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Lutathera® (Lutetium Lu 177 Dotatate) (Independence Administrators)
08.01.57

Policy


This policy only applies to members for whom Independence Administrators​ serves as the claims administrator and whose group has not enrolled in the UM vendor program.  For those groups who have been given the option to enroll in the UM vendor program, this policy is no longer applicable upon their renewal effective date. Individual member benefits must be verified before/prior to providing services.


When services can be administered in various settings, the Company reserves the right to reimburse only those services that are furnished in the most appropriate and cost-effective setting that is appropriate to the member’s medical needs and condition. This decision is based on the member’s current medical condition and any required monitoring or additional services that may coincide with the delivery of this service.

MEDICALLY NECESSARY

Lutathera® (Lutetium Lu 177 Dotatate) is considered medically necessary and, therefore, covered in adult individuals 18 years of age or older for the treatment of inoperable, locally advanced, or metastatic somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs) of the pancreas, foregut, midgut and hindgut, bronchopulmonary tumors, and thymic tumors when ALL of the following criteria are met:
  • The tumor is low-, intermediate-, or well-differentiated high-grade (pathology report documents a Ki-67 index 20 percent or less)
  • Documented somatostatin receptor expression of a neuroendocrine tumor as detected by somatostatin receptor-based imaging including:
    • 68-Ga-Dotatate Positron Emission Tomography (PET)/Computed Tomography (CT)
    • 68-Ga-Dotatate Positron Emission Tomography (PET)/Magnetic Resonance Imaging (MRI)
    • Somatostatin receptor scintigraphy
  • The individual has documented disease progression while on somatostatin analog therapy (e.g., octreotide, lanreotide)
  • The individual is not receiving long-acting somatostatin analogs (e.g., octreotide, lanreotide) for at least 4 weeks prior to initiating Lutathera (Lutetium Lu 177 Dotatate)
  • The individual is not receiving short-acting somatostatin analogs (e.g., octreotide) for at least 24 hours prior to initiating Lutathera (Lutetium Lu 177 Dotatate)
  • The individual does not have severe renal impairment (creatinine clearance, <30 mL/min)
  • The individual has adequate bone marrow function (hemoglobin [hgb] > 8 g/dl; white blood cells [WBC] 2000/mm3 or more; platelets 75,000 mm or more)
  • The individual has adequate hepatic function (total bilirubin 3 times the upper limit of normal or less)
  • The individual has a documented Karnofsky Performance Status score of 60 or more
  • The prescribing regimen must be in compliance with the Food and Drug Administration approved dosing, with dosing regimen of 7.4 GBq (200 mCi) every 8 weeks for a total of 4 doses
  • Females of reproductive potential are not pregnant and are using effective contraception
The continuation of Lutathera (Lutetium Lu 177 Dotatate) is considered medically necessary and, therefore, covered when ALL of the following criteria are met:
  • No recurrent grade 2, 3, or 4 thrombocytopenia (see Guidelines)
  • No recurrent grade 3 or 4 anemia and neutropenia (see Guidelines)
  • No recurrent hepatotoxicity (see definition of hepatotoxicity in the Guidelines)
  • No recurrent grade 3 or 4 nonhematologic toxicity (see Guidelines)
  • No renal toxicity requiring a treatment delay of 16 weeks or longer (see definition of renal toxicity in the Guidelines section)
EXPERIMENTAL/INVESTIGATIONAL

Lutathera (Lutetium Lu 177 Dotatate) is considered experimental/investigational and, therefore, not covered in all other situations in which the above criteria are not met because the safety and/or effectiveness of this service cannot be established by review of the available published peer-reviewed literature.

Lutathera (Lutetium Lu 177 Dotatate) greater than a total of 4 doses as per the Food and Drug Administration approved regimen is considered experimental/investigational and, therefore, not covered.

REQUIRED DOCUMENTATION

The individual's medical record must reflect the medical necessity for the care provided. These medical records may include, but are not limited to: records from the health care professional's office, hospital, nursing home, home health agencies, therapies, and test reports.

The Company may conduct reviews and audits of services to our members, regardless of the participation status of the provider. All documentation is to be available to the Company upon request. Failure to produce the requested information may result in a denial for the service.

Guidelines

The recommended dose of Lutathera (Lutetium Lu 177 Dotatate) is 7.4 GBq (200 mCi) every 8 weeks for a total of 4 doses.

There are concerns regarding the competition between somatostatin analogs and Lutathera (Lutetium Lu 177 Dotatate) for somatostatin receptor binding. Therefore, the following is recommended:
  • Do not administer long-acting somatostatin analogs for 4 to 6 weeks prior to each Lutathera (Lutetium Lu 177 Dotatate) dose.
  • Discontinue short-acting somatostatin analogs at least 24 hours before each Lutathera (Lutetium Lu 177 Dotatate) dose.
  • Both long-acting and short-acting somatostatin analogs can be resumed 4 to 24 hours after each Lutathera (Lutetium Lu 177 Dotatate) dose.
Lutathera (Lutetium Lu 177 Dotatate) should be discontinued permanently if the individual develops hepatotoxicity defined as bilirubinemia greater than 3 times the upper limit of normal (grade 3 or 4), or hypoalbuminemia less than 30 g/L with a decreased prothrombin ratio less than 70 percent.

Lutathera (Lutetium Lu 177 Dotatate) should be discontinued permanently if the individual develops renal toxicity defined as a creatinine clearance of less than 40 mL/min calculated using Cockcroft-Gault equation with actual body weight, or 40 percent increase in baseline serum creatinine, or 40 percent decrease in baseline creatinine clearance calculated using Cockcroft-Gault equation with actual body weight.

Common Toxicity Criteria for Adverse Events
Grad​e
Description
1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated.
2
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living and refer to preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc.
3
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living and refer to refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden.
4
Life-threatening consequences; urgent intervention indicated.
5
Death related to adverse event.

KARNOFSKY PERFORMANCE STATUS (KPS)

A scale measuring the ability of individuals to perform ordinary tasks. KPS scores range from 0 to 100; a higher score means a person is better able to carry out daily activities.

KPS
Definition
100
Normal; no complaint; no evidence of disease
90
Able to carry on normal activity; minor signs of symptoms of disease
80
Normal activity with effort; some sign or symptoms of disease
70
Cares for self; unable to carry on normal activity of do active work
60
Requires occasional assistance, but is able to care for most personal needs
50
Requires considerable assistance and frequent medical care
40
Disabled; requires special care and assistance
30
Severely disabled; hospitalization is indicated, although death not imminent
20
Very sick; hospitalization necessary; active support treatment is necessary
10
Moribund; fatal processes progressing rapidly
0
Dead

BENEFIT APPLICATION

Subject to the terms and conditions of the applicable benefit contract, Lutathera (Lutetium Lu 177 Dotatate) is covered under the medical benefits of the Company’s products when the medical necessity criteria and Dosing and Frequency Requirements listed in this medical policy are met.

Services that are experimental/investigational are a benefit contract exclusion for all products of the Company. Therefore, they are not eligible for reimbursement consideration.

US FOOD AND DRUG ADMINISTRATION (FDA) STATUS

Lutathera (lutetium Lu 177 dotatate) was approved by FDA on January 26, 2018, for the treatment of somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors, including foregut, midgut, and hindgut neuroendocrine tumors in adults.

PEDIATRIC USE

Lutathera (Lutetium Lu 177 Dotatate) is not indicated for use in pediatric individuals less than 18 years of age.

Description

NEUROENDOCRINE TUMORS

Neuroendocrine tumors are a heterogeneous group of tumors that originate from the neuroendocrine cells in the diffuse neuroendocrine system anywhere in the body but more commonly in the gastrointestinal tract and the respiratory system. Approximately 61 percent of all neuroendocrine tumors originate from gastrointestinal system or pancreas and are referred to as gastroenteropancreatic neuroendocrine tumors. Lung neuroendocrine tumors may also be referred to as pulmonary neuroendocrine tumors, pulmonary carcinoids, or bronchopulmonary neuroendocrine tumors. Gastroenteropancreatic neuroendocrine tumors may further be characterized as functional or nonfunctional based on whether they secrete hormones that result in clinical symptoms particularly serotonin, which results in “carcinoid syndrome” that is characterized by flushing and diarrhea.

Neuroendocrine tumors are classified as orphan diseases by the Food and Drug Administration (FDA). Based on an analysis of Surveillance, Epidemiology, and End Results Program registry data from 1973 to 2012 (Dasari A, 2017), the overall incidence of neuroendocrine tumors has been reported to be in the range of 6.98 per 100,000 people per year.

DIAGNOSIS

Neuroendocrine tumors are not easy to diagnose because of the rarity of the condition. Symptoms are often nonspecific or mimic other disorders such as irritable bowel syndrome (in the case of gastroenteropancreatic neuroendocrine tumors) or asthma (in the case of a lung neuroendocrine tumors) resulting in an average diagnosis delay of 5 to 7 years after symptom onset (Frilling A, 2012). In many cases, diagnosis is incidental to imaging for other unrelated cause. Most gastroenteropancreatic neuroendocrine tumors express somatostatin receptors that can be imaged using a radiolabeled form of the somatostatin analogue octreotide (e.g., 111In pentetreotide).

TREATMENT APPROACH

There is a general lack of prospective data to guide the treatment of neuroendocrine tumors. Gastroenteropancreatic neuroendocrine tumors are chemotherapy-responsive neoplasms, and platinum-based chemotherapy represents the backbone of treatment for both early and advanced-stage tumors (Sorbye H, 2014). Surgery alone or followed by chemotherapy along with treatment of hormone-related symptoms may be the initial approach for localized disease. For asymptomatic individuals with slow progression, observation with routine surveillance imaging is an option. The prognosis for individuals with metastatic well-differentiated gastroenteropancreatic neuroendocrine tumors is highly variable. Based on retrospective analyses of large databases, the prognosis for individuals with metastatic gastroenteropancreatic neuroendocrine tumors is variable. The median overall survival (from diagnosis) for individuals with metastatic pancreatic neuroendocrine tumors has been reported to range from 2 to 5.8 years (Yao JC, 2008; Strosberg J, 2009), while the median overall survival for small bowel neuroendocrine tumors has been reported as 7.9 years (Ter-Minassian M, 2013).

PHARMACOLOGICAL TREATMENT
First-Line Treatment Options

Somatostatin Analogues (Octreotide and Lanreotide)

Somatostatin is a peptide that binds to somatostatin receptors that are expressed in a majority of carcinoid tumors and inhibits the secretion of a broad range of hormones. Somatostatin analogues (e.g., octreotide, lanreotide) were initially developed to manage the hormonal symptoms related to neuroendocrine tumors, they were found to exert antiproliferative activity, and clinical studies have demonstrated prolonged progression-free survival (PFS) in individuals with neuroendocrine tumors treated with somatostatin analogues (Rinke A, 2009; Caplin ME, 2015). However, the role of somatostatin analogues in individuals with nonfunctioning neuroendocrine tumors is unclear (Ramage JK, 2012).

Commercially available long-acting release forms of octreotide and lanreotide (e.g., Sandostatin LAR, Somatuline Depot), which are administered intramuscularly on a monthly basis, have largely eliminated the need for daily self-injection of short-acting subcutaneous formulations (A-berg K, 2015; O'Toole D, 2000).

Second-Line Treatment Options

Currently, there are no data to support a specific sequence of therapies and only streptozocin, everolimus, and sunitinib are FDA approved for the treatment of pancreatic neuroendocrine tumors.

Mechanistic Target of Rapamycin Inhibitors

The mechanistic target of rapamycin is an enzyme that regulates cell metabolism and proliferation in response to environmental stimuli. It is upregulated in a variety of malignancies in response to stimulation by growth factors and cytokines. Whole-exome genomic analysis has shown that approximately 15 percent of pancreatic neuroendocrine tumors are associated with somatic variants in genes associated with the mechanistic target of rapamycin pathway (Strosberg J, 2013). Everolimus, an oral mechanistic target of rapamycin inhibitor, has been shown to significantly prolonged PFS vs placebo in individuals with pancreatic neuroendocrine tumors (RADIANT-3 trial) (Yao JC, 2011), and lung and gastrointestinal neuroendocrine tumors nonfunctional (RADIANT-4 trial) (Yao JC, 2016). Note that everolimus is approved by FDA for adults with progressive neuroendocrine tumors of pancreatic origin and adults with progressive, well-differentiated, nonfunctional neuroendocrine tumors of gastrointestinal or lung origin that are unresectable, locally advanced or metastatic. The RADIANT-2 trial individuals with progressive advanced neuroendocrine tumors associated with carcinoid syndrome failed to show a statistically significant improvement in the primary end point of PFS (Pavel ME, 2011).

Tyrosine Kinase Receptor Inhibitors

Neuroendocrine tumors frequently overexpress the vascular endothelial growth factor and receptor. Sunitinib, is a multi-targeted tyrosine kinase inhibitor that targets multiple signaling pathways and growth factors and receptors including vascular endothelial growth factor and receptor 1, 2, and 3 (Strosberg J, 2013). It has been shown that daily sunitinib at a dose of 37.5 mg improves PFS, overall survival, and the overall response rate as compared with placebo among individuals with advanced pancreatic neuroendocrine tumors (Raymond E, 2011). Note that sunitinib is FDA approved for the treatment of progressive, well-differentiated pancreatic neuroendocrine tumors in individuals with unresectable locally advanced or metastatic disease.

Chemotherapy

Response to chemotherapy for advanced neuroendocrine tumors of the gastrointestinal tract and lung is highly variable and, at best, modest. Tumor response rates are generally low and no PFS benefit has been clearly demonstrated. Therefore, the careful selection of individuals is critical to maximize the chance of response and avoid unnecessary toxicity. In advanced neuroendocrine tumors, platinum-based regimens are generally used. They include cisplatin and etoposide (most widely used), carboplatin and etoposide, 5-fluorouracil, capecitabine, dacarbazine, oxaliplatin, streptozocin, and temozolomide (Garcia-Carbonero R, 2016).

Lutetium 177 Dotatate

Lutetium 177 dotatate is a radiolabeled-somatostatin analogue that binds to somatostatin receptor expressing cells, including malignant somatostatin receptor-positive tumors. It is then internalized and beta particle emission from lutetium 177 induces cellular damage by formation of free radicals in somatostatin receptor-positive and neighboring cells.

Lutathera (Lutetium Lu 177 dotatate) [Advanced Accelerator Applications (AAA), New York, NY] received FDA approval on January 26, 2018. Lutathera is approved for the treatment of somatostatin receptor positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs), including foregut, midgut, and hindgut neuroendocrine tumors, in adults. Lutathera is the first available FDA-approved Peptide Receptor Radionuclide Therapy (PRRT), a form of treatment comprising of a targeting molecule that carries a radioactive component. Currently, there are no other radiolabeled somatostatin analog conjugates that are FDA approved specifically for use in PRRT.

FDA approval for Lutathera was based on the results from two studies, NETTER 1 (Strosberg J, 2017; U.S. Food and Drug Administration, 2018) and ERASMUS (Kwekkeboom DJ, 2008; Brabander T, 2017; U.S. Food and Drug Administration, 2018).

NETTER 1 was an open-label randomized, controlled trial (RCT) that compared treatment with Lutathera to octreotide in individuals with inoperable, progressive somatostatin receptor-positive midgut carcinoid tumors. Eligibility included a Ki-67 index 20 percent or less, confirmed presence of somatostatin receptors on all lesions (octreoscan uptake greater than or equal to that of the normal liver), Karnofsky Performance Status score of 60 or more, creatinine clearance of 50 mL/min or more, no prior treatment with Peptide Receptor Radionuclide Therapy (PRRT), and no prior external radiation therapy to more than 25 percent of the bone marrow. Randomization was stratified by octreoscan tumor uptake score (grade 2, 3 or 4) and the length of time that individuals had been on the most recent constant dose of octreotide prior to randomization (less than or equal to 6 months or > 6 months). The primary outcome was progression free survival (PFS). A total of 229 individuals were randomized to either Lutathera (7.4 GBq [200 mCi]) for four infusions every 8 weeks concurrently with 30 mg of long-acting octreotide (n = 116) or 60 mg of high-dose octreotide alone (n = 113). At the data-cutoff date for the primary analysis, PFS at 20 months was 65.2 percent (95 percent confidence interval [CI], 50.0 to 76.8) in the Lutathera group and 10.8 percent (95 percent CI, 3.5 to 23.0) in the control group. The response rate was 18 percent in the Lutathera group versus 3 percent in the control group (p<0.001). In the planned interim analysis of overall survival (OS), 14 deaths occurred in the Lutathera group and 26 in the control group ([hazard ratio: 0.40] p=0.004). Grade 3 or 4 neutropenia, thrombocytopenia, and lymphopenia occurred in 1 percent, 2 percent, and 9 percent, respectively, of individuals in the Lutathera group as compared with no individuals in the control group, with no evidence of renal toxic effects during the observed time frame. Adverse events (AEs) that were considered by the investigator to be related to trial treatment occurred in 129 individuals: 95 individuals (86 percent) in the Lutathera group and 34 individuals (31 percent) in the control group. The most common AEs among individuals in the Lutathera group were nausea (65 individuals [59 percent]) and vomiting (52 individuals [47 percent]). Other common AEs in the Lutathera group included fatigue or asthenia, abdominal pain, and diarrhea.

The ERASMUS study was a retrospective, case series that included 1214 individuals with bronchial and gastroenteropancreatic neuroendocrine tumors (GEP-NETs) who received Lutathera, 610 of whom were treated with a cumulative dose of at least 100 mCi (3.7 GBq) for safety analysis. Another subgroup of 443 Dutch individuals were treated with a cumulative dose of at least 600 mCi (22.2 GBq). The objective response rate (ORR) of the total group of individuals was 39 percent. Stable disease (SD) was reached in 43 percent of individuals. PFS and OS for all neuroendocrine tumor individuals were 29 months [95 percent confidence interval (CI), 26–33 months] and 63 months (95 percent CI, 55–72 months). Long-term toxicity included acute leukemia in four individuals (0.7 percent) and myelodysplastic syndrome in nine individuals (1.5 percent). No therapy-related long-term renal or hepatic failure occurred.

References

American Hospital Formulary Service (AHFS). Lutathera® (Lutetium Lu 177 Dotatate). AHFS Drug Information 2023. [LexiComp Web site]. 04/21/2023. Available at: https://online.lexi.com/lco/action/home [via subscription only]. Accessed October 23, 2023.

Ballal S, Yadav MP, Damle NA, et al. Concomitant 177Lu-DOTATATE and capecitabine therapy in patients with advanced neuroendocrine tumors: a long-term-outcome, toxicity, survival, and quality-of-life study. Clin Nucl Med. 2017;42(11):e457-e466.

Barber TW, Hofman MS, Thomson BNJ, Hicks RJ. The potential for induction peptide receptor chemoradionuclide therapy to render inoperable pancreatic and duodenal neuroendocrine tumours resectable. Eur J Surg Oncol. 2012;38(1):64-71.

Baum RP, Kluge AW, Kulkarni H, et al. [(177)Lu-DOTA](0)-D-Phe(1)-Tyr(3)-Octreotide ((177)Lu-DOTATOC) for peptide receptor radiotherapy in patients with advanced neuroendocrine tumours: a phase-II study. Theranostics. 2016;6(4):501-510.

Baum RP, Puranik AD, Kulkarni HR. Peptide receptor radionuclide therapy (PRRT) of neuroendocrine tumors: current state and future perspectives. Int J Endo Oncol. 2015;2(2):151-158.

Bergsma H, Konijnenberg MW, Kam BLR, et al. Subacute haematotoxicity after PRRT with (177)Lu-DOTA-octreotate: prognostic factors, incidence and course. Eur J Nucl Med Mol Imaging. 2016;43(3):453-463.

Bodei L, Cremonesi M, Ferrari M, et al. Long-term evaluation of renal toxicity after peptide receptor radionuclide therapy with 90Y-DOTATOC and 177Lu-DOTATATE: the role of associated risk factors. Eur J Nucl Med Mol Imaging. 2008;35(10):1847-1856.

Bodei L, Cremonesi M, Grana CM, et al. Peptide receptor radionuclide therapy with 177 Lu-DOTATATE: the IEO phase I-II study. Eur J Nucl Med Mol Imaging. 2011;38(12):2125-2135.

Bodei L, Cremonesi M, Grana CM, et al. Yttrium-labelled peptides for therapy of NET. Eur J Nucl Med Mol Imaging. 2012;39(Suppl 1):S93-S102.

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.

Bodei L, Ferone D, Grana CM, et al. Peptide receptor therapies in neuroendocrine tumors. J Endocrinol Invest. 2009;32(4):360-369.

Bodei L, Pepe G, Paganelli G. Peptide receptor radionuclide therapy (PRRT) of neuroendocrine tumors with somatostatin analogues. Eur Rev Med Pharmacol Sci. 2010;14(4):347-351.

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

Brabander T, van der Zwan WA, Teunissen JJM, et al. Pitfalls in the response evaluation after peptide receptor radionuclide therapy with [(177)Lu-DOTA0,Tyr3]octreotate. Endocr Relat Cancer. 2017;24(5):243-251.

Caplin ME, Baudin E, Ferolla P, et al. Pulmonary neuroendocrine (carcinoid) tumors: European Neuroendocrine Tumor Society expert consensus and recommendations for best practice for typical and atypical pulmonary carcinoids. Ann Oncol. 2015;26(8):1604-1620.

Claringbold PG, Turner JH. NeuroEndocrine tumor therapy with lutetium-177-octreotate and everolimus (NETTLE): a phase I study. Cancer Biother Radiopharm. 2015;30(6):261-269.

Czepczynski R, Matysiak-Grzes M, Gryczynska M, et al. Peptide receptor radionuclide therapy of differentiated thyroid cancer: efficacy and toxicity. Arch Immunol Ther Exp (Warsz). 2015;63(2):147-154.

Dasari A, Shen C, Halperin D, et al. Trends in the incidence, prevalence, and survival outcomes in patients with neuroendocrine tumors in the United States. JAMA Oncol. 2017;3(10):1335-1342.

Elsevier's Clinical Pharmacology Compendium. Lutathera® (Lutetium Lu 177 Dotatate). [Clinical Key Web site]. 09/28/2023. Available at: https://www.clinicalkey.com/#!/ [via subscription only]. Accessed October 23, 2023.

Ezziddin S, Attassi M, Yong-Hing CJ, et al. Predictors of long-term outcome in patients with well-differentiated gastroenteropancreatic neuroendocrine tumors after peptide receptor radionuclide therapy with 177Lu-octreotate. J Nucl Med. 2014;55(2):183-190.

Ezziddin S, Sabet A, Heinemann F, et al. Response and long-term control of bone metastases after peptide receptor radionuclide therapy with (177)Lu-octreotate. J Nucl Med. 2011;52(8):1197-1203.

Forrer F, Riedweg I, Maecke HR, Mueller-Brand J. Radiolabeled DOTATOC in patients with advanced paraganglioma and pheochromocytoma. Q J Nucl Med Mol Imaging. 2008;52(4):334-340.

Frilling A, Akerstrom G, Falconi M, et al. Neuroendocrine tumor disease: an evolving landscape. Endocr Relat Cancer. 2012;19(5):R163-185.

Garcia-Carbonero R, Sorbye H, Baudin E, et al. ENETS consensus guidelines for high-grade gastroenteropancreatic neuroendocrine tumors and neuroendocrine carcinomas. Neuroendocrinology. 2016;103(2):186-194.

Grozinsky-Glasberg S, Barak D, Fraenkel M, et al. Peptide receptor radioligand therapy is an effective treatment for the long-term stabilization of malignant gastrinomas. Cancer. 2011;117(7):1377-1385.

Hamiditabar M, Ali M, Roys J, et al. Peptide receptor radionuclide therapy with 177Lu-Octreotate in patients with somatostatin receptor expressing neuroendocrine tumors: six years' assessment. Clin Nucl Med. 2017;42(6):436-443.

Horsch D, Ezziddin S, Haug A, et al. Effectiveness and side-effects of peptide receptor radionuclide therapy for neuroendocrine neoplasms in Germany: a multi-institutional registry study with prospective follow-up. Eur J Cancer. 2016;58:41-51.

Ianniello A, Sansovini M, Severi, S, et al. Peptide receptor radionuclide therapy with (177)Lu-DOTATATE in advanced bronchial carcinoids: prognostic role of thyroid transcription factor 1 and (18)F-FDG PET. Eur J Nucl Med Mol Imaging. 2016; 43:1040-1046.

Imhof A, Brunner P, Marincek N, et al. Response, survival, and long-term toxicity after therapy with the radiolabeled somatostatin analogue [90Y-DOTA]-TOC in metastasized neuroendocrine cancer. J Clin Oncol. 2011;29(17):2416-2423.

Iyer R, Phan AT, Boudreaux JP. Recent advances in the management of gastroenteropancreatic neuroendocrine tumors: insights from the 2017 ASCO Gastrointestinal Cancers Symposium. Clin Adv Hematol Oncol. 2017;15 suppl 4(4):1-24.

Khanna G, Bushnell D, O'Dorisio MS. Utility of radiolabeled somatostatin receptor analogues for staging/restaging and treatment of somatostatin receptor-positive pediatric tumors. Oncologist. 2008;13(4):382-389.

Kim SJ, Pak K, Koo PJ, et al. The efficacy of 177Lu-labeled peptide receptor radionuclide therapy in patients with neuroendocrine tumours: a meta-analysis. Eur J Nucl Med Mol Imaging. 2015;42(13):1964-1970.

Kong G, Callahan J, Hofman MS, et al. High clinical and morphologic response using 90Y-DOTA-octreotate sequenced with 177Lu-DOTA-octreotate induction peptide receptor chemoradionuclide therapy (PRCRT) for bulky neuroendocrine tumours. Eur J Nucl Med Mol Imaging. 2017;44(3):476-489.

Kong G, Grozinsky-Glasberg S, Hofman MS, et al. Efficacy of peptide receptor radionuclide therapy for functional metastatic paraganglioma and pheochromocytoma. J Clin Endocrinol Metab. 2017;102(9):3278-3287.

Kunikowska J, Pawlak D, Bak MI, et al. Long-term results and tolerability of tandem peptide receptor radionuclide therapy with 90Y/177Lu-DOTATATE in neuroendocrine tumors with respect to the primary location: a 10-year study. Ann Nucl Med. 2017;31(5):347-356.

Kwekkeboom DJ, de Herder WW, Kam BL, et al. Treatment with the radiolabeled somatostatin analog [177 Lu-DOTA o,Tyr3]octreotate: toxicity, efficacy, and survival. J Clin Oncol. 2008;26(13):2124-2130.

Kwekkeboom DJ, de Herder WW, Krenning EP. Somatostatin receptor-targeted radionuclide therapy in patients with gastroenteropancreatic neuroendocrine tumors. Endocrinol Metab Clin North Am. 2011;40(1):173-185.

Lexi-Drugs Compendium. Lutathera® (Lutetium Lu 177 Dotatate). [LexiComp Web site]. 07/06/2023. Available at: https://online.lexi.com/lco/action/home [via subscription only]. Accessed October 23, 2023.

Limouris GS, Poulantzas V, Trompoukis N, et al. Comparison of 111in-[DTPA0]octreotide versus non carrier added 177Lu-[DOTA0,Tyr3]-octreotate efficacy in patients with GEP-NET treated intra-arterially for liver metastases. Clin Nucl Med. 2016;41(3):194-200.

Lo Russo G, Pusceddu S, Prinzi N, et al. Peptide receptor radionuclide therapy: focus on bronchial neuroendocrine tumors. Tumor Biol. 2016;37(10):12991-13003.

Lutathera® (Lutetium Lu 177 Dotatate) [Prescribing Information]. Millburn, NJ: Advanced Accelerator Applications USA, Inc.; 03/2023. Available at: https://www.lutathera.com. Accessed October 23, 2023.

Mariniello A, Bodei L, Tinelli C, et al. Long-term results of PRRT in advanced bronchopulmonary carcinoid. Eur J Nucl Med Mol Imaging. 2016;43(3):441-452.

Medina-Ornelas SS, García-Pérez FO. Effectiveness of radiolabelled somatostatin analogues (90Y-DOTATOC and 177Lu-DOTATATE) in patients with metastatic neuroendocrine tumours: a single centre experience in Mexico. Rev Esp Med Nucl Imagen Mol. 2017;36(3):166-174.

Merative Micromedex® DRUGDEX® (electronic version). Lutathera® (Lutetium Lu 177 Dotatate). [Micromedex Web site]. Merative L.P., Ann Arbor, Michigan, USA. 08/12/2023. Available at: https://www.micromedexsolutions.com/micromedex2/librarian [via subscription only]. Accessed October 23, 2023.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology®. Neuroendocrine and Adrenal Tumors V1.2023. [NCCN Web site]. 08/02/2023. Available from: https://www.nccn.org/professionals/physician_gls/pdf/neuroendocrine.pdf. [via subscription only]. Accessed October 23, 2023.

National Comprehensive Cancer Network (NCCN). NCCN Drugs & Biologics Compendium®. [NCCN Web site]. Lutathera® (Lutetium Lu 177 Dotatate). Available at: https://www.nccn.org/professionals/drug_compendium/content/ [via subscription only]. Accessed October 23, 2023.

Öberg K, Leyden J, Goldstein G, et al. Neuroendocrine tumor European patient experience: results from the first global NET patient survey - a collaboration between the International Neuroendocrine Cancer Alliance and Novartis [abstract]. Endocrine Abstracts. 2015;37:EP1139.

Oksuz MO, Winter L, Pfannenberg C, et al. Peptide receptor radionuclide therapy of neuroendocrine tumors with (90)Y-DOCATOC: is treatment response predictable by pre-therapeutic uptake of (68)Ga-DOTATOC? Diagn Interv Imaging. 2014;95(3):289-300.

O'Toole D, Ducreux M, Bommelaer G, et al. Treatment of carcinoid syndrome: a prospective crossover evaluation of lanreotide versus octreotide in terms of efficacy, patient acceptability, and tolerance. Cancer. 2000;88(4):770-776.

Parghane RV, Talole S, Prabhash K, Basu S. Clinical response profile of metastatic/advanced pulmonary neuroendocrine tumors to peptide receptor radionuclide therapy with 177Lu-DOTATATE. Clin Nucl Med. 2017;42(6):428-435.

Pavel ME, Hainsworth JD, Baudin E, et al. Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): a randomised, placebo-controlled, phase 3 study. Lancet. 2011;378(9808):2005-2012.

Puranik AD, Kulkarni HR, Singh A, Baum RP. Peptide receptor radionuclide therapy with (90)Y/(177)Lu-labelled peptides for inoperable head and neck paragangliomas (glomus tumours). Eur J Nucl Med Mol Imaging. 2015;42(8):1223-1230.

Ramage JK, Ahmed A, Ardill J, et al. Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours (NETs). Gut. 2012;61(1):6-32.

Raymond E, Dahan L, Raoul JL, et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med. 2011;364(6):501-513.

Rinke A, Muller HH, Schade-Brittinger C, et al. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol. 2009;27(28):4656-4663.

Romer A, Seiler D, Marincek N, et al. Somatostatin-based radiopeptide therapy with [177Lu-DOTA]-TOC versus [90Y-DOTA]-TOC in neuroendocrine tumours. Eur J Nucl Med Mol Imaging. 2014;41(2):214-222.

Sabet A, Dautzenberg K, Haslerud T, et al. Specific efficacy of peptide receptor radionuclide therapy with (177)Lu-octreotate in advanced neuroendocrine tumours of the small intestine. Eur J Nucl Med Mol Imaging. 2015;42(8):1238-1246.

Sabet A, Ezziddin K, Pape UF, et al. Accurate assessment of long-term nephrotoxicity after peptide receptor radionuclide therapy with (177)Lu-ostreotate. Eur J Nucl Med Mol Imaging. 2014;41(3):505-510.

Sabet A, Haslerud T, Pape UF, et al. Outcome and toxicity of salvage therapy with 177Lu-octreotate in patients with metastatic gastroenteropancreatic neuroendocrine tumours. Eur J Nucl Med Mol Imaging. 2014;41(2):205-210.

Sampaio IL, Luiz HV, Violante LS, et al. Treatment of gastroenteropancreatic neuroendocrine tumors with 177Lu-DOTA-TATE: experience of the Portuguese Institute of Oncology in Porto. Acta Med Port. 2016;29(11):726-733.

Savelli G, Bertagna F, Franco F, et al. Final results of a phase 2A study for the treatment of metastatic neuroendocrine tumors with a fixed activity of 90Y-DOTA-D-Phe1-Tyr3 octreotide. Cancer. 2012;118(11):2915-2924.

Seregni E, Maccauro M, Chiesa C, et al. Treatment with tandem [90y]DOTA-TATE and [177Lu]DOTA-TATE of neuroendocrine tumours refractory to conventional therapy. Eur J Nucl Med Mol Imaging. 2014;41(2):223-230.

Severi S, Sansovini M, Ianniello A, et al. Feasibility and utility of re-treatment with (177)Lu-DOTATATE in GEP-NENs relapsed after treatment with (90)Y-DOTATOC. Eur J Nucl Med Mol Imaging. 2015;42(13):1955-1963.

Spetz J, Langen B, Rudqvist N, et al. Hedgehog inhibitor sonidegib potentiates 177Lu-octreotate therapy of GOT1 human small intestine neuroendocrine tumors in nude mice. BMC Cancer. 2017;17(1):528.

Sorbye H, Strosberg J, Baudin E, et al. Gastroenteropancreatic high-grade neuroendocrine carcinoma. Cancer. 2014;120(18):2814-2823.

Sowa-Staszczak A, Pach D, Chrzan R, et al. Peptide receptor radionuclide therapy as a potential tool for neoadjuvant therapy in patients with inoperable neuroendocrine tumours (NETs). Eur J Nucl Med Mol Imaging. 2011;38(9):1669-1674.

Soydal Ç, Peker A, Özkan E, et al. The role of baseline Ga-68 DOTATATE positron emission tomography/computed tomography in the prediction of response to fixed-dose peptide receptor radionuclide therapy with Lu-177 DOTATATE. Turk J Med Sci. 2016;46(2):409-413.

Strosberg J. Advances in the treatment of pancreatic neuroendocrine tumors (pNETs). Gastrointest Cancer Res. 2013;6(4 Suppl 1):S10-S12.

Strosberg J, El-Haddad G, Wolin E, et al. Phase 3 trial of 177Lu-Dotatate for midgut neuroendocrine tumors. N Engl J Med. 2017;376(2):125-135.

Strosberg J, Gardner N, Kvols L. Survival and prognostic factor analysis in patients with metastatic pancreatic endocrine carcinomas. Pancreas. 2009;38(3):255-258.

Strosberg J, Wolin E, Chasen B, et al. NETTER-1 phase III in patients with midgut neuroendocrine tumors treated with 177Lu-Dotatate: efficacy and safety results. J Nucl Med. 2016;57(Suppl 2):629.

Ter-Minassian M, Chan JA, Hooshmand SM, et al. Clinical presentation, recurrence, and survival in patients with neuroendocrine tumors: results from a prospective institutional database. Endocr Relat Cancer. 2013;20(2):187-196.

Thapa P, Ranade R, Ostwal V, et al. Performance of 177Lu-DOTATATE-based peptide receptor radionuclide therapy in metastatic gastroenteropancreatic neuroendocrine tumor: a multiparametric response evaluation correlating with primary tumor site, tumor proliferation index, and dual tracer imaging characteristics. Nucl Med Commun. 2016;37(10):1030-1037.

U.S. Food and Drug Administration, Center for Drug Evaluation and Research. Application Number: 208700Orig1s000 Multi-Disciplinary Review. Addendum to Review, NDA 208700. January 25, 2018. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/208700Orig1s000MultidisciplineR.pdf. Accessed October 23, 2023.

U.S. Food and Drug Administration. FDA approves new treatment for certain digestive tract cancers. Silver Spring, MD: FDA; January 26, 2018. Available at: https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm594043.htm. Accessed October 23, 2023.

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. Lutathera® (lutetium Lu 177 dotatate). Prescribing information. [FDA Web site]. 03/07/2023. Available at: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm. Accessed October 23, 2023.

van Adrichem RCS, Kamp K, van Deurzen CHM, et al. Is there an additional value of using somatostatin receptor subtype 2a immunohistochemistry compared to somatostatin receptor scintigraphy uptake in predicting gastroenteropancreatic neuroendocrine tumor response? Neuroendocrinology. 2016;103(5):560-566.

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

Vinjamuri S, Gilbert TM, Banks M, et al. Peptide receptor radionuclide therapy with (90)Y-DOTATATE/(90)Y-DOTATOC in patients with progressive metastatic neuroendocrine tumours: assessment of response, survival and toxicity. Br J Cancer. 2013;108(7):1440-1448.

Werner RA, Lapa C, Ilhan H, et al. Survival prediction in patients undergoing radionuclide therapy based on intratumoral somatostatin-receptor heterogeneity. Oncotarget. 2017;8(4):7039-7049.

Wetz C, Apostolova I, Steffen IG, et al. Predictive value of asphericity in pretherapeutic [111In]DTPA-octreotide SPECT/CT for response to peptide receptor radionuclide therapy with [177Lu]DOTATATE. Mol Imaging Biol. 2017;19(3):437-445.

Yalchin M, Oliveira A, Theocharidou E, et al. The impact of radiological response to peptide receptor radionuclide therapy on overall survival in patients with metastatic midgut neuroendocrine tumors. Clin Nucl Med. 2017;42(3):e135-e141.

Yalcin S, Bayram F, Erdamar S, et al. Gastroenteropancreatic neuroendocrine tumors: recommendations of Turkish multidisciplinary neuroendocrine tumor study group on diagnosis, treatment and follow-up. Arch Med Sci. 2017;13(2):271-282.

Yao JC, Fazio N, Singh S, et al. Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study. Lancet. 2016;387(10022):968-977.

Yao JC, Hassan M, Phan A, et al. One hundred years after "carcinoid": epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol. 2008;26(18):3063-3072.

Yao JC, Shah MH, Ito T, et al. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med. 2011;364(6):514-523.

Yordanova A, Mayer K, Brossart P, et al. Safety of multiple repeated cycles of 177Lu-octreotate in patients with recurrent neuroendocrine tumour. Eur J Nucl Med Mol Imaging. 2017;44(7):1207-1214.

Zerbi A, Capitanio V, Boninsegna L, et al. Treatment of malignant pancreatic neuroendocrine neoplasms: middle-term (2-year) outcomes of a prospective observational multicentre study. HPB (Oxford). 2013;15(12):935-943.​
​

Coding

CPT Procedure Code Number(s)
N/A
ICD - 10 Procedure Code Number(s)
N/A
ICD - 10 Diagnosis Code Number(s)
MEDICALLY NECESSARY
C25.4 Malignant neoplasm of endocrine pancreas
C74.10 Malignant neoplasm of medulla of unspecified adrenal gland
C74.11Malignant neoplasm of medulla of right adrenal gland
C74.12Malignant neoplasm of medulla of left adrenal gland
C74.90Malignant neoplasm of unspecified part of unspecified adrenal gland
C74.91Malignant neoplasm of unspecified part of right adrenal gland
C74.92Malignant neoplasm of unspecified part of left adrenal gland
C75.5 Malignant neoplasm of aortic body and other paraganglia
C7A.00 Malignant carcinoid tumor of unspecified site
C7A.010Malignant carcinoid tumor of the duodenum
C7A.011Malignant carcinoid tumor of the jejunum
C7A.012Malignant carcinoid tumor of the ileum
C7A.019Malignant carcinoid tumor of the small intestine, unspecified portion
C7A.020Malignant carcinoid tumor of the appendix
C7A.021Malignant carcinoid tumor of the cecum
C7A.022Malignant carcinoid tumor of the ascending colon
C7A.023Malignant carcinoid tumor of the transverse colon
C7A.024Malignant carcinoid tumor of the descending colon
C7A.025Malignant carcinoid tumor of the sigmoid colon
C7A.026Malignant carcinoid tumor of the rectum
C7A.029Malignant carcinoid tumor of the large intestine, unspecified portion
C7A.090Malignant carcinoid tumor of the bronchus and lung
C7A.091Malignant carcinoid tumor of the thymus
C7A.092Malignant carcinoid tumor of the stomach
C7A.093Malignant carcinoid tumor of the kidney
C7A.094Malignant carcinoid tumor of the foregut, unspecified
C7A.095Malignant carcinoid tumor of the midgut, unspecified
C7A.096Malignant carcinoid tumor of the hindgut, unspecified
C7A.098Malignant carcinoid tumors of other sites
C7A.1Malignant poorly differentiated neuroendocrine tumors
C7A.8Other malignant neuroendocrine tumors
C7B.00Secondary carcinoid tumors, unspecified site
C7B.01Secondary carcinoid tumors of distant lymph nodes
C7B.02Secondary carcinoid tumors of liver
C7B.03Secondary carcinoid tumors of bone
C7B.04Secondary carcinoid tumors of peritoneum
C7B.09Secondary carcinoid tumors of other sites
C7B.8 Other secondary neuroendocrine tumors
D3A.00 Benign carcinoid tumor of unspecified site
D3A.010Benign carcinoid tumor of the duodenum
D3A.011Benign carcinoid tumor of the jejunum
D3A.012Benign carcinoid tumor of the ileum
D3A.019Benign carcinoid tumor of the small intestine, unspecified portion
D3A.020Benign carcinoid tumor of the appendix
D3A.021Benign carcinoid tumor of the cecum
D3A.022Benign carcinoid tumor of the ascending colon
D3A.023Benign carcinoid tumor of the transverse colon
D3A.024Benign carcinoid tumor of the descending colon
D3A.025Benign carcinoid tumor of the sigmoid colon
D3A.026Benign carcinoid tumor of the rectum
D3A.029Benign carcinoid tumor of the large intestine, unspecified portion
D3A.090Benign carcinoid tumor of the bronchus and lung
D3A.091Benign carcinoid tumor of the thymus
D3A.092Benign carcinoid tumor of the stomach
D3A.094Benign carcinoid tumor of the foregut, unspecified
D3A.095Benign carcinoid tumor of the midgut, unspecified
D3A.096Benign carcinoid tumor of the hindgut, unspecified
D3A.098Benign carcinoid tumors of other sites
D3A.8 Other benign neuroendocrine tumors

HCPCS Level II Code Number(s)

A9513 Lutetium Lu 177, dotatate, therapeutic, 1 mC​​

Revenue Code Number(s)
N/A


Coding and Billing Requirements

Policy History

Revisions From 08.01.57:
​11/01/2023
​​This policy has been reissued in accordance with the Company's annual review process.​
07/01/2022The policy has been reviewed and reissued to communicate the Company's continuing position on Lutathera® (Lutetium Lu 177 Dotatate)​.​

Effective July 1, 2022, the policy disclaimer was revised to communicate:
This policy only applies to members for whom Independence Administrators serves as the claims administrator and whose group has not enrolled in the UM vendor program.  For those groups who have been given the option to enroll in the UM vendor program, this policy is no longer applicable upon their renewal effective date. Individual member benefits must be verified before/prior to providing services.​​​​
​06/16/2021

​This policy has been reissued in accordance with the Company's annual review process.
​10/07/2020

​This policy has been reissued in accordance with the Company's annual review process.
​07/01/2019
​The following new policy has been developed to communicate the Company's coverage criteria for Lutathera® (Lutetium Lu 177 Dotatate).

6/29/2019
6/29/2019
11/1/2023
08.01.57
Medical Policy Bulletin
Commercial
No
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