Medical Policy: 06.01.38
Original Effective Date: May 2018
Reviewed: May 2019
Revised: May 2019
Benefit determinations are based on the applicable contract language in effect at the time the services were rendered. Exclusions, limitations or exceptions may apply. Benefits may vary based on contract, and individual member benefits must be verified. Wellmark determines medical necessity only if the benefit exists and no contract exclusions are applicable. This medical policy may not apply to FEP. Benefits are determined by the Federal Employee Program.
This Medical Policy document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy will be reviewed regularly and be updated as scientific and medical literature becomes available.
January 2018, the U.S. Food and Drug Administration (FDA) approved Lutathera® (Lutetium Lu 177 dotatate), a radiolabeled somatostatin analog indicated for the treatment of adults with somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs), including foregut (gastroduodenal), midgut (distal small intestine and proximal colon), and hindgut (distal colorectal and pancreas) neuroendocrine tumors.
Neuroendocrine cells are widely distributed throughout the body, and tumors arising from these cells can occur in most organs. GEP-NETs in the digestive system, including the tubular gastrointestinal tract and the pancreas (gastroenteropancreatic), are generally divided into two major categories, well-differentiated neuroendocrine tumors (NETs) and poorly differentiated (high-grade) neuroendocrine carcinomas. These two major categories of neuroendocrine tumors behave differently in terms of biologic aggressiveness and in approach to treatment.
Well-differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NETs), which have been referred to as carcinoid tumors or pancreatic islet cell tumors, are generally indolent, but all are potentially malignant, and the clinical course may be highly variable. Symptomatic disease may be due to either tumor bulk, including pain and/or bowel obstruction, or due to secretion of serotonin and other vasoactive substances, sometimes referred to as carcinoid syndrome.
The general treatment approach to well-differentiated GEP-NETs involves resecting potentially resectable disease, including metastasectomy (surgical removal of metastases). Unresectable, asymptomatic disease may involve observation, especially if tumor burden is limited, or initial therapy with a somatostatin analog if tumor burden is high. Unresectable, symptomatic disease usually involves initial therapy with a somatostatin analog (e.g. octreotide or lanreotide), and dose escalation as needed for control of symptoms of carcinoid symdrome and control of tumor growth. Patients with radiologic or symptom progression despite somatostatin analog therapy may benefit from non-curative debulking therapy or nonsurgical liver-directed therapy. Patients with more widespread disease that is not eligible for liver-directed therapy may benefit from systemic treatment with molecularly targeted agents, such as everolimus.
Lutathera® is a targeted form of systemic radiotherapy (radioactive drug), peptide receptor radionuclide therapy (PRRT) that binds to cell surface somatostatin receptors which may be present in certain tumors, and after binding to the receptor, the drug enters the cell allowing radiation to cause damage to the tumor cells. Most GEP-NETs express high-affinity receptors for somatostatin, and somatostatin-based imaging can provide information on tumor burden and location. Lutathera® has been proposed as a treatment option in adult patients with GEP-NETs who progress despite first-line therapy.
Lutathera® is given by intravenous infusion every 8 weeks for a total of 4 doses. It is a radiopharmaceutical and must be handled with appropriate safety measures to minimize radiation exposure.
Based on the product information label (2018) for Lutathera® (Lutetium Lu 177 dotatate), the common side effects include low levels of white blood cells (lymphopenia), high levels of enzymes in certain organs (increased GGT, AST and/or ALT), vomiting, nausea, high levels of blood sugar (hyperglycemia) and low levels of potassium in the blood (hypokalemia). Serious side effects include low levels of blood cells (myelosuppression), development of certain blood or bone marrow cancers (secondary myelodysplastic syndrome and leukemia), kidney damage (renal toxicity), liver damage (hepatotoxicity), abnormal levels of hormones in the body (neuroendocrine hormonal crises) and infertility. Lutathera® (Lutetium Lu 177 dotatate) can cause harm to a developing fetus; women should be advised of the potential risk to the fetus and to use effective contraception. Patients taking Lutathera® (Lutetium Lu 177 dotatate) are exposed to radiation. Exposure of other patients, medical personnel, and household members should be limited in accordance with radiation safety practices.
Early case series and retrospective studies report that treatment of advanced GEP-NETs with Lutathera® (Lutetium Lu 177 Dotatate) was associated with tumor response, improved survival outcomes (such as stable disease, tumor regression, or longer median time to progression), and quality of life (Delpassand and et. al. 2014; Ezziddin et. al. 2014; Sabet et. al. 2015).
The FDA approval for the efficacy of Lutathera® (Lutetium Lu 177 Dotatate) is based on the results of two published studies:
In January 2018, the U.S. Food and Drug Administration approved Lutathera® (Lutetium Lu 177 Dotatate) for the treatment of somatostatin receptor-positive GEP-NETs in adults, largely based on support from the NETTER-1 trial. This phase 3, open-label, randomized, multicenter clinical trial included 229 patients with advanced, progressive, well-differentiated midgut neuroendocrine tumors. The 229 patients were randomly assigned to receive either 177-Lu-Dotatate (116 patients) at a dose of 7.4 GBq every 8 weeks (four intravenous infusions, plus best supportive care including octreotide long-acting repeatable [LAR] administered intramuscularly at a dose of 30 mg) (Lu-Dotatate group) or octreotide LAR alone (113 patients) administered intramuscularly at a dose of 60 mg every 4 weeks (control group). The primary end point was progression free survival. Secondary end points included the objective response rate, overall survival, safety, and the side-effect profile. The final analysis of overall survival will be conducted in the future as specified in the protocol; a pre-specified interim analysis of overall survival was conducted and is reported here. At the data-cutoff date for the primary analysis, the estimated rate of progression-free survival at month 20 was 65.2% (95% confidence interval [CI], 50.0 to 76.8) in the Lu-Dotatate group and 10.8% (95% CI, 3.5 to 23.0) in the control group. The response rate was 18% in the 177-Lu-Dotatate group versus 3% in the control group (P<0.001). In the planned interim analysis of overall survival, 14 deaths occurred in the 177-Lu-Dotatate group and 26 in the control group (P = 0.004). Grade 3 or 4 neutropenia, thrombocytopenia, and lymphopenia occurred in 1%, 2%, and 9%, respectively, of patients in the 177-Lu-Dotatate group as compared with no patients in the control group, with no evidence of renal toxic effects during the observed time frame. The authors concluded treatment with Lu-Dotatate resulted in markedly longer progression-free survival and a significantly higher response rate than high-dose octreotide LAR among patients with advanced midgut neuroendocrine tumors. Preliminary evidence of an overall survival benefit was seen in an interim analysis; confirmation will be required in the planned final analysis. Clinically significant myelosuppression occurred in less than 10% of patients in the 177Lu-Dotatate group. (Funded by Advanced Accelerator Applications; NETTER-1 ClinicalTrials.gov number, NCT01578239)
Long-term safety and survival were evaluated in an investigator-sponsored, open-label, single-arm, single-institution (Erasmus) retrospective study of over 1200 patients with somatostatin receptor positive neuroendocrine tumors who received 177-Lu-Dotatate treatment. Primary tumor sites included bronchus, foregut, midgut, hindgut, pancreas and unknown. Patient populations were heterogeneous for baseline tumor status (progressive versus non-progressive) and treatments received prior to 177-Lu-Dotatate. Of these patients, the safety analysis included 610 patients, 360 (60%) of which had metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs), treated with a cumulative dose of at least 100 mCi (3.7 GBq) 177-Lu-Dotatate. Median follow-up was 78 months. Long-term toxicity included acute leukemia in four patients (0.7%) and myelodysplastic syndrome in nine patients (1.5%). There was no therapy-related long-term renal or hepatic failure. Overall response rate, defined as complete or partial response, in patients with midgut and pancreatic NETs with progressive disease at baseline was 84% and 81%, respectively. Median overall survival for GEP-NETs was only reported for pancreas (71 months [95% CI 56-86]) and midgut (60 months [52-68]), due to small numbers of other gastrointestinal primaries. A subset analysis of PFS in patients with midgut tumors and progressive disease at baseline was 24 months [95% CI 18-30].
Gastroenteropancreatic neuroendocrine tumors (GEP-NET) are a rare group of cancers that affects the pancreas or different parts of the gastrointestinal tract, such as the stomach, intestines, colon and rectum. Approximately one of 27,000 people are diagnosed with GEP-NET each year. GEP-NETs have limited treatment options after initial therapy fails to keep the cancer from growing. Lutathera® (Lutetium Lu 177 Dotatate) is the first radioactive drug, or radiopharmaceutical, that has been approved for the treatment of GEP-NETs. More spefically Lutathera® is indicated for adult patients with somatostatin receptor-positive GEP-NETs, including foregut, midgut and hindgut neuroendocrine tumors. Lutathera received an orphan drug designation and is also the first available FDA approved Peptide Receptor Radionuclide Therapy (PRRT), a form of treatment comprising of a targeting molecule that carries a radioactive component. The safety and effectiveness of Lutathera® (Lutetium Lu 177 Dotatate) for the treatment of somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs) in adults has been evaluated in a multi-center open label phase 3 trial the NETTER-1 trial and the Erasmus retrospective study. Based on the clinical data from these two trials the evidence is sufficient to determine that this technology results in meaningful improvement in net health outcomes for the treatment of somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs), including foregut (gastroduodenal), midgut (distal small intestine and proximal colon), and hindgut (distal colorectal and pancreas) neuroendocrine tumors in adults.
See also Medical Policy 05.01.09 Off-Label Drug Use
Bronchopulmonary and Thymus Neuroendocrine Tumors: Neuroendocrine tumors are thought to arise from cells throughout the diffuse endocrine system. They comprise a broad family of tumors, the most common of which are the gastrointestinal (GI) tract, lung and bronchi (so-called bronchopulmonary), thymus, and pancreas. Sites of origin within the GI tract include the stomach, small intestine, appendix and rectum. Other less common neuroendocrine tumors include those arising in the parathyroid, thyroid, adrenal, and pituitary glands.
Approximately one-third of neuroendocrine (carcinoid) tumors arise in the lungs or thymus, and two-thirds arise in the GI tract. Bronchial and thymic neuroendocrine tumors have been associated with adrenocorticotropic hormone (ACTH) production and are a cause of Cushing’s syndrome.
Neuroendocrine tumors are generally subclassified by site of origin, stage and histologic characteristics.
The classification of lung and thymus neuroendocrine tumors varies from that of gastropancreatic neuroendocrine tumors in some classification systems, and in particular does not include Ki-67 and includes the assessment of necrosis. Well differentiated neuroendocrine tumors of the lung and thymus are either considered typical (low grade, < 2 mitoses/10 HPF, and no necrosis) or atypical (intermediate grade, 2-10 months/10 HPF and/or foci of necrosis), using histologic criteria.
Neuroendocrine tumors are classified histologically based on tumor differentiation and tumor grade (1-3):
Pheochromocytomas/Paragangliomas: Pheochromocytomas are neoplasms of the chromaffin cells of the adrenal medulla in 80% to 90% of cases. Ectopic/extra-adrenal pheochromocytomas that arise from sympathetic and para-aortic sympathetic ganglia are called paragangliomas. Pheochromocytomas and paragangliomas occur in 0.05% to 0.1% of hypertensive patients, and their combined annual incidence in the United States is estimated to be between 500 and 600 cases. Approximately 10% to 15% of pheochromocytomas and paragangliomas are malignant, but it could be up to 40%. Pheochromocytomas release catecholamines (epinephrine and norepinephrine and their metabolites metanephrine and normetanephrine, resulting in hypertension, arrhythmia, and or hyperglycemia). About 40% of paragangliomas secrete catecholamines. Head and neck paragangliomas only secrete catecholamines about 5% of the time and often it is dopamine.
The peak incidence of occurrence for pheochromocytomas is between the third and fifth decades of life, but they generally occur at a younger age and are more likely to be bilateral in patients with familial disease. Paragangliomas are more likely to be malignant than pheochromocytomas in the adrenal medulla (about 40% versus 10%). Pheochromocytomas and paragangliomas associated with a familial syndrome tend to be more aggressive and are more likely to metastasize than sporadic tumors.
The National Comprehensive Cancer Network (NCCN) clinical practice guidelines for neuroendocrine and adrenal tumors version 1.2019 and the NCCN Drugs and Biologics Compendium® (2019) include category 2A recommendations for use of Lutathera® (Lutetium Lu 177 Dotatate) in the treatment of the following:
Consider as subsequent therapy for management of locoregional unresectable bronchopulmonary/thymic disease if somatostatin receptor positive imaging and progression on octreotide or lanreotide.
The management of distant metastatic bronchopulmonary/thymus disease if somatostatin receptor positive imaging and progression on octreotide/lanreotide in patients with clinically significant tumor burden and low grade (typical) histology, evidence of progression, or intermediate grade (atypical) histology
As the primary treatment for pheochromocytoma/paraganglioma that is locally unresectable disease or distant metastases if somatostatin receptor positive imaging.
Both category 2A recommendations are “based upon lower-level evidence, there is National Comprehensive Cancer Network (NCCN) consensus that the intervention is appropriate” and outcomes reported from a subset of participants with primary bronchial NETs in the ERASMUS study and a retrospective case series of individuals with functional metastatic paraganglioma and pheochromocytoma treated with lutetium Lu 177 dotatate (Brabander et. al. 2017; Kong et. al. 2017). Also, based on medical policy 05.01.09 Off-Label Drug Use the above indications meet the criteria of this medical policy for off- label use.
Lutetium Lu 177 Dotatate (177Lu-Dotatate) is a radiolabeled somatosatatin analog used as PRRT (peptide receptor radionuclide therapy). It is approved by the FDA for the treatment of somatostatin receptor positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs) including foregut, midgut, and hindgut NET in adults.
Key Eligibility
Preparing Eligible Patients for 177Lu-Dotatate
Dose and Administration
Post Treatment Instructions
Timing of Somatostatin Analogs (SSAs) (Octreotide or Lanreotide) in relation to 177Lu-Dotatate
Recommended: Brochopulmonary/thymus locoregional unresectable low grade (typical) consider peptide receptor radionuclide therapy (PRRT) with Lutathera (177Lu-dotatate) (if somatostatin receptor positive and progression on octreotide/lanreotide)
Recommended: Management of distant metastatic bronchopulmonary/thymic disease if somatostatin receptor positive imaging and progression on octreotide/lanreotide in patients with clinically significant tumor burden and low grade (typical) histology, evidence of progression, or intermediate grade (atypical) histology
Category of evidence: 2A
Recommended: Treatment for locally unresectable disease or distant metastases if somatostatin receptor positive imaging.
Category of evidence: 2A
Lutathera® (Lutetium Lu 177 Dotatate) was FDA approved January 2018 for the treatment of somatostatin receptor-positive gastroenteropacreatic neuroendocrine tumors (GEP-NETs), including foregut, midgut, and hindgut neuroendocrine tumors in adults.
The safety and effectiveness of Lutathera® (Lutetium Lu 177 Dotatate) has not been established in pediatric patients.
Dosage and Administration: Aminister 7.4 GBg (200 mCi) every 8 weeks for a total of 4 doses.
Prior Approval is Required
See Related Medical Policy:
Lutathera® (Lutetium Lu 177 Dotatate) is considered medically necessary for the treatment somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs), including foregut (gastroduodenal), midgut (distal small intestine and proximal colon), and hindgut (distal colorectal and pancreas) neuroendocrine tumors in adults when ALL of the following criteria are met:
Lutathera® (Lutetium Lu 177 Dotatate) is considered medically necessary as primary treatment for locally unresectable or metastatic pheochromocytoma or paraganglioma when ALL of the following criteria are met:
Note: See Policy Guidelines below
Lutathera® (Lutetium Lu 177 Dotatate) is considered medically necessary for the treatment of bronchopulmonary or thymus neuroendocrine tumors (NETs) when ALL of the following criteria are met:
Note: See Policy Guidelines below
Lutathera® (Lutetium Lu 177 Dotatate) is considered investigational when the above criteria is not met, and including but not limited to any of the following:
Based on the peer reviewed medical literature the safety and effectiveness for indications other than the medically necessary indication listed above has not been established. Also, the FDA approved label indication state the safety and efficacy beyond 4 doses of Lutathera® (Lutetium Lu 177 Dotatate) has not been studied and the safety and effectiveness of Lutathera has not been established in pediatric patients. Additional studies are needed to further investigate the safety and efficacy of Lutathera® (Lutetium Lu 177 Dotatate) for patient populations for other than those indications listed above. The evidence is insufficient to demonstrate the effects on net health outcomes except for the indications listed above as medically necessary.
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