The most frequent adverse effects with Lutathera were lymphopenia (44%), increased GGT (20%), vomiting (7%), nausea (5%), and elevated AST (5%). In the median follow-up of 24 months, 2.7% of patients in the Lutathera group reported to have myelodysplastic syndrome whereas the control group had no reports of myelodysplastic syndrome.

Policy:

(NOTE: For Medicare Advantage, please refer to the Medicare Coverage Section below for coverage guidance.)

I. Indications:

Lutetrium 177 dotatate is considered medically necessary in the treatment of select patients with low-, intermediate- or well-differentiated high-grade neuroendocrine tumors who have progressed on somatastatin-analogs (SSA) in the following setting:
A. Inoperable or metastatic somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs) of the pancreas, foregut. midgut and hindgut in adults.
B. Inoperable or metastatic somatostatin receptor-positive bronchopulmonary or thymic tumors in adults.

When ALL of the following criteria are met:
A. For neuroendocrine tumors pathology report documenting a Ki67 index < 20%
B. Positive somatostatin receptor scintigraphy with correlative Magnetic Resonance Imaging (MRI) or Computed Tomography (CT) imaging of metastatic measurable disease or 68-Ga-Dotate Positron Emission Tomography (PET) scan positive for metastatic disease
C. In the absence of metastatic disease, a surgical or medical consult documenting the reason for inoperability.
D. Progression of disease following treatment with SSA therapy.

A. Serum creatinine: > 1.7 mg per deciliter or creatinine clearance of < 50 ml/minute
B. Hgb: < 8.0 g/dl; WBC < 2000/mm3; platelets < 75,000 mm

A. The official manufacturers prescribing information, precautions and radiation safety instructions packaged with the medication should be fully reviewed and understood before using Lutetium-177.
B. This radiopharmaceutical should be used by or under the supervision of physicians with specific training in the use of radiopharmaceuticals who have been authorized and approved by the appropriate governmental agency.
C. Concerns about the use of this radiopharmaceutical include but are not limited to:
1. Radiation safety in handling the preparation
2. Pregnancy, lactation and precautions for both women and men of reproductive potential on appropriate contraception methods including embryo-fetal toxicity and risks of infertility
3. Risk from radiation exposure
4. Myelosuppression
5. Leukemia and Secondary Myelodysplastic Syndrome
6. Renal toxicity including use with renal impairment
7. Hepatic Toxicity including use with hepatic impairment
8. Neuroendocrine hormonal crisis: flushing, diarrhea bronchospasm, bronchoconstriction, hypotension, and other symptoms.
9. Pediatric and geriatric use

A. Users should read the manufacturer’s insert for all specific instructions as they could change as more experience is gained in the patient population.
1. The current recommended dose of Lutathera is 7.4 GBq (200 mCi) every 8 weeks for a total of 4 doses.
2. Users should familiarize themselves with the restrictions and usage of long and short acting octreotide agents before, during, and after Lutathera treatment as well as the manufacturer’s recommended use of anti-emetics and a specialized amino acid solution.
3. Users should be aware of detailed manufacturer's instructions on dosing or withholding of treatment for circumstances including, but not limited to, thrombocytopenia, anemia neutropenia, renal toxicity, hepatotoxicity, and possible other non-hematologic toxicities.

[INFORMATIONAL NOTE: Neuroendocrine tumors are relatively rare but appear to be rising in the U.S. with an incidence reported from 5.25 to 7.0 per 100,000 people. It is unclear as to whether this is a true increase or a better recognition of the entity or combination of these factors. They are classified by site of origin, stage, grade, and histologic classification. There appears to be a correlation between mitotic count and Ki67 proliferation. Additionally, these tumors may be classified as being functional or non-functional depending on their ability to secrete hormones or other peptides which are responsible for hypertension, flushing, diarrhea as documented in the carcinoid syndrome, or hyperinsulinemia and other associated syndromes.

Gastrointestinal Tumors: Over 60% of carcinoid tumors arise in gastrointestinal tract sites such as the stomach, small intestine, appendix and rectum which secrete serotonin, histamine and other substances. The portal circulation and its hepatic enzymes however rapidly metabolize most of these products. As such, only up to 25% of these tumors are responsible for the classic carcinoid and related syndromes, with the symptoms most likely due to liver metastases entering the circulatory system via the hepatic veins or other remote disease. Other common sites of metastases include the mesentery and peritoneum. Patients with non-secreting tumors usually are discovered at surgery after presenting with symptoms secondary to the presence of a mass lesion. Systemic treatment for metastatic disease has been with a somatostatin medication for control of tumor growth and hormonal secretion. Non-functioning tumors have few systemic options such as everolimus or trials of chemotherapy.

Pancreatic Neuroendocrine Tumors: There is an annual incidence of 1.8 per million in women and 2.6 per million in men. Approximately 60% are functioning tumors. Most pancreatic neuroendocrine tumors are sporadic. They are reported in several familial syndromes including, but not limited to, MEN1, MEN2, VHL, neurofibromatosis type 1, tuberous sclerosis, and Carney Complex. Pancreatic tumors occurring in MEN1 often have multiple tumors and require different management. Surgery is the mainstay for local and regional treatment. Debulking surgery has proven helpful in the management of more advanced disease. Systemic treatment options are similar to those mentioned above for gastrointestinal neuroendocrine disease. Systemic syndrome management and evaluation and treatment of inherited syndromes are best guided under current NCCN Guidelines™.

Recently, the FDA announced approval of Lutathera for treatment of neuroendocrine tumors arising from the foregut, midgut, hindgut and pancreas. The approval for this agent was based on two published studies NETTER 1 and the Erasmus Study.

In addition to the contraindications and precautions listed above, the use of Lutathera requires that long acting somatostatin analogs such as octreotide be discontinued for at least 4 weeks prior to the commencement of Lutathera treatment. Short-acting octreotide may be administered as needed but must be discontinued at least 24 hours before each Lutathera treatment. Currently, the prescribing information states that following Lutathera treatment long-acting octreotide 30 mg intramuscularly should be given every 4 weeks until disease progression or for up to 18 months following the commencement of Lutathera. The treating physician should be familiar with the prescribing information accompanying the Lutathera medication as information is subject to change by the manufacturer.

Additional prescribing information includes pre-medication with antiemetics and the use of a specialized amino acid infusion to significantly reduce the dose of radiation to the kidneys. Details of the time and method of administration, components, volume, and osmolarity may be found in the manufacturer’s prescribing information. The manufacturer has cautioned that this infusion should not be changed if the dose of Lutathera is reduced.

The FDA approval for the use of Lutathera is based on the results of two published studies. NETTER 1 compared treatment with Lutathera to octreotide in patients with inoperable, progressive somatostatin receptor-positive midgut carcinoid tumors. The study participants had tumors that had metastasized or were inoperable, and showed disease progression on either CT or MRI during treatment with LAR over the course of a period of 3 years during treatment with octreotide LAR. Eligibility included a Ki67 index of 20% or lower, OctreoScan uptake greater than or equal to that of the normal liver, creatinine clearance of 50 mL/min or greater, no prior treatment with Peptide Receptor Radionuclide Therapy (PRRT), and no prior external radiation therapy to more than 25% of the bone marrow. The primary outcome was progression free survival (PFS). A total of 229 patients were randomized to Lutathera 200 mCi for four infusions every 8 weeks concurrently with long-acting octreotide (30 mg) or high-dose octreotide alone (60 mg). Baseline characteristics were balanced between the groups. It was noted that 74% of patients had an ileal primary and 96% had metastatic disease in the liver.

At the data-cutoff date for the primary analysis, PFS at 20 months was 65.2% in the 177-Lu arm vs. 10.8% in the control group. The response rate was 18% in the 177-Lu group vs. 3% in the control group. In an updated analysis, progressive disease was seen in 23% of the 177-Lu group and 69% of the control group. Median PFS was not reached for the experimental group and was 8.5 months for the control group. Median overall survival (OS) was also not reached in the experimental group and was 27.4 months in the control arm. The authors concluded that for patients with progressive midgut neuroendocrine tumors treatment with 177LU-Dotatate resulted in a significantly longer progression-free survival and a significantly higher response rate than treatment with high dose octreotide LAR.

The ERASMUS study included 1214 patients who received Lutathera, 610 of whom were treated with a cumulative dose of at least 100 mCi for safety analysis. Another subgroup of 443 Dutch patients were treated with a cumulative dose of at least 600 mCi. The objective response rate (ORR) of the combined group was 39%. Stable disease was seen in 43%. PFS was 29 months. OS was 63 months. The group included not only gastrointestinal tumors but also pancreatic and bronchial neuroendocrine tumors. Toxicity included acute leukemia in 0.7% and myelodysplastic syndrome in 1.5%.]
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Horizon BCBSNJ Medical Policy Development Process:

This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.

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Index:
Radiation Treatment with Lutathera (Lutetium; Lu 177 dotatate)
Lutetium Lu 177 dotatate (Lutathera)
Lutathera (Lutetium Lu 177 dotatate)

References:
1. Bodei L, Ćwikla JB, Kidd M, Modlin IM. The role of peptide receptor radionuclide therapy in advanced/metastatic thoracic neuroendocrine tumors. J Thorac Dis 2017;9(Suppl 15):S1511-S1523. doi: 10.21037/jtd.2017.09.82

2. Brabander T, van der Zwan WA, Teunissen JJM, et al. Long-term efficacy, survival and safety of (177Lu-DOTA0,Tyr3) octreotate in patients with gastroenteropancreatic and bronchial neuroendocrine tumors. Clin Cancer Res. 2017 Aug 15;23(16):4617-4624.

3. FDA News Release: January 26, 2018: FDA approves new treatment for certain digestive tract cancers.

4. Highlighted and Full Prescribing Information revised 1/2018.

5. Ianniello A, Sansovini M, Severi, S, et al. Peptide receptor radionuclide therapy with 177Lu-DOTATATE in advanced bronchial carcinoids: prognostic role of thyroid transcription factor 1 and 18F-FDG PETEur J Nucl Med Mol Imaging (2016) 43: 1040.

6. Lo Russo, G, Pusceddu S, Prinzi N, et al. Peptide receptor radionuclide therapy: focus on bronchial neuroendocrine tumors. Tumor Biol. (2016) 37: 12991. https://doi.org/10.1007/s13277-016-5258-9

7. Mariniello, A., Bodei, L., Tinelli, C. et al. Eur J Nucl Med Mol Imaging (2016) 43: 441. https://doi.org/10.1007/s00259-015-3190

8. National Comprehensive Cancer Network (NCCN) Guidelines Version 1.2019 – March 5, 2019. Neuroendocrine and Adrenal Tumors. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines™) for Neuroendocrine Tumors Version 1.2019©. 2019 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines™ and illustrations herein may not be reproduced in any form for any purpose without the express written permission of the NCCN. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org.

9. Strosberg J, El-Haddad G, Wolin E, et al. Phase 3 Trial of 177Lu-Dotate for midgut neuroendocrine tumors. N Engl J Med. 2017 Jan 12;376:125-135.

10. U.S. National Library of Medicine Clinical Trials.gov: Identifier NCT01578239: a study comparing treatment with 177Lu-DOTA0-Tyr3-Octreotate to octreotide LAR in patients with inoperable, progressive, somatostatin receptor positive midgut carcinoid tumours (NETTER-1).

11. van Vliet EI, Krenning EP, Teunissen JJ, et al. Comparison of response evaluation in patients with gastropancreatic and thoracic neuroendocrine tumors after treatment with (177Lu-DOTA0,Tyr3) octreotate. J Nucl Med. 2013 Oct;54(10):1689-1696.

Codes:
(The list of codes is not intended to be all-inclusive and is included below for informational purposes only. Inclusion or exclusion of a procedure, diagnosis, drug or device code(s) does not constitute or imply authorization, certification, approval, offer of coverage or guarantee of payment.)

CPT*

A9699
A9513