Therapeutic Radiopharmaceuticals for Neuroendocrine Tumors

POLICY NUMBER

A.6.01.60

DESCRIPTION

Radiopharmaceuticals are composed of a radioisotope bond to an organic molecule and are used for diagnostic and therapeutic purposes. The organic molecule conveys the radioisotope to specific organs, tissues, or cells. Lutetium 177 (Lu 177) dotatate, classified as peptide receptor radionuclide therapy is a radiolabeled-somatostatin analogue that binds to somatostatin receptor expressing cells, including malignant somatostatin receptor-positive tumors such as neuroendocrine tumors. It is then internalized and beta particle emission from Lu 177 induces cellular damage by formation of free radicals in somatostatin receptor-positive and neighboring cells.

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% of all neuroendocrine tumors originate from the gastrointestinal system or pancreas and are referred to as gastroenteropancreatic 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. Lung neuroendocrine tumors may also be referred to as pulmonary neuroendocrine tumors, pulmonary carcinoids, or bronchopulmonary neuroendocrine tumors. Bronchopulmonary neuroendocrine tumors comprise approximately 20% of all lung cancers and are classified into 4 subgroups: typical carcinoid tumor, atypical carcinoid tumor, large-cell neuroendocrine carcinoma, and small-cell lung carcinoma. Less than 5% of bronchopulmonary neuroendocrine tumors exhibit hormonally-related symptoms such as carcinoid syndrome. Neuroendocrine tumors of the thymus account for only 5% of all tumors in the thymus and mediastinum.

Neuroendocrine tumors are classified as orphan diseases by the U.S. Food and Drug Administration (FDA). Based on an analysis of Surveillance, Epidemiology, and End Results Program registry data from 1973 to 2012, 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. In many cases, diagnosis is incidental to imaging for other unrelated causes. Most gastroenteropancreatic neuroendocrine tumors express somatostatin receptors that can be imaged using a radiolabeled form of the somatostatin analogue octreotide (eg, 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. Surgery alone or followed by chemotherapy along with treatment of hormone-related symptoms may be the initial approach for localized disease. For asymptomatic patients with slow progression, observation with routine surveillance imaging is an option. The prognosis for patients with metastatic well-differentiated gastroenteropancreatic neuroendocrine tumors is highly variable. The median overall survival (from diagnosis) for patients with metastatic pancreatic neuroendocrine tumors has been reported to range from 2 to 5.8 years, while the median overall survival for small bowel neuroendocrine tumors has been reported as 7.9 years.

Pharmacologic 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 (eg, 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 patients with neuroendocrine tumors treated with somatostatin analogues. However, the role of somatostatin analogues in patients with nonfunctioning neuroendocrine tumors is unclear.

Commercially available long-acting release forms of octreotide and lanreotide (eg, 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.

Second-Line Treatment OptionsCurrently, 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 InhibitorsThe 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% of pancreatic neuroendocrine tumors are associated with somatic variants in genes associated with the mechanistic target of rapamycin pathway. Everolimus, an oral mechanistic target of rapamycin inhibitor, has been shown to significantly prolong PFS vs placebo in patients with pancreatic neuroendocrine tumors (RADIANT-3 trial), and lung and gastrointestinal neuroendocrine tumors nonfunctional (RADIANT-4 trial). Everolimus is approved by the 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, conducted in patients with progressive advanced neuroendocrine tumors associated with carcinoid syndrome, failed to show a statistically significant improvement in the primary endpoint of PFS.

Tyrosine Kinase Receptor InhibitorsNeuroendocrine 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. 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 patients with advanced pancreatic neuroendocrine tumors. Sunitinib is FDA-approved for the treatment of progressive, well-differentiated pancreatic neuroendocrine tumors in patients with unresectable locally advanced or metastatic disease.

ChemotherapyResponse 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 patients 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.

Peptide Receptor Radionuclide Therapy: Lutetium 177 DotatateLutetium 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.

Pheochromocytoma and ParagangliomaPheochromocytoma and paraganglioma are rare neuroendocrine tumors that originate from the chromaffin cells of the adrenal glands. Chromaffin cells produce catecholamine neurotransmitters, such as epinephrine, norepinephrine, and dopamine. Compared to the normal chromaffin cells, pheochromocytomas and paraganglioma express high levels of the norepinephrine transporter on their cell surfaces. The excess amount of norepinephrine causes the clinical signs and symptoms like hypertension, headache, sweating, tremor, and palpitation. While most pheochromocytoma and paraganglioma are non-malignant (non-metastatic), about 10% of pheochromocytoma are malignant and about 25% of paraganglioma are malignant (metastatic) which can spread to other parts of the body, such as the liver, lungs, bone, or distant lymph nodes.

The average age of diagnosis is 43 years old. The estimated annual incidence of pheochromocytoma and paraganglioma is approximately 1 in 300,000 population. The 5-year mortality rates for patients with metastatic pheochromocytoma and paraganglioma has been reported as 37% depending on the primary tumor site and sites of metastases. In addition, the medical overall and disease-specific survival were 24.6 and 33.7 years for pheochromocytoma and paraganglioma.

DiagnosisThe initial diagnosis of pheochromocytomas and paragangliomas includes biochemical testing, such as blood tests and urinalysis which measure the levels of metanephrine, a catecholamine metabolite in blood and urine. Imaging may be used to detect the location and size of tumors within the organs or tissues. Other advanced diagnostic procedures, such as ¹²³I-metaiodobenzylguanidine (MIBG) scintigraphy, octreotide scan, and fluorodeoxyglucose-positron emission tomography scan are used to further determine whether the tumors are malignant and metastatic.

Certain genetic disorders such as multiple endocrine neoplasia 2 syndrome, von Hippel-Lindau syndrome, Neurofibromatosis type 1, and hereditary paraganglioma syndrome are considered risk factors for pheochromocytomas and paragangliomas and therefore genetic testing is recommended for all patients with pheochromocytoma or paraganglioma.

Treatment ApproachSurgical resection is mostly reserved for benign tumors as curative surgical resection is nearly impossible in metastatic disease. For patients with local, unresectable disease, palliative external beam radiotherapy may be used with or without cytoreductive resection for patients with bone metastases.

Peptide Receptor Radionuclide TherapyPrior to the approval of Iobenguane I 131, there were no FDA approved therapies for this indication. Lutetium 177 dotatate has been used off-label in this population. There is limited evidence for chemotherapy. In the case of unresectable progressive pheochromocytoma or paraganglioma, combination use of cyclophosphamide, dacarbazine, vincristine, doxorubicin, temozolomide, and thalidomide have been used. Tyrosine kinase receptor inhibitors such as sunitinib have also been used.

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

On May 5, 2022, Novartis announced that it had temporarily suspended production of Lutathera at production sites in Ivrea, Italy and Millburn, New Jersey out of an abundance of caution as a result of potential quality issues identified in its manufacturing processes. This production suspension will impact both commercial and clinical trial supply in the U.S. and Canada. At the time of announcement, the company expected resolution of these issues and resumption of some product supply within 6 weeks, subject to confirmation via an ongoing review. Novartis noted that there is currently no indication of risk to patients from doses previously produced at these sites, but has notified treatment sites to closely monitor patients. Production of Lutathera was resumed ahead of schedule in early June 2022.

On July 30, 2018, AZEDRA (iobenguane I 131) injection was approved by the FDA for the treatment of adult and pediatric patients age 12 years and older with iobenguane scan positive, unresectable, locally advanced or metastatic pheochromocytoma or paraganglioma who require systemic anticancer therapy. The manufacturer discontinued production of AZEDRA in August 2023 with the intention to ensure sufficient supply for existing patients through Q1 2024. The decision was not related to safety or efficacy concerns. Azedra is not further addressed in this policy.

A iobenguane I 123 product (AdreView™) has been available since 2008. Use of this product is limited to diagnosis of metastatic pheocromocytoma or neuroblastoma, with no therapeutic indications. It is not reviewed in this policy.

POLICY

Lutetium 177

Initial Treatment

Lutetium 177 (Lu 177) dotatate treatment is considered medically necessary when conditions 1 through 8 are met:

1. Individual is an adult (≥18 years of age).

2. Individual has documented low or intermediate grade (Ki-67 index ≤20%), locally advanced or metastatic, gastroenteropancreatic (including foregut, midgut, and hindgut) or metastatic bronchopulmonary or thymus neuroendocrine tumor.

3. Individual has documented somatostatin receptor expression of a neuroendocrine tumor as detected by somatostatin receptor-based imaging (see Policy Guidelines)

4. Individual has documented disease progression while on octreotide long-acting release or lanreotide therapy.

5. Individual is not receiving long-acting somatostatin analogues (e.g., octreotide long-acting release or lanreotide) for at least 4 weeks prior to initiating Lu 177 dotatate and has discontinued use of short-acting octreotide for at least 24 hours prior to initiating Lu 177 dotatate.

6. Individual does not have severe renal impairment (creatinine clearance, <30 mL/min).

7. Individual has adequate bone marrow and hepatic function as determined by the treating physician.

8. Individual has documented Karnofsky Performance Status score of 60 or greater.

Continuation of Treatment

Continuation of Lu 177 dotatate is considered medically necessary when conditions 1 through 5 are met:

1. No recurrent grade 2, 3, or 4 thrombocytopenia (see Policy Guidelines).

2. No recurrent grade 3 or 4 anemia and neutropenia (see Policy Guidelines).

3. No recurrent hepatotoxicity (see definition of hepatotoxicity in the Policy Guidelines section).

4. No recurrent grade 3 or 4 nonhematologic toxicity (see Policy Guidelines).

5. No renal toxicity requiring a treatment delay of 16 weeks or longer (see definition of renal toxicity in the Policy Guidelines section).

Lu 177 dotatate treatment is considered investigational in all other situations in which the above criteria are not met.

Lu 177 dotatate treatment greater than a total of 4 doses as per the Food and Drug Administration-approved regimen is considered investigational.

Lu 177 dotatate treatment is considered investigational for all other indications including pheochromocytoma and paraganglioma.

POLICY EXCEPTIONS

Federal Employee Program (FEP) may dictate that all FDA-approved devices, drugs or biologics may not be considered investigational and thus these devices may be assessed only on the basis of their medical necessity.

State Health Plan (State and School Employees) Participants

POLICY GUIDELINES

The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.

Somatostatin Receptor-Based Imaging

Preferred somatostatin receptor (SSTR)-based imaging options to assess receptor status include SSTR-positron emission tomography (PET)/computed tomography (CT) or SSTR-PET/magnetic resonance imaging (MRI). Octreotide single-photon emission computed tomography (SPECT)/CT may be used only if SSTR-PET is not available, as it is much less sensitive for defining SSTR-positive disease. Appropriate SSTR-PET radiotracers include Gallium 68 (Ga 68) dotatate, Ga 68 dotatoc, or Copper 64 (Cu 64) dotatate. SSTR-positive status is confirmed when uptake in measurable lesions is greater than the liver.

Lutetium 177

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

There are theoretical concerns regarding the competition between somatostatin analogues and Lu 177 dotatate for somatostatin receptor binding. Therefore, the following is recommended:

• Do not administer long-acting somatostatin analogues for 4 to 6 weeks prior to each Lu 177 dotatate treatment.

• Stop short-acting somatostatin analogues 24 hours before each Lu 177 dotatate treatment.

• Both long-acting and short-acting somatostatin analogues can be resumed 4 to 24 hours after each Lu 177 dotatate treatment.

Lu 177 dotatate is a radiopharmaceutical and should be used by or under the control of physicians who are qualified by specific training and experience in the safe use and handling of radiopharmaceuticals, and whose experience and training have been approved by the appropriate governmental agency authorized to license the use of radiopharmaceuticals.

Lu 177 dotatate should be discontinued permanently if the patient 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%.

Lu 177 dotatate should be discontinued permanently if patient 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% increase in baseline serum creatinine, or 40% decrease in baseline creatinine clearance calculated using Cockcroft-Gault equation with actual body weight.

The table below describes the grading of severity used in the Common Toxicity Criteria for Adverse Events (version 4.03).

Common Toxicity Criteria for Adverse Events, Version 4.03

Medically Necessary is defined as those services, treatments, procedures, equipment, drugs, devices, items or supplies furnished by a covered Provider that are required to identify or treat a Member's illness, injury or Mental Health Disorders, and which Company determines are covered under this Benefit Plan based on the criteria as follows in A through D:

1. consistent with the symptoms or diagnosis and treatment of the Member's condition, illness, or injury; and 

2. appropriate with regard to standards of good medical practice; and

3. not solely for the convenience of the Member, his or her Provider; and

4. the most appropriate supply or level of care which can safely be provided to Member. When applied to the care of an Inpatient, it further means that services for the Member's medical symptoms or conditions require that the services cannot be safely provided to the Member as an Outpatient.

For the definition of medical necessity, “standards of good medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. BCBSMS makes no payment for services, treatments, procedures, equipment, drugs, devices, items or supplies which are not documented to be Medically Necessary. The fact that a Physician or other Provider has prescribed, ordered, recommended, or approved a service or supply does not in itself, make it Medically Necessary.

Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.

POLICY HISTORY

08/01/2019: New policy added. Approved by Medical Policy Advisory Committee.

02/01/2021: Policy description updated to add information regarding Iobenguane I 131 and neuroendocrine tumors. Policy section updated to add medically necessary and investigational indications for Iobenguane I 131. Policy Guidelines updated regarding administration of Iobenguane I 131. Code Reference section updated to add HCPCS code A9590.

04/15/2022: Policy description updated. Medically necessary policy statement for continuation of treatment (condition #5) updated to change "renal toxicity" to "no renal toxicity."

03/15/2023: Policy title changed from "Therapeutic Radiopharmaceuticals in Oncology" to "Therapeutic Radiopharmaceuticals for Neuroendocrine Tumors." Policy description updated regarding neuroendocrine tumors, treatment approach, and treatment therapies. Policy statements updated to change "patient" to "individual." Medically necessary criteria for initial treatment of Lu 177 dotatate updated for clarification and consistency with NCCN guidelines. Added statement that Lu 177 dotatate treatment is considered investigational for all other indications including pheochromocytoma and paraganglioma. Policy Guidelines updated regarding somatostatin receptor-based imaging.

07/01/2023: Policy Exceptions updated regarding State Health Plan (State and School Employees) Participants.

08/09/2023: Policy description updated regarding treatments. Policy statements unchanged. Policy Guidelines updated to change "patients" to "individuals."

03/15/2024: Policy reviewed; no changes.

03/01/2025: Policy description updated regarding products. Policy section and Policy Guidelines updated to remove policy statements regarding Iobenguane I 131 as this product has been withdrawn from the market by the manufacturer. Code Reference section updated to remove HCPCS code A9590.

SOURCE(S)

Blue Cross Blue Shield Association policy # 6.01.60

CODE REFERENCE

This may not be a comprehensive list of procedure codes applicable to this policy.

The code(s) listed below are ONLY medically necessary if the procedure is performed according to the "Policy" section of this document.

Medically Necessary Codes

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