Clinical UM Guideline

 

Subject: Radioimmunotherapy and Somatostatin Receptor Targeted Radiotherapy
Guideline #: CG-THER-RAD-03 Publish Date:    12/12/2018
Status: Revised Last Review Date:    11/08/2018

Description

This document addresses somatostatin receptor targeted radiotherapies and radioimmunotherapies, which are intravenously administered treatments generated by combining therapeutic agents with a radionuclide, to target and treat certain types of cancer.  Somatostatin receptor targeted therapeutic radiotherapy involves the combination of a somatostatin analogue with a radionuclide.  Radioimmunotherapy involves a targeting monoclonal antibody that is coupled with a radionuclide.

The United States (U.S.) Food and Drug Administration (FDA) has approved the following somatostatin receptor targeted therapies and radioimmunotherapies:

Note: Somatostatin analogues that are not radiolabeled have diagnostic and clinical indications that are outside the scope of this document.

Note: Please see the following related document for additional information:

Clinical Indications

Medically Necessary:

  1. Ibritumomab tiuxetan (Zevalin)
    1. A single course of ibritumomab tiuxetan is considered medically necessary for one of the following:
      1. Individuals with CD20+ relapsed or refractory, low-grade or follicular B-cell non-Hodgkin lymphoma (NHL); or
      2. Individuals with previously untreated CD20+ follicular NHL who achieve a partial or complete response to first-line chemotherapy.
  2. Iobenguane I 131
    1. Iobenguane I 131 is considered medically necessary as primary treatment for locally unresectable or metastatic pheochromocytoma or paraganglioma when the following criteria are met:
      1. Individual is 12 years of age or older; and
      2. Individual has target lesions confirmed by an iobenguane scan (such as iodine-123 meta-iodobenzylguanidine [MIBG] scan); and
      3. Individual has an ECOG performance status of 0 to 2; and
      4. Individual has not received prior treatment with a radiolabeled somatostatin analog.
  3. Lutetium Lu 177 dotatate
    1. Lutetium Lu 177 dotatate is considered medically necessary for the treatment of the following tumors when criteria are met:
      1. Locally advanced, inoperable, or metastatic well-differentiated gastroenteropancreatic neuroendocrine tumors (including foregut, midgut and hindgut neuroendocrine tumors); or
      2. Locally advanced bronchopulmonary or thymus neuroendocrine tumors; and
      3. All of the following:
        1. Individual is 18 years of age or older; and
        2. Tumor has progressed while receiving greater than or equal to 4 months of somatostatin analog therapy (such as octreotide LAR or lanreotide) with evidence of tumor progression on imaging; and
        3. Individual has target lesions overexpressing somatostatin receptors confirmed by an appropriate somatostatin receptor-based imaging study (such as, 68Ga-dotatate PET/CT or somatostatin receptor scintigraphy); and
        4. Individual has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2; and
        5. Individual has not received prior treatment with a radiolabeled somatostatin analog.
    2. Lutetium Lu 177 dotatate is considered medically necessary as primary treatment for locally unresectable or metastatic pheochromocytoma or paraganglioma when the following criteria are met:
      1. Individual is 18 years of age or older; and
      2. Individual has target lesions overexpressing somatostatin receptors confirmed by an appropriate somatostatin receptor-based imaging study (such as 68Ga-dotatate PET/CT or somatostatin receptor scintigraphy); and
      3. Individual has an ECOG performance status of 0 to 2; and
      4. Individual has not received prior treatment with a radiolabeled somatostatin analog.

Not Medically Necessary:

  1. Ibritumomab tiuxetan (Zevalin)
    1. Ibritumomab tiuxetan, individually or in combination with other forms of irradiation or chemotherapy, is considered not medically necessary when the criteria above are not met.
    2. A repeat course of treatment with ibritumomab tiuxetan is considered not medically necessary.
    3. As part of CD20+ lymphoma pre-transplant conditioning regimen ibritumomab tiuxetan is considered not medically necessary.
  2. Iobenguane I 131
    Iobenguane I 131 is considered not medically necessary when the above criteria are not met and for all other indications.
  3. Lutetium Lu 177 dotatate
    Lutetium Lu 177 dotatate is considered not medically necessary when the above criteria are not met and for all other indications.
  4. Other treatments
    1. The use of other yttrium-labeled humanized antibody therapies is considered not medically necessary.
    2. Somatostatin analogs (including octreotide, lanreotide and vapreotide), which are not FDA approved for use as therapeutic receptor targeted radionuclide therapy, are considered not medically necessary.
Coding

The following codes for treatments and procedures applicable to this guideline are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

I.     Ibritumomab tiuxetan (Zevalin)

CPT

 

79403

Radiopharmaceutical therapy, radiolabeled monoclonal antibody by intravenous infusion

 

 

HCPCS

 

A9543

Yttrium Y-90 ibritumomab tiuxetan, therapeutic, per treatment dose, up to 40 millicuries [Zevalin therapeutic]

 

 

ICD-10 Diagnosis

 

C82.00-C82.99

Follicular lymphoma

C83.00-C83.99

Non-follicular lymphoma

C85.10-C85.99

Other specified and unspecified types of non-Hodgkin lymphoma

C88.4

Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue [MALT-lymphoma]

II.    Iobenguane I 131

CPT

 

79101

Radiopharmaceutical therapy, by intravenous administration [injection of Iobenguane I-131 (Azedra)]

 

 

HCPCS

 

A9699

Radiopharmaceutical, therapeutic, not otherwise classified [when specified as Iobenguane I 131 (Azedra)]

C9408

Iodine I-131 iobenguane, therapeutic, 1 millicurie [Azedra] [Note: code effective 01/01/2019]

 

 

ICD-10 Diagnosis

 

C74.10-C74.12

Malignant neoplasm of medulla of adrenal gland

C74.90-C74.92

Malignant neoplasm of unspecified part of adrenal gland

C75.5

Malignant neoplasm of aortic body and other paraganglia

III.   Lutetium Lu 177 dotatate

CPT

 

79101

Radiopharmaceutical therapy, by intravenous administration [when specified as injection of lutetium Lu 177 dotatate (Lutathera)]

 

 

HCPCS

 

A9513

Lutetium Lu 177, dotatate, therapeutic, 1 millicurie [Lutathera] [Note: code effective 01/01/2019; NOC code A9699 until 12/31/2018]

C9031

Lutetium Lu 177, dotatate, therapeutic, 1 mCi [Lutathera] [Note: code will be deleted 12/31/2018]

 

 

ICD-10 Diagnosis

 

C25.4

Malignant neoplasm of endocrine pancreas

C74.10-C74.12

Malignant neoplasm of medulla of adrenal gland

C74.90-C74.92

Malignant neoplasm of unspecified part of adrenal gland

C75.5

Malignant neoplasm of aortic body and other paraganglia

C7A.00-C7A.8

Malignant carcinoid tumors

C7B.00-C7B.09

Secondary carcinoid tumors

C7B.8

Other secondary neuroendocrine tumors

E34.0

Carcinoid syndrome

Z85.020

Personal history of malignant carcinoid tumor of stomach

Z85.030

Personal history of malignant carcinoid tumor of large intestine

Z85.040

Personal history of malignant carcinoid tumor of rectum

Z85.060

Personal history of malignant carcinoid tumor of small intestine

Z85.07

Personal history of malignant neoplasm of pancreas

Z85.110

Personal history of malignant carcinoid tumor of bronchus and lung

Z85.230

Personal history of malignant carcinoid tumor of thymus

Z85.858

Personal history of malignant neoplasm of other endocrine glands

Discussion/General Information

Non-Hodgkin lymphoma
Non-Hodgkin lymphoma (NHL), the most common hematologic cancer in the United States, is a collection of more than a dozen different cancers of the lymphatic system which generates the body's immune defenses.  NHL can be divided into two prognostic groups: indolent lymphomas and aggressive lymphomas.  Most of the indolent types are nodular (or follicular) in morphology.  Prior to the introduction of monoclonal antibody therapy, the most commonly used therapeutic options for indolent NHL were single-agent alkylating chemotherapy, combination chemotherapy with or without an alkylating agent, lymphoid or total-body irradiation, or a combination of these modalities, including protocols inducing sufficient cytotoxicity to require stem cell transplantation.  Indolent NHL has proven to be highly responsive to treatment with radiation in experimental studies, but the obstacles to external beam delivery in advanced-stage disease may explain its limited efficacy in individuals with relapsed indolent NHL.

Neuroendocrine tumors
Neuroendocrine tumors (NETs) are a rare group of tumors originating in neuroendocrine cells and account for about 0.5% of new cancers.  NETS can affect the foregut (thymus, esophagus, lung, stomach, duodenum, pancreas), midgut (appendix, ileum, cecum, ascending colon), or hindgut (distal bowel, rectum).  About two-thirds of the 171,000 cases in the United States are GEP-NETs which occur throughout the gastrointestinal tract and pancreas. GEP-NETs are classified as ‘functional’ or ‘non-functional.’  Functional tumors secrete peptides and neuroamines (for example, serotonin) that cause symptoms such as carcinoid syndrome, while non-functional tumors are usually asymptomatic and tend to be diagnosed at a later stage.  Surgery is first-line treatment for non-metastatic tumors, and is also used to reduce tumor burden and symptoms in advanced cases.  First-line treatment for unresectable or metastatic GEP-NETs is a long-acting somatostatin analog, either octreotide acetate (Sandostatin® LAR Depot, Sandoz GmbH, Schaftenau, Austria [Novartis Pharmaceuticals Corporation, East Hanover, NY, USA]) or lanreotide (Somatuline® Depot, Ipsen Pharma Biotech, Signes, France [Ipsen Biopharmaceuticals, Inc., Basking Ridge, NJ]).  Somatostatin analogs control symptoms from peptide secretion and reduce tumor growth.  Other drug therapy options, such as, everolimus or sunitinib and cytotoxic chemotherapy are available for disease progression during treatment with a somatostatin analog.  Additional treatment with lutetium Lu 177 dotatate has been developed as the prognosis for these tumors is poor.  For individuals with distant metastases, the median overall survival ranges from 4 months to 5.8 years depending on the primary tumor site (Dasari, 2017; National Cancer Institute [NCI], 2018; NCCN, 2018).

Pheochromocytoma and paraganglioma are rare and clinically heterogeneous NETs arising from neural crest cells.  They usually form inside and near the adrenal gland and can be found within the autonomic nervous system anywhere from the skull base to the sacrum (Kong, 2017).  Not all these tumors can be surgically removed,

Targeted therapies
Targeted treatments are forms of cancer therapy that take advantage of the biological differences between cancerous and noncancerous cells by "targeting" faulty genes or proteins that contribute to cancer.  Many times these drugs are combined with chemotherapy, radiation, or biological therapy.  Interruption, interference, or inhibition of the target should yield a clinical response in a significant proportion of individuals whose tumors express the target but in few individuals whose tumors do not express the target.  As such, targeted therapy offers the twin hopes of maximizing efficacy while minimizing toxicity.

Monoclonal antibodies locate and bind to specified targets on the surface of a cell.  Radioimmunotherapy utilizes monoclonal antibodies to deliver radioactive substances to specific targets on a cancer cell to maximize radiation and cell death while minimizing the effects on normal cells.

Somatostatin is a 14-amino-acid peptide hormone found on many cells of neuroendocrine origin.  It acts as a neurotransmitter in the central nervous system.  Hormonally, when it binds to cells, it inhibits the release of growth hormone, insulin, glucagon and gastrin.  Somatostatin receptors have been demonstrated on the surface of human tumor cells which includes the cells with amine precursor uptake and decarboxylation (APUD) properties such as pituitary tumors, endocrine pancreatic tumors, carcinoids, paragangliomas, small cell lung cancers, medullary thyroid carcinomas and pheochromocytomas.  Other non-APUD cells may also bear somatostatin receptors, such as activated lymphocytes, astrocytomas, and some breast carcinomas. 

Ibritumomab tiuxetan (Zevalin)
In 2002, the FDA granted accelerated approval to ibritumomab tiuxetan for the treatment of individuals with relapsed or refractory low-grade, follicular, or transformed B-cell NHL, including individuals with rituximab-refractory follicular NHL.  Ibritumomab tiuxetan is a type of radioimmunotherapy comprised of the monoclonal antibody, ibritumomab, coupled with radiolabeled tiuxetan (contains the radioactive isotope yttrium-90 [Y-90]). In 2009, the FDA expanded the labeled indications to include treatment of individuals with previously untreated follicular NHL who achieve a partial or complete response to first-line chemotherapy.  The single course administration of the ibritumomab tiuxetan therapeutic regimen includes rituximab and ibritumomab tiuxetan given in two steps.  The first step involves an infusion of rituximab.  The second step, administered 7 to 9 days after the first, consists of a second infusion of rituximab followed by ibritumomab tiuxetan.  Ibritumomab tiuxetan has been studied in two clinical settings, as consolidation therapy for lymphoma with a complete or partial response to first line therapy, and secondly as a pre-transplant conditioning regimen.

Ibritumomab tiuxetan as consolidation therapy
The FIT trial (first-line induction therapy) was a randomized study comparing treatment with and without ibritumomab tiuxetan consolidation therapy in 414 individuals with advanced stage CD20+ follicular lymphoma who achieved a complete response (CR) or partial response (PR) with first-line (induction) therapy.  Progression-free survival (PFS) at a median of 3.5 years was 36.5 months in the treatment cohort versus 13.3 months in the control group (p<0.0001) (Morschhauser, 2008).  After a median follow-up of 7.3 years, the PFS benefit continued to favor the ibritumomab tiuxetan cohort with an overall PFS of 41% compared to 22% for the control arm (hazard ratio [HR], 0.47; p<0.001) (Morschhauser, 2013).

The National Comprehensive Cancer Network® (NCCN®) Clinical Practice Guidelines (CPGs)® (2018) provide a category 1 recommendation for the use of radioimmunotherapy as second-line or subsequent therapy for follicular lymphoma and for progressive generalized extracutaneous disease in primary cutaneous B-cell lymphoma.  The latter is based on a retrospective pilot study with 9 individuals enrolled (Maza, 2008).

Pre-transplant conditioning regimen
High-dose chemotherapy and hematopoietic stem cell support is an established therapy for individuals with relapsed diffuse large cell lymphoma.  Conditioning regimens prior to the stem cell support typically include total body irradiation (TBI), and ibritumomab tiuxetan has been investigated as an alternative.  Clinical studies have focused on both autologous and allogeneic stem cell support, different subtypes of B-cell lymphoma, different chemotherapy regimens and different doses of ibritumomab tiuxetan.  Phase II trials have reported promising results (Berger, 2016; Bethge, 2010; Cabrero, 2017; Gopal, 2011; Khouri, 2012; Krishnan, 2012; Nadamanee, 2005), but there have been no randomized trials that have reported that a ibritumomab tiuxetan-containing pre-transplant conditioning regimen is associated with improved outcomes.  In the only published randomized study, Shimoni and colleagues (2012) compared the PFS at 2 years in 43 individuals with aggressive NHL randomized to receive a conditioning regimen of BEAM with or without ibritumomab tiuxetan followed by autologous stem cell support.  The PFS at 2 years was not significantly different between the 2 groups.  The study was halted early due to slow accrual rates.

Given the gaps in the published data, specialty consensus opinion no longer recommends the use of radioimmunotherapy with ibritumomab tiuxetan as a conditioning regimen for hematopoietic stem cell transplants to treat individuals with NHL.

Adverse Events and Warnings:
The product information label (2013) for ibritumomab tiuxetan includes the following Black Box Warnings and information:

Iobenguane I 131 (AZEDRA)
On July 30, 2018, the US FDA approved iobenguane I 131, a radiolabeled norepinephrine analog, for the treatment of individuals 12 and older with iobenguane scan-positive, unresectable, locally advanced or metastatic pheochromocytoma or paraganglioma.  The FDA granted iobenguane I 131 breakthrough therapy designation as well as priority review, orphan product and fast track status. 

The safety and efficacy for FDA approval of iobenguane I 131 was based on two clinical trials.  The first, a phase 1, open-label, single-arm, multicenter, dose-finding, 12-month, efficacy study enrolled 21 adults (18 years of age or older) with recurrent or metastatic pheochromocytoma or paraganglioma.  Main outcome measures included dose-limiting toxicities, adverse events, absorbed radiation dose estimates, tumor and biochemical response, and survival.  From this trial, the maximum tolerated dose was determined and OS was estimated at 85.7% after 12 months, and 61.9% at 24 months following treatment.  The majority (84%) of adverse events in the phase 1 trial were considered mild or moderate in severity.  The most common (> 10%) grade 3-4 events were cytopenias, nausea, and vomiting; no study discontinuations occurred as a result for adverse events.  From approximately 2.5 months to 22 months, 5 deaths occurred; none were determined to be related to treatment (Noto, 2014). 

An unpublished, phase 2 open-label, single-arm, multicenter clinical trial was conducted in which 68 individuals, 12 years of age and older, with iobenguane scan-positive, unresectable, locally advanced or metastatic pheochromocytoma or paraganglioma were enrolled.  Study inclusion criteria included a Karnofsky performance status ≥ 60, ineligible for curative therapy, absence of active central nervous system lesions, and no changes to their antihypertensive regimen in the 30 days prior to the first therapeutic dose.  The primary outcome of interest was the proportion of individuals who experienced at least a 50% reduction in antihypertensive medication, and sustained the reduction for at least 6 months.  Overall tumor response, as measured by the Response Evaluation Criteria in Solid Tumors (RECIST; version 1.0), was also measured.  Initial follow-up was for a 12-month time period, an additional 4 years of outcomes were analyzed and included in the FDA application.  Overall, 17 study enrollees (25%; 95 % confidence interval [CI], 16 to 37) had a reduction in antihypertensive medications of at least 50% that was sustained for at least 6 months.  The overall response rate based on the RECIST was 22% (95% CI, 14 to 33; n=15).  The most common grade 3-4 adverse reactions (≥ 10%) were lymphopenia, neutropenia, thrombocytopenia, fatigue, anemia, increased international normalized ratio, nausea, dizziness, hypertension, and vomiting (Iobenguane I 131 PI Label, 2018).

Adverse Events and Warnings:
The product information label (2018) for iobenguane I 131 includes the following warnings and information:

Lutetium Lu 177 dotatate (Lutathera)
On January 26, 2018, the U.S. FDA approved lutetium Lu 177 dotatate, a radiolabeled somatostatin analog, for the treatment of adults with somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs) including foregut, midgut, and hindgut NETs.  Lutetium Lu 177 dotatate is a radiopharmaceutical treatment called peptide receptor radionuclide therapy (PRRT) which binds to, and is internalized by, somatoreceptor expressing cells, including malignant somatostatin receptor-positive tumors.  The cells in most well-differentiated NETs have an abundance (overexpression) of surface receptors for somatostatin.  Octreotide is a laboratory-made version of somatostatin that binds to somatostatin receptors on NETs.  In PRRT, octreotide is combined with a therapeutic dose of the radionuclides creating lutetium Lu 177 dotatate.

Treatment of GEP-NETs with lutetium Lu 177 dotatate
Early case series and retrospective studies report that treatment of advanced GEP-NETs with 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, 2014; Ezziddin, 2014; Kwekkeboom, 2003; Kwekkeboom, 2005; Kwekkeboom, 2008; Sabet, 2014; Sabet, 2015; Teunissen, 2004).

The efficacy of lutetium Lu 177 dotatate was evaluated in a phase 3, randomized, multicenter, open-label, active controlled trial of 229 individuals with progressive, well-differentiated, locally advanced, inoperable or metastatic somatostatin receptor-positive midgut carcinoid tumors. Study inclusion criteria included adults (median age, 64 years; range 28-87 years) with a Karnofsky performance status ≥ 60, confirmed presence of somatostatin receptors on all lesions (OctreoScan uptake ≥ normal liver), no prior treatment with PRRT, and no prior external radiation therapy to more than 25% of the bone marrow.  For those individuals enrolled, the median Karnofsky performance score was 90 (range, 60 to 100), 74% received a constant dose of octreotide for > 6 months, and 12% had prior treatment with everolimus.  Participants were randomized (1:1) to receive either lutetium Lu 177 dotatate (7.4 GBq [200 mCi]) every 8 weeks for up to 4 administrations (maximum cumulative dose of 29.6 GBq) or high-dose long-acting octreotide (60 mg by intramuscular injection every 4 weeks).  Participants in the lutetium Lu 177 dotatate arm also received long-acting octreotide 30 mg as an intramuscular injection 4 to 24 hours after each lutetium Lu 177 dotatate dose and every 4 weeks after completion of lutetium Lu 177 dotatate treatment until disease progression or until week 76 of the study.  Participants in both arms could receive short-acting octreotide for symptom management until 24 hours before each lutetium Lu 177 dotatate dose.  Among participants receiving lutetium Lu 177 dotatate with octreotide, 79% received a cumulative dose > 22.2 GBq (> 600 mCi) and 76% of participants received all 4 planned doses.  A total of 6% of participants required a dose reduction and 13% of participants discontinued lutetium Lu 177 dotatate.  The primary efficacy outcome measure was PFS determined using RECIST version 1.1.  An independent image reading center performed tumor assessment every 12 weeks.  Additional efficacy outcome measures were overall response rate (ORR), overall survival (OS), toxicity and safety, and quality of life.  At the data-cutoff date for the primary analysis, the estimated rate of PFS at month 20 was 65.2% (95% CI, 50.0 to 76.8) in the lutetium Lu 177 dotatate arm and 10.8% (95% CI, 3.5 to 23.0) in the 60 mg long-acting octreotide arm.  The study met its primary endpoint, showing a 79% reduction in risk of disease progression or death using lutetium Lu 177 dotatate compared to 60 mg long-acting octreotide (HR, 0.21; 95% CI, 0.13-0.32; p<0.0001).  Median PFS was not yet reached in the lutetium Lu 177 dotatate arm (not evaluable) compared to 8.5 months in the 60 mg long-acting octreotide arm.  A pre-planned interim OS analysis determined that lutetium Lu 177 dotatate treatment lead to a 48% reduction in the estimated risk of death (HR, 0.52; 95% CI, 0.32-0.84) compared to treatment with 60 mg long-acting octreotide.  The objective response rate, composed of complete and partial responses, was 13% for the lutetium Lu 177 dotatate arm compared to 4% in the 60 mg long-acting octreotide arm (p<0.0148) (Lutathera PI label, 2018).

The FDA also considered the efficacy of lutetium Lu 177 dotatate in individuals with foregut, midgut, and hindgut GEP-NETs in a subset analysis of 360 participants enrolled in the ERASMUS Medical Center study (Brabander, 2017).  Study participants received lutetium Lu 177 dotatate as expanded access under a general PRRT protocol at a single site in the Netherlands.  Lutetium Lu 177 dotatate (7.4 GBq [200 mCi]) was administered every 6 to 13 weeks for up to 4 doses concurrently with the recommended amino acid solution.  A total of 81% of participants in the subset received a cumulative dose ≥ 22.2 GBq (≥ 600 mCi).  The primary efficacy outcome was investigator assessed ORR.  The median age in the efficacy subset was 61 years (25 to 88 years), 52% were male, 61% had a baseline Karnofsky performance status ≥ 90 (60 to 100), 60% had progressed within 12 months of treatment, and 15% had received prior chemotherapy.  A total of 55% of participants received a concomitant somatostatin analog. Baseline tumor assessments were obtained in 39% of participants.  The investigator-assessed ORR was 16% (n=58 participants; 95% CI, 13 to 20) in the 360 participants with GEP-NETs.  A total of 3 complete responses were observed (< 1%) (Lutathera PI label, 2018).

Treatment-related adverse reactions occurred in 86% and 31% of participants in the lutetium Lu 177 dotatate group and control arm, respectively.  In NETTER-1, the most common grade 3-4 adverse reactions occurred with a greater frequency (at least 4%) in participants receiving lutetium Lu 177 dotatate with long-acting octreotide compared with those receiving high-dose long-acting octreotide alone.  Adverse reactions included lymphopenia (44%), increased gamma-glutamyl transpeptidase (GGT) (20%), vomiting (7%), nausea and elevated aspartate aminotransferase (AST) (5% each), and increased alanine aminotransferase (ALT), hyperglycemia, and hypokalemia (4% each).  In total, 5 participants discontinued lutetium Lu 177 dotatate for renal-related events and 4 discontinued for hematological toxicities.  With a median follow-up of 24 months, myelodysplastic syndrome (MDS) was reported in 2.7% of participants in the lutetium Lu 177 dotatate group compared to 0 participants receiving high-dose long-acting octreotide.  In ERASMUS, safety data from 1214 evaluable participants was examined and retrospective medical record review on a subset of 811 participants was conducted to document serious adverse reactions.  With a median follow-up time of more than 4 years, serious adverse reactions were reported as MDS (n=15 participants, 2%), acute leukemia (n=4 participants, 1%), renal failure (2%), hypotension (1%), cardiac failure (2%), myocardial infarction (1%), and neuroendocrine hormonal crisis (1%).  The median time to development of MDS was 28 months (9 to 41 months), and 55 months (32 to 155 months) for acute leukemia (Lutathera PI label, 2018).  In a subsequent analysis of ERASMUS trial data, the prevalence of persistent hematologic dysfunction (PHD) (defined as a diagnosis of MDS, acute myeloid leukemia, myeloproliferative neoplasm, or otherwise unexplained cytopenias for > 6 months) after PRRT with lutetium Lu 177 dotatate was analyzed in 274 of 367 participants with GEP-NETs with somatostatin receptor-positive tumors (Bergsma, 2018).  The frequency of PHD was reported as 4%, with a median time to PHD development of 41 months after the first PRRT cycle.  The relative risk for developing a hematopoietic neoplasm was 2.7.  No risk factors were found for the development of PHD in GEP-NET participants.

Off-label use of lutetium Lu 177 dotatate
Bronchopulmonary NETs, Thymus NETs, and Metastatic Pheochromocytoma/Paraganglioma
The NCCN CPG for neuroendocrine and adrenal tumors (V2.2018) and the NCCN Drugs and Biologics Compendium® (2018) include a category 2A recommendation for use of lutetium Lu 177 dotatate in the treatment of incompletely resected, locoregionally advanced and/or metastatic neuroendocrine bronchopulmonary/thymus tumors (carcinoid) if somatostatin receptor positive imaging and progression on octreotide/lanreotide:

Additionally, the NCCN guideline includes a category 2A recommendation for use of lutetium Lu 177 dotatate as primary treatment for locally unresectable pheochromocytoma/paraganglioma with distant metastases if somatostatin receptor positive imaging.  Both category 2A recommendations are “based upon lower-level evidence, there is 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, 2017; Kong, 2017).

In ERASMUS, 2 participants with thymus NETs and 23 participants with primary bronchial NETs were treated with lutetium Lu 177 dotatate every 6 to 13 weeks for up to 4 doses (Brabander, 2017).  For participants with bronchial NETs, the median PFS, time to progression, and OS were 20 months, 25 months, and 52 months (95% CI, 49-55 months), respectively.  Partial response, stable disease, and progressive disease were reported in 7 (30%), 7 (30%), and 6 (26%) participants, respectively.  No participant experienced a complete response.  Outcomes data were not separately reported for the 2 participants with thymus NETs.  Adverse effects and long-term toxicities of treatment with lutetium Lu 177 dotatate were not reported for the participants with either neuroendocrine tumor types.  There was no evaluable data on 3 of 23 (13%) participants with bronchial NETs treated at the Netherland’s institution as they were from different countries and follow-up was conducted in their own country.

Kong and colleagues (2017) retrospectively reviewed outcomes of individuals treated with lutetium Lu 177 dotatate for unresectable or metastatic paraganglioma/pheochromocytoma, including those with uncontrolled secondary hypertension.  A total of 20 participants (age range, 21 to 77 years) with high somatostatin receptor expressing tumors were treated at 2 institutions with lutetium Lu 177 dotatate every 6 to 10 weeks for up to 4 doses and followed at least 3 months from the last cycle of treatment or until death or study close-out.  Some participants at one treatment site were given radiosensitizing chemotherapy (that is, capecitabine or capecitabine and temozolomide) unless contraindicated.  The median cumulative activity was 22 GBq (median 4 cycles).  A total of 14 of 20 participants were treated for uncontrolled hypertension and 6 participants for progressive or symptomatic metastatic disease or local recurrence.  At 3 months after lutetium Lu 177 dotatate, 8 of 13 (62%) participants treated for hypertension required reduced medication doses; the remaining 5 (38%) participants had no change in antihypertensive medication doses.  One participant was lost to follow-up.  Of 17 participants evaluable for response to lutetium Lu 177 dotatate, 8 (47%) had a partial response, 7 (41%) had stable findings, and 2 (12%) had disease progression.  Of 14 evaluable participants, 4 (29%) had partial and 7 (50%) had stable disease on computed tomography as defined by RECIST version 1.1.  A total of 3 other participants had osseous metastatic disease evaluable only on somatostatin receptor imaging (n=2, partial response; n=1, stable).  Of the 7 participants with stable disease on computed tomography, 4 participants were treated for functional hypertension (not prior disease progression), 2 participants had stabilization of previously progressive disease, and 1 participant had no objective evidence of previous progression before lutetium Lu 177 dotatate.  Median PFS was 39 months; median OS was not reached (5 deaths; median follow-up, 28 months).  Grade 3 lymphopenia or thrombocytopenia was experienced by 4 and 2 participants, respectively.  Renal impairment in 2 participants was attributed to underlying disease processes.  No documented MDS or myelodysplasia was reported.

Adverse Events and Warnings:
The product information label (2018) for lutetium Lu 177 dotatate includes the following warnings and information:

Definitions

Carcinoid tumors: Rare, slow-growing tumors of the neuroendocrine cells (enterochromaffin or Kulchitsky cells) widely found in many organs of body, but usually originate in the digestive tract (foregut, midgut, or hindgut) or lung; also called carcinoids or well-differentiated NETs.

Cytotoxic: Chemicals that are directly toxic to cells, preventing their reproduction or growth.

Eastern Cooperative Oncology Group (ECOG) performance status (PS): A scale used to determine the individual's level of functioning. This scale may also be referred to as the WHO (World Health Organization) or Zubrod score which is based on the following scale:

0    Fully active, able to carry on all pre-disease performance without restriction
1    Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work
2    Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about more than 50% of waking hours.
3    Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours
4    Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair.
5    Dead

Line of therapy:

Malignant: Cancerous. Malignant cells can invade and destroy nearby tissue and spread to other parts of the body.

Metastasis: A cancer that has spread from one part of the body to another; a metastatic tumor contain cells that are like those in the original (primary) tumor that has spread beyond the local lymph nodes.

Monoclonal antibody: A form of biologic therapy that acts specifically against a particular antigen.

Neuroendocrine tumor (NET): A tumor that forms from cells that release hormones into the blood in response to a signal from the nervous system.  NETs may make higher-than-normal amounts of hormones, which can cause many different symptoms.  These tumors may be benign (not cancerous) or malignant (cancerous).

Non-Hodgkin Lymphoma (NHL): A group of malignant solid tumors of lymphoid tissues.

Phenotype: The total characteristics displayed by the tumor.

Radioisotope: A radioactive form of an element or isotope.

Radionuclide: An unstable form of a chemical element that releases radiation as it breaks down and becomes more stable.  Radionuclides may occur in nature or be made in a laboratory.  In medicine, they are used in imaging tests and in treatment; also called radioisotope.

Radiotherapy: Systemic radiotherapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that travels in the blood to tissues throughout the body.

Refractory disease: Illness or disease that does not respond to treatment.

Somatostatin-receptor scintigraphy (SRS): A type of radionuclide scan used to find carcinoid and other types of tumors.  Radioactive octreotide, a drug similar to somatostatin, is injected into a vein and travels through the bloodstream. The radioactive octreotide attaches to tumor cells that have receptors for somatostatin. A radiation-measuring device detects the radioactive octreotide, and take pictures showing where the tumor cells are in the body; also called octreotide scan.

References

Peer Reviewed Publications:

  1. Andrade-Campos MM, Liévano P, Espinosa-Lara N, et al. Long-term complication in follicular lymphoma: assessing the risk of secondary neoplasm in 242 patients treated or not with 90-yttrium-ibritumomab-tiuxetan. Eur J Haematol. 2016; 97(6):576-582.
  2. Ansell SM, Ristow KM, Habermann TM, et al. Subsequent chemotherapy regimens are well tolerated after radioimmunotherapy with yttrium-90 ibritumomab tiuxetan for non-Hodgkin's lymphoma. J Clin Oncol. 2002; 20(18):3885-3890.
  3. Auger-Quittet S, Duny Y, Daures JP, Quittet P. Outcomes after (90) Yttrium-ibritumomab tiuxetan-BEAM in diffuse large B-cell lymphoma: a meta-analysis. Cancer Med. 2014; 3(4):927-938.
  4. Berger MD, Branger G, Klaeser B, et al. Zevalin and BEAM (Z-BEAM) versus rituximab and BEAM (R-BEAM) conditioning chemotherapy prior to autologous stem cell transplantation in patients with mantle cell lymphoma. Hematol Oncol. 2016; 34(3):133-139.
  5. Bergsma H, Konijnenberg MW, Kam BL, 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.
  6. Bergsma H, van Lom K, Raaijmakers MHGP, et al. Persistent hematologic dysfunction after peptide receptor radionuclide therapy with (177)Lu-DOTATATE: incidence, course, and predicting factors in patients with gastroenteropancreatic neuroendocrine tumors. J Nucl Med. 2018; 59(3):452-458.
  7. Bethge WA, Lange T, Meisner C, et al. Radioimmunotherapy with yttrium-90-ibritumomab tiuxetan as part of a reduced-intensity conditioning regimen for allogeneic hematopoietic cell transplantation in patients with advanced non-Hodgkin lymphoma: results of a phase 2 study. Blood. 2010; 116(10):1795-1802.
  8. 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; 23(16):4617-4624.
  9. Brabander T, van der Zwan WA, Teunissen JJM, et al. Long-term efficacy, survival, and safety of [(177)Lu-DOTA(0),Tyr(3)]octreotate in patients with gastroenteropancreatic and bronchial neuroendocrine tumors. Clin Cancer Res. 2017; 23(16):4617-4624.
  10. Cabrero M, Martin A, Briones J, et al. Phase II study of yttrium-90-ibritumomab tiuxetan as part of reduced-intensity conditioning (with melphalan, fludarabine ± thiotepa) for allogeneic transplantation in relapsed or refractory aggressive B cell lymphoma: A GELTAMO Trial. Biol Blood Marrow Transplant. 2017; 23(1):53-59.
  11. 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.
  12. Delpassand ES, Samarghandi A, Zamanian S, et al. Peptide receptor radionuclide therapy with 177Lu-DOTATATE for patients with somatostatin receptor-expressing neuroendocrine tumors: the first US phase 2 experience. Pancreas. 2014; 43(4):518-525.
  13. Epperla N, Pham AQ, Burnette BL, et al. Risk of histological transformation and therapy-related myelodysplasia/acute myeloid leukaemia in patients receiving radioimmunotherapy for follicular lymphoma. Br J Haematol. 2017; 178(3):427-433.
  14. Ezziddin S, Khalaf F, Vanezi M, et al. Outcome of peptide receptor radionuclide therapy with 177Lu-octreotate in advanced grade 1/2 pancreatic neuroendocrine tumours. Eur J Nucl Med Mol Imaging. 2014; 41(5):925-933.
  15. Fruchart C, Tilly H, Morschhauser F, et al. Upfront consolidation combining Yttrium-90 ibritumomab tiuxetan and high-dose therapy with stem cell transplantation in poor-risk patients with diffuse large B cell lymphoma.  Blood Marrow Transplant. 2014; 20(12):1905-1911.
  16. Gopal AK, Guthrie KA, Rajendran J, et al. Y-ibritumomab tiuxetan, fludarabine, and TBI-based nonmyeloablative allogeneic transplantation conditioning for patients with persistent high-risk B-cell lymphoma. Blood. 2011; 118(4):1132-1139.
  17. Hertzberg M, Gandhi MK, Trotman J, et al. Early treatment intensification with R-ICE and 90Y-ibritumomab tiuxetan (Zevalin)-BEAM stem cell transplantation in patients with high-risk diffuse large B-cell lymphoma patients and positive interim PET after 4 cycles of R-CHOP-14. Haematologica. 2017; 102(2):356-363.
  18. Illidge TM, Mayes S, Pettengell R, et al. Fractionated 90Y-ibritumomab tiuxetan radioimmunotherapy as an initial therapy of follicular lymphoma: an international phase II study in patients requiring treatment according to GELF/BNLI criteria. J Clin Oncol. 2014; 32(3):212-218.
  19. Illidge TM, McKenzie HS, Mayes S et al. Short duration immunochemotherapy followed by radioimmunotherapy consolidation is effective and well tolerated in relapsed follicular lymphoma: 5-year results from a UK National Cancer Research Institute Lymphoma Group study. Br J Haematol. 2016; 173(2):274-282.
  20. Karmali R, Kassar M, Venugopal P, et al. Safety and efficacy of combination therapy with fludarabine, mitoxantrone, and rituximab followed by yttrium-90 ibritumomab tiuxetan and maintenance rituximab as front-line therapy for patients with follicular or marginal zone lymphoma. Clin Lymphoma Myeloma Leuk. 2011; 11(6):467-474.
  21. Khouri IF, Saliba RM, Erwin WD, et al. Nonmyeloablative allogeneic transplantation with or without 90yttrium ibritumomab tiuxetan is potentially curative for relapsed follicular lymphoma: 12-year results. Blood. 2012; 119(26):6373-6378.
  22. 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.
  23. Krishnan A, Nademanee A, Fung HC, et al. Phase II trial of a transplantation regimen of yttrium-90 ibritumomab tiuxetan and high dose chemotherapy in patients with non-Hodgkin’s lymphoma. J Clin Oncol. 2008; 26(1):90-95.
  24. Krishnan A, Palmer JM, Tsai N, et al. Matched-cohort analysis of autologous hematopoietic cell transplantation with radioimmunotherapy versus total body irradiation-based conditioning for poor-risk diffuse large cell lymphoma. Biol Blood Marrow Transplant. 2012; 18(3):441-450.
  25. Kulke MH, Siu LL, Tepper JE, et al. Future directions in the treatment of neuroendocrine tumors: consensus report of the National Cancer Institute Neuroendocrine Tumor clinical trials planning meeting. J Clin Oncol. 2011; 29(7):934-943.
  26. Kwekkeboom DJ, Bakker WH, Kam BL, et al. Treatment of patients with gastro-entero-pancreatic (GEP) tumours with the novel radiolabelled somatostatin analogue [177Lu-DOTA(0),Tyr3] octreotate. Eur J Nucl Med Mol Imaging. 2003; 30(3):417-422.
  27. Kwekkeboom DJ, de Herder WW, Kam BL, et al. Treatment with the radiolabeled somatostatin analog [177 Lu-DOTA 0,Tyr3] octreotate: toxicity, efficacy, and survival. J Clin Oncol. 2008; 26(13):2124-2130.
  28. Kwekkeboom DJ, Teunissen JJ, Bakker WH, et al. Radiolabeled somatostatin analog [177Lu DOTA0,Tyr3] octreotate in patients with endocrine gastroenteropancreatic tumors. J Clin Oncol. 2005; 23(12):2754-2762.
  29. Maza S, Gellrich S, Assaf C, et al. Yttrium-90 ibritumomab tiuxetan radioimmunotherapy in primary cutaneous B-cell lymphomas: first results of a prospective, monocentre study. Leuk Lymphoma. 2008; 49(9):1702-1709.
  30. Mei M, Wondergem MJ, Palmer JM, et al. Autologous transplantation for transformed non-Hodgkin lymphoma using an Yttrium-90 ibritumomab tiuxetan conditioning regimen. Biol Blood Marrow Transplant. 2014; 20(12):2072-2075.
  31. Morschhauser F, Radford J, Van Hoof A, et al. 90Yttrium-ibritumomab tiuxetan consolidation of first remission in advanced-stage follicular non-Hodgkin lymphoma: updated results after a median follow-up of 7.3 years from the International, Randomized, Phase III First-Line Indolent trial. J Clin Oncol. 2013; 31(16):1977-1983.
  32. Morschhauser F, Radford J, Van Hoof A, et al. Phase III trial of consolidation therapy with Yttrium-90-ibritumomab tiuxetan compared with no additional therapy after first remission in advanced follicular lymphoma. J Clin Oncol. 2008; 28(32):5156-5164.
  33. Nadamanee A, Forman S, Molina A, et al. A phase 1/2 trial of high-dose yttrium-90-ibritumomab tiuxetan in combination with high-dose etoposide and cyclophosphamide followed by autologous stem cell transplantation in patients with poor-risk or relapsed non-Hodgkin lymphoma. Blood. 2005, 106(8):2896-2902.
  34. Noto RB, Pryma DA, Jensen J, et al. Phase 1 Study of high-Specific-activity I-131 MIBG for metastatic and/or recurrent pheochromocytoma or paraganglioma. J Clin Endocrinol Metab. 2018; 103(1):213-220.
  35. Rose AC, Shenoy PJ, Garrett G, et al. A systematic literature review and meta-analysis of radioimmunotherapy consolidation for patients with untreated follicular lymphoma. Clin Lymphoma Myeloma Leuk. 2012; 12(6):393-399.
  36. 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.
  37. 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.
  38. Scholz CW, Pinto A, Linkesch W, et al. 90Yttrium-ibritumomab-tiuxetan as first-line treatment for follicular lymphoma: 30 months of follow-up data from an international multicenter phase II clinical trial. J Clin Oncol. 2013; 31(3):308-313.
  39. Shimoni A, Avivi I, Rowe JM, et al. A randomized study comparing Yttrium-90 ibritumomab tiuxetan (Zevalin) and high-dose BEAM chemotherapy versus BEAM alone as the conditioning regimen before autologous stem cell transplantation in patients with aggressive lymphoma. Cancer. 2012; 118(19):4706-4714.
  40. Shimoni A, Zwas ST, Oksman Y, et al. Yttrium-90-irbritumomab tiutexan (Zevalin) combined with high-dose BEAM chemotherapy and autologous stem cell transplantation for chemo-refractory aggressive non-Hodgkin’s lymphoma. Exp Hematol. 2007; 35(4):534-540. 
  41. Strosberg J, El-Haddad G, Wolin E, et al. Phase 3 trial of (177)Lu-dotatate for midgut neuroendocrine tumors. N Engl J Med. 2017; 376(2):125-135.
  42. Teunissen JJ, Kwekkeboom DJ, Krenning EP. Quality of life in patients with gastroenteropancreatic tumors treated with [177Lu-DOTA0,Tyr3] octreotate. J Clin Oncol. 2004; 22(13):2724-2729.
  43. Turaga KK, Kvols LK. Recent progress in the understanding, diagnosis, and treatment of gastroenteropancreatic neuroendocrine tumors. CA Cancer J Clin. 2011; 61(2):113-132.
  44. van Hulsteijn LT, Niemeijer ND, Dekkers OM, Corssmit EP. (131)I-MIBG therapy for malignant paraganglioma and phaeochromocytoma: systematic review and meta-analysis. Clin Endocrinol (Oxf). 2014; 80(4):487-501.
  45. Witzig TE, Flinn IW, Gordon LI, et al. Treatment with ibritumomab tiuxetan radioimmunotherapy in patients with rituximab-refractory follicular non-Hodgkin's lymphoma. J Clin Oncol. 2002; 20(15):3262-3269.
  46. Witzig TE, Gordon LI, Cabanillas F, et al. Randomized controlled trial of yttrium-90-labeled ibritumomab tiuxetan radioimmunotherapy versus rituximab immunotherapy for patients with relapsed or refractory low-grade, follicular, or transformed B cell non-Hodgkin's lymphoma. J Clin Oncol. 2002; 20(10):2453-2463.
  47. Witzig TE, Hong F, Micallef IN, et al. A phase II trial of RCHOP followed by radioimmunotherapy for early stage (stages I/II) diffuse large B-cell non-Hodgkin lymphoma: ECOG3402. Br J Haematol. 2015; 170(5):679-686.
  48. Yoshinaga K, Oriuchi N, Wakabayashi H, et al. Effects and safety of ¹³¹I-metaiodobenzylguanidine (MIBG) radiotherapy in malignantneuroendocrine tumors: results from a multicenter observational registry. Endocr J. 2014; 61(12):1171-1180.

Government Agency, Medical Society and Other Authoritative Publications:

  1. Azedra (iobenguane I 131). In: DrugPoints System (electronic version). Truven Health Analytics, Greenwood Village, CO. Updated August 08, 2018. Available at: http://www.micromedexsolutions.com. Accessed on September 23, 2018.
  2. Azedra [Product Information], New York, NY. Progenics Pharmaceuticals, Inc. July 31, 2018. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/209607s000lbl.pdf. Accessed on September 26, 2018.
  3. Gordon LI, Molina A, Witzig T, et al.  Durable response after ibritumomab tiuxetan radioimmunotherapy for CD20+ B-cell lymphoma: long-term follow-up of a phase I/II study. American Society of Hematology. Blood. 2004; 103(12):4429-4431.
  4. Henkin RE, Del Rowe JD, Grigsby PW, et al.  ACR-ASTRO Practice guideline for the performance of therapy with unsealed radiopharmaceutical sources.  Clin Nucl Med. 2011; 36(8):e72-e80.
  5. Ibritumomab tiuxetan Monograph. Lexicomp® Online, American Hospital Formulary Service® (AHFS®) Online, Hudson, Ohio, Lexi-Comp., Inc. Last revised July 2, 2012. Accessed on September 24, 2018.
  6. Ibritumomab tiuxetan. NCCN Drugs & Biologics Compendium (NCCN®) © 2018 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website: http://www.nccn.org/index.asp. Accessed on September 24, 2018.
  7. Iobenguane I 131 Monograph. Lexicomp® Online, American Hospital Formulary Service® (AHFS®) Online, Hudson, Ohio, Lexi-Comp., Inc. Last revised August 20, 2018. Accessed on September 24, 2018.
  8. Lutathera [Product Information]. Colleretto Giacosa, Italy. Advanced Accelerator Applications, S.r.l., and Advanced Accelerator Applications USA, Inc., NJ; January 26, 2018. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/208700s000lbl.pdf. Accessed on September 21, 2018.
  9. National Comprehensive Cancer Network®. NCCN Drugs & Biologics Compendium® (electronic version). For additional information visit the NCCN website: http://www.nccn.org. Accessed on September 21, 2018.
  10. National Institutes of Health (NIH). Lu-177-DOTATATE (Lutathera) in therapy of inoperable pheochromocytoma/ paraganglioma. NLM Identifier: NCT03206060. Last updated August 17, 2018. Available at: https://clinicaltrials.gov/ct2/show/NCT03206060. Accessed on September 21, 2018.
  11. National Institutes of Health (NIH). Phase I/II trial of anti-PD-1 checkpoint inhibitor nivolumab and 177Lu-DOTA0-Tyr3-octreotate for patients with extensive-stage small cell lung cancer. NLM Identifier: NCT03325816. Last updated June 13, 2018. Available at: https://clinicaltrials.gov/ct2/show/NCT03325816. Accessed on September 21, 2018.
  12. NCCN Clinical Practice Guidelines in Oncology® (NCCN). © 2018 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website: http://www.nccn.org/index.asp. Accessed on: September 21, 2018.
    • Neuroendocrine and Adrenal Tumors (V3.2018). Revised September 11, 2018.
    • B-Cell Lymphomas (V4.2018). Revised May 14, 2018.
  13. Zevalin (ibritumomab tiuxetan). In: DrugPoints System (electronic version). Truven Health Analytics, Greenwood Village, CO. Updated September 12, 2018. Available at: http://www.micromedexsolutions.com.  Accessed on September 23, 2018.
  14. Zevalin [Product Information], Rockville, MD. CASI Pharmaceuticals, Inc.  August 30, 2013. Available at: Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/125019s210s213lbl.pdf. Accessed on September 23, 2018.
Websites for Additional Information
  1. American Cancer Society. Available at: http://www.cancer.org/. Accessed on September 23, 2018.
  2. Leukemia and Lymphoma Society. Ibritumomab Tiuxetan. Available at: http://www.lls.org/treatment/types-of-treatment/chemotherapy-and-other-drug-therapies/drug-listings/ibritumomab. Accessed on September 23, 2018.
  3. National Cancer Institute (NCI). Cancer Topics. Available at: http://www.cancer.gov/cancertopics. Accessed on September 23, 2018.
    • Gastrointestinal Carcinoid Tumors Treatment (PDQ®). Updated February 7, 2018.
    • Pancreatic Neuroendocrine Tumors (Islet Cell Tumors) Treatment (PDQ®). Updated February 8, 2018.
  4. National Cancer Institute. Targeted cancer therapies: questions and answers. Reviewed May 08, 2018. Available at: http://www.cancer.gov/cancertopics/factsheet/Therapy/targeted. Accessed on September 23, 2018.
Index

Ibritumomab Tiuxetan
Non-Hodgkin Lymphoma (NHL)
Peptide Receptor Radionuclide Therapy
Radioimmunotherapy
Rituximab
Yttrium-90
Zevalin

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

History

Status

Date

Action

Revised

11/08/2018

Medical Policy & Technology Assessment Committee (MPTAC) review.

Revised

10/31/2018

Hematology/Oncology Subcommittee review. Combined contents of DRUG.00098 Lutetium Lu 177 dotatate (Lutathera®) with CUMG. Added MN and NMN criteria for iobenguane I 131. Updated Description, Discussion/General Information, Definitions, References and Website sections. Updated Coding section to include 01/01/2019 HCPCS changes; added A9513 and C9408; C9031 is deleted 12/31/2018.

Revised

07/26/2018

MPTAC review.

Revised

07/18/2018

Hematology/Oncology Subcommittee review. Updated NMN criteria with non-FDA approved somatostatin analogs. Updated References and Website sections.

New

01/25/2018

MPTAC review. Initial document development.

New

01/17/2018

Hematology/Oncology Subcommittee review. Moved content of THER-RAD.00005 Radioimmunotherapy and Somatostatin Receptor Targeted Radiotherapy to new clinical utilization management guideline document with the same title.