serious local reactions that may develop due to extravasation.
Antiemetic drugs
Before the procedure, it is important that the patient is adequately informed about nausea and vomiting. Nausea and vomiting are common during amino acid infusion when the infusion rate is above 250 mL / hour.
Therefore; Administration of an intravenous premedication regimen consisting of 5-HT3 antagonist (granisetron, ondansetron, palonosetron etc.), neurokinin 1 (NK1) receptor antagonist (aprepitant, etc.) and H2 receptor antagonist (famotidine, etc.) recommended 30 minutes before amino acid infusion. While the amino acid infusion rate is increased to the target of 320 mL / hour, an additional dose of 5-HT3 antagonist may be required with the addition of D2 receptor antagonist (domperidone etc.).
Steroids such as dexamethasone can be administered after Lu-177 DOTA-TATE infusion.
Amino acid solution
An amino acid solution containing lysine and arginine is administered before, during and after Lu-177 DOTA-TATE infusion to reduce reabsorption of Lu-177 DOTA-TATE through the proximal renal tubules and thus reduce the renal radiation dose. Combining the treatment with an amino acid solution reduces the mean radiation dose in the kidneys by 47% and increases the mean beta phase blood clearance by 36%.
Currently, a high amino acid concentration commercial solution containing the correct arginine and lysine concentration is available. However, these solutions cause high osmolarity associated with the presence of additional amino acids, resulting in nausea and vomiting during infusion.
Amino acid acid solution properties
|
Lysine |
18-24 g |
|
Arginine |
18-24 g |
|
Volume |
1.5 ile 2.2 L |
|
Osmolarity |
<1050 mOsmol |
The target infusion rate of amino acid solutions should reach 320 mL/hour. Typically, amino acid infusion is started 30 minutes before Lu-177 DOTA-TATE administration.
Lu-177 DOTA-TATE should not be administered until this rate has been reached or the amount of amino acid solution administered exceeds one eighth of the total amount. The amino acid solution should be infused simultaneously with Lu-177 DOTA-TATE and continued infusing at a rate of 320 mL / hr or higher until the total volume is administered. In routine practice, amino acid infusion is continued for at least 3 more hours after the application of Lu-177 DOTA-TATE.
Starting the amino acid solution infusion at a low rate of 100 mL/hr and slowly increasing it (eg 20-50 mL/hr every 15-20 minutes) is relatively successful in reducing side effects such as nausea or vomiting.
In cases where the Lu-177 DOTA-TATE dose is reduced, the amino acid solution dose should not be reduced.
Lu-177 DOTA-TATE administration
Gravity, infusion pump or syringe pump can be used for Lu-177 DOTA-TATE infusion. As a standard dose, 7.4 GBq (200 mCi) Lu-177 DOTA-TATE should be administered as an infusion in at least 30 minutes, bolus injection should never be done.
Timeline of administration of antiemetics, amino acid solution and Lu-177 DOTA-TATE during Lu-177 DOTA-TATE therapy. Antiemetics can be repeated as needed during amino acid infusion.
Dosage changes due to side effects
In patients with initial kidney, liver or bone marrow dysfunction and patients who developed toxicity during treatment, it may be necessary to modify the doses of Lu-177 DOTA-TATE administered.
In patients with pre-existing toxicity, a reduced administration dose or longer waiting times between two cycles may be considered.
Bone marrow toxicity is the most common side effect that occurs during treatment. In patients with more than first degree myelosuppression, treatment may be delayed, a lower activity (eg 3.7 GBq [100 mCi]) used for the next course of therapy, or permanently discontinued to allow recovery of bone marrow function. Most of the time, thrombocytopenia resolves late.
Renal and liver toxicity is rarely seen during treatment, but when patients develop Lu-177 DOTA-TATE-associated toxicity (e.g. high bilirubin or decreased renal function), treatment should be interrupted until toxicity has resolved.
Dosage Change Recommendations
|
Renal dysfunction – before treatment |
|
|
Mild to moderate (Creatinine clearance 30-70 mL/min) |
No dose adjustment is required, however, patients may be at greater risk of toxicity. Kidney functions should be evaluated more frequently. |
|
Severe (creatinine clearance <30 mL/min) or end- grade renal disease |
Not studied |
|
Liver dysfunction – before treatment |
|
|
Mild – Moderate |
No dose adjustment is required. |
|
Severe (Total bilirubin> 3 X upper limit of normal and any AST) |
Not studied |
|
Thrombocytopenia |
|
|
2., 3. or 4. grade
|
Stop treatment until complete or partial recovery (0 to 1 grade). When there is improvement, continue the treatment at a low (3.7 GBq (100 mCi)) dose. After low dose ≥2. If 2nd grade thrombocytopenia does not develop, increase to the standard dose for the next dose (7.4 GBq (200 mCi)). ≥2. If grade thrombocytopenia develops, treatment is permanently discontinued as a 16-week break is required. |
|
2., 3. or 4. grade recurrence |
Treatment is stopped permanently. |
|
Anemia and neutropenia |
|
|
3.or 4. grade |
Stop treatment until complete or partial recovery (0-2. grade). When there is improvement, continue the treatment at a low (3.7 GBq (100 mCi)) dose. After low dose ≥3 grade If anemia or neutropenia does not develop, increase to standard dose for next dose (7.4 GBq (200 mCi)) ≥3. grade If anemia or neutropenia develops, treatment is permanently discontinued as a 16-week break is required. |
|
3. or 4. grade recurrence |
Treatment is stopped permanently. |
|
Renal toxicity |
|
|
Creatinine clearance <40 mL/min or 40% reduction from baseline creatinine clearance or 40% increase from baseline serum creatinine |
Stop treatment until complete recovery. When there is complete recovery, continue treatment at a low (3.7 GBq (100 mCi)) dose.
If renal toxicity does not develop after low dose, increase to standard dose for next dose (7.4 GBq (200 mCi)). If renal toxicity develops, treatment is permanently discontinued as a 16-week break is required.
|
|
Hepatotoxicity |
|
|
Total bilirubin> 3 X upper limit of normal or
Hypoalbuminemia (<30 g / L) with decreased prothrombin rate (<70%) |
Stop treatment until complete recovery.
When there is complete recovery, continue treatment at a low (3.7 GBq (100 mCi)) dose.
If no hepatotoxicity develops after low dose, move up to the standard dose for the next dose (7.4 GBq (200 mCi)).
If hepatotoxicity develops, treatment is permanently discontinued as a 16-week break is required. |
|
Other non-haematological toxicities |
Stop the treatment until complete or partial recovery (0-2 grade).
When there is improvement, continue the treatment at a low (3.7 GBq (100 mCi)) dose.
After low dose ≥3. If grade toxicity does not develop, increase to standard dose for next dose (7.4 GBq (200 mCi)).
≥3. If severe toxicity develops, treatment is permanently discontinued as a 16-week break is required. |
|
3. or 4. grade recurrence |
Treatment is stopped permanently. |
Potential reactions
Hormonal crisis (Carcinoid Crisis)
Neuroendocrine hormonal crises are caused by excessive release of hormones or bioactive substances and develop in 1% of all patients. It typically occurs during initial treatment or within 2 days following. Classical clinical manifestations include skin flushing, diarrhea, bronchospasm, and hypertension.
Hormonal crises are treated with intravenous high-dose somatostatin analogue, intravenous fluid, corticosteroids. Electrolyte disturbances may also need to be corrected in patients with diarrhea or vomiting.
Although it is not applied routinely, premedication is recommended for patients at high risk of crisis.
Subcutaneous Lu-177 DOTA-TATE infiltration
It is important to prevent subcutaneous infiltration and
- Testing intravenous line patency before administering Lu-177 DOTA-TATE,
- Direct observation of the area during the administration and
- If swelling or pain develops requires rapid intervention.
In case of infiltration, to facilitate the removal of Lu-177 DOTA-TATE from tissue;
- Hot application,
- Compression,
- Elevation can be applied.
Radiation safety
Contamination
Lutetium-177’s half-life of 6.6 days increases the likelihood of long-term contamination. Blood and urine are the main sources of contamination during and after Lu-177 DOTA-TATE administration.
Since Lu-177 DOTA-TATE is mainly excreted in the urine, attention should be paid to the prevention of urinary contamination during the first 3 days after treatment.
Discharge criteria
The patient should be given the necessary instructions at discharge to ensure that the radiation dose of community members is less than 5 mSv (500 mrem). Average radiation exposure is 1.8 ± 0.5 mrem / hour at 1 m immediately after treatment, and 0.9 ± 0.4 mrem / hour during discharge.
Radiation Safety Recommendations After Lu-177 DOTA-TATE Treatment
|
Time |
Recommendations |
|
|
Sleeping |
|
3 Days |
You should sleep in a separate bed and avoid close contact. The period should be extended for babies / children or pregnant partners. |
|
|
Urinating |
|
3 Days |
After each use, the toilet lid should be closed and flushed twice, sit down and use a separate towel while urinating to minimize / prevent splashes. |
|
|
General recommendations |
|
3 Days |
There should be at least 2 meters distance from other people. When necessary, adult individuals can be next to the patient at a maximum distance of 1 meter, not exceeding 1 hour a day.
Public transport and use of public environments should be minimized.
The patient starts work after 3 days, depending on his tolerance. |
Pregnancy
Lu-177 DOTA-TATE therapy is contraindicated during pregnancy as with other radionuclide treatments. Treatment; should be postponed until the birth or termination of pregnancy. Breastfeeding should be stopped for treatment and should not be started until 2.5 months after the last treatment. However, future children can be safely breastfed. Contraception should be used for 6 months after completion of the last course of therapy.
Toxicity
Bone marrow toxicity
Grade 3 and 4 thrombocytopenia and neutropenia occur in less than 5% of patients and resolve within 8 weeks. Grade 3 and 4 lymphopenia is more common, but rarely of clinical significance, as opportunistic infections associated with Lu-177 DOTA-TATE therapy have not been observed. The most important long-term haematological risk is myelodysplastic syndrome or acute leukemia occurring in the median 2 years after treatment, in an average of 2% to 3% of patients. There is not much that can be done to minimize bone marrow toxicity during treatment, however, the presence of chemotherapy prior to Lu-177 DOTA-TATE treatment is a possible risk factor for the development of toxicity.
Renal toxicity
Due to the renal excretion of Lu-177 DOTA-TATE, the kidneys are exposed to high amounts of radiation. On the other hand, simultaneous administration of amino acids to protect the kidneys considerably reduces the renal toxicity rates. The incidence of long-term 3rd-4th grade renal toxicity is less than 2%.
Individual differences in renal radiation sensitivity can be observed in patients. For example, patients with longstanding diabetes or hypertension are at higher risk of developing renal toxicity after Lu-177 DOTA-TATE therapy. However, using current practice guidelines, serious renal toxicity is rare (<5%).
Patient follow-up
Follow-up of the patients after Lu-177 DOTA-TATE treatment is an important part of the treatment plan. Recommended monitoring includes clinical evaluation to assess symptoms and identification of possible therapeutic sequelae, laboratory tests and imaging tests.
Clinical evaluation
The clinical evaluation by the primary physician / team should ideally be performed 1 month, 3 months, 6 months and 12 months after Lu-177 DOTA-TATE treatment. If there is no laboratory abnormality or clinical symptom after the treatment, the patients can be followed up by the primary physician / team. NCCN guidelines recommend 3-12 month follow-up intervals according to the clinical picture. The presence of clinical symptoms that may suggest possible progression, increase in symptoms caused by carcinoid syndrome or the presence of sequelae after treatment require closer monitoring.
Laboratory tests
Approximately 1 month, 3 months, 6 months and 12 months after treatment, the following tests should be evaluated :
Complete blood count
ALP (alkaline phosphatase)
AST (aspartate aminotransferase)
ALT (alanine aminotransferase) AST
Total bilirubin
Serum albumin
Serum creatinine / GFR
If all blood tests are within normal limits, a complete blood count and serum creatinine levels should be measured at least once a year. More frequent monitoring is recommended if there are any abnormalities in blood tests.
Both secondary myelodysplastic syndrome and acute leukemia are rare known toxicities of Lu-177 DOTA-TATE. In patients with persistent cytopenia in blood tests, strict follow-up is recommended until improvement occurs. In addition, a hematology consultation should be considered for patients with persistent cytopenia.
Patients with mild to moderate renal impairment after Lu-177 DOTA-TATE therapy require closer monitoring with serum creatinine measurements. In addition, nephrology consultation should be considered in patients with persistent or worsening renal failure.
There are no specific recommendations for monitoring tumor markers after Lu-177 DOTA-TATE therapy. On the other hand, NCCN NET guidelines recommend monitoring for tumor markers every 3-12 months when clinically applicable.
Diagnostic imaging
Diagnostic imaging should generally be performed 1-3 months, 6 months, and 12 months after the completion of all treatment courses. NCCN guidelines recommend that patients be followed up every 3-12 months with contrast-enhanced abdominal and pelvic CT or MRI, as well as chest CT with or without contrast. Contrast-enhanced MRI should be considered first for patients with liver disease. A closer follow-up is recommended in patients with progressive disease, worsening of the clinical condition, or sequelae after treatment. If there is progression or suspicious findings on CT or MRI, Ga-68 DOTA-TATE PET / CT imaging should be considered.
It should be noted that the initial imaging study performed after the completion of Lu-177 DOTA-TATE therapy may be complicated by pseudoprogression. Because approximately 10% of patients with stable disease may experience a temporary increase in metastatic disease volume, possibly due to radiation-induced tumoral edema. Therefore, diagnostic imaging may be considered in patients with relatively aggressive tumors or clinical signs of progression during Lu-177 DOTA-TATE therapy.