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NEUROENDOCRINE TUMORS: PREVALENCE AND PATHOLOGY

Since the 1970s, the incidence of neuroendocrine tumors (NETs) has grown more than 6-fold, from a rate of 1.09 per 100,000 people in 1973 to 6.98 per 100,000 people in 2012. A particular increase has been seen in older adults: an 8-fold increase in NETs has been observed in patients older than 65 years.^1,2 The reason for the increase is not entirely clear, but research based on available Surveillance, Epidemiology, and End Results databases compiled by the National Cancer Institute is ongoing.³

Now, each year in the United States, there are approximately 8000 new diagnoses of NETS within the gastrointestinal system.¹ As with increases in the incidences other neoplasms, the increase in NETs has been at least partly attributed to improved diagnosis, classification, and patient management within the current healthcare environment. Recent data on the incidence and prevalence of NETs are challenging the conventional assertion that NETs are rare,^3-5 and common risk factors for NETs have been identified, including behavioral factors (smoking, alcohol consumption, and nutrition), genetic/medical risk factors (family history of cancer and diabetes), and occupational factors.⁶ Additionally, most NETs occur in males.¹

NETs are a heterogeneous group of neoplasms that arise in the neuroendocrine system and are characterized by the secretion of peptides resulting in distinctive hormonal syndromes in a variety of different organs.^1-6 NETs were originally referred to as “carcinoids” due to the findings of German pathologist Siegfried Oberndorfer who described the characteristics of the tumors as similar to those of carcinomas and adenomas; efforts in the mid- to late-1900s confirmed the origination of NETs from pluripotent neuroendocrine stems cells located in the gastrointestinal tract, the bronchopulmonary system, and the genitourinary tract.^6-8 The term “neuroendocrine tumor” was first used in the World Health Organization (WHO) 2000 classification of digestive tumors to describe a system of tumors made up of both nerve cells and epithelial cells.⁹ A majority of NETs are localized and classified as slow growing; however, non-indolent NETs have been observed. These features of growth, hormone production, and organ-specific isolation are indicative of and now define NETs.¹⁰

Diagnosis and classification

The appropriate diagnosis and treatment of NETs requires collaboration among multiple disciplines.^11,12 NETs are classified according to organ origination, histology, and activity. Historically, NETs have been classified as originating in the foregut (the lungs, thymus, stomach, pancreas, and duodenum), the midgut (gastrointestinal tract from the duodenum to the proximal transverse colon), and the hindgut (distal colon and rectum). NETs are most common in the lungs and the gastroenteropancreatic (GEP) system.^13,14

A singularly recognized classification system for NETs has yet to be established. The WHO system is most commonly used along with the European Neuroendocrine Tumour Society (ENETS) and American Joint Commission on Care (AJCC) staging recommendations. NETs are distinguished by 2 subgroups (well differentiated and poorly differentiated) with subdivision according to a proliferation index based on measured levels of a nuclear protein, Ki-67.^14-18 In cytology, differentiation refers to the extent of malignant cells that resemble normal cells. A low degree of differentiation is associated with poorer outcomes. According to this classification, most NETs fall into 3 histological grades: grade 1 (well differentiated, low grade), grade 2 (well differentiated, intermediate grade), and grade 3 (poorly differentiated, high grade). In general, grade 3 tumors have higher proliferation rates (> 20%) than lower-grade tumors (Table 1).^16,19

Since the 2010 WHO guidelines were published, classifications of GEP-NETs have undergone adjustments within each of the described NET classification guidelines. Confusion exists among the WHO, ENETS, and AJCC models and there are documented deficiencies in each.^5,12 Further adjustments to these classification systems are expected as new diagnostic and treatment modalities become available.^20,21 

GEP-NETs are localized to the gastrointestinal tract and pancreas. Functional GEP-NETs are marked by active hormone secretion. Original research categorized most GEP-NETs as functional tumors with hormone production, but recent literature supports an alternative view, with up to 85% being classified as non-functional tumors, making establishing accurate diagnosis and prognosis challenging.^2,22,23 Non-functional GEP-NETs clinically present with symptoms associated with metastatic lesions.¹³

GEP-NETs are associated with a higher lifetime incidence of development according to the associated hereditary endocrinopathies, including multiple endocrine neoplasia type 1 (80%-100% incidence of GEP-NETs), neurofibrosis type 1 (approximate 10% incidence), tuberous sclerosis (< 1% incidence), and von Hippel-Lindau syndrome (up to 20% incidence). Patients with pancreatic GEP-NETs due to inherited syndrome tend to have a more indolent course of tumor activity.^13,22 Biomarkers such as chromogranin A, synaptophysin, and CD56 may be useful for less well-differentiated tumors. Thyroid transcription factor 1, CDX2, and PAX8 are under investigation for assistance in determining the location of lung, intestine, and pancreatic GEP-NETs, respectively.¹⁹

Initial diagnosis of GEP-NETs can occur via contrast-enhanced computed tomography (CT) of the neck-thorax-abdomen and pelvis. Preference is given to contrast-enhanced magnetic resonance imaging (MRI) for examination of the pancreas. Ultrasonography (US) frequently provides initial diagnosis of metastasis. Endoscopic US (EUS) is preferred for diagnosis and biopsy of pancreatic involvement, with intraoperative US allowing lesion detection in the pancreas and liver. Somatostatin receptor imaging allows for class differentiation and metastatic assessment. In each situation, appropriate diagnosis is based on imaging examination and consideration of tumor markers.^19,22 

CT and MRI are the most common techniques used for diagnosis of GEP-NETs. MRI techniques have the highest sensitivity and specificity for pancreatic GEP-NETs, with rates of 82% and 92%, respectively. Additionally, MRI is preferred for tissue contrast examination.^24,25 CTs are superior to MRIs in the imaging of anatomy and overall cost impact. EUS, although limited by availability, is preferred for detection of small tumors (2-5 mm): Detection rates are greater than 90% and EUS allows biopsy for histologic diagnosis.²⁶ Functional imaging techniques such as radiolabeled somatostatin (also known as somatostatin receptor scintigraphy [SRS]) should be considered for GEP-NETs with metastatic concerns. SRS is limited by receptor expression and will not provide diagnostic information for anatomy location and surgical options.^27,28

Carcinoid syndrome and treatment considerations

Patients presenting with diffuse hormonal symptoms (e.g., flushing, diarrhea, etc.) should be assessed for carcinoid syndrome (CS). The production of hormones by NETs, including bradykinin, histamine, serotonin, and tachykinins, is responsible for CS. The incidence of CS ranges from 3.2% to 18.7% and varies based on the site of tumor origin and degree of metastases.^29,30 In addition to the suggestive symptoms, diagnostic testing includes urinary excretion of serotonin and a serotonin metabolite (5-hydroxyindoleacetic acid [5-HIAA]). A 24-hour urinary excretion measurement of 5-HIAA, the end product of serotonin metabolism, is highly sensitive and indicative of CS. Occurrence of CS is most common in metastatic cases of NETs originating from the jejunum, ileum, and cecum. It occurs less often with NETs arising from the lung, pancreas, rectum, and colon. The presence of CS is associated with lower overall survival for patients with NETs.³¹

Therapy for CS follows the treatment recommendations associated with the somatostatin analogs (SSAs): octreotide and lanreotide. These therapies will be reviewed in detail in the section entitled Therapeutic Approaches in the Treatment of GEP-NETs.¹⁹ Refractory CS symptoms have limited available treatment options,^32-34 but serotonin pathway inhibitors have been evaluated for activity associated with CS physiologic activity.³⁵

Telotristat ethyl (Xermelo; Lexicon Pharmaceuticals, Inc.) is an oral tryptophan hydroxylase inhibitor that was approved by the United States Food and Drug Administration (FDA) in 2017 for use in combination with SSAs to control diarrhea associated with CS. It is administered as an oral dose of 250 mg 3 times daily. The TELESTAR trial randomized 135 patients with a history of CS to treatment with telotristat or placebo. Treatment with telotristat was associated with a reduction in bowel movement frequency from baseline. Flushing was not impacted.³⁶ Currently, treatments specifically targeting CS have been reported in studies with limited impact.^19,35 For persistent CS symptoms, options outlined in the Therapeutic Approaches in the Treatment of GEP-NETs can be considered, although data supporting their effectiveness are lacking.

Carcinoid crisis must be considered for patients undergoing elective or required surgical procedures. This intraoperative sequela is acute and can be life-threatening. Historically, it was hypothesized that carcinoid crisis appeared abruptly with a pathway of onset marked by massive release of the previously mentioned vasoactive hormones.^32-34 However, recent data are questioning the merits of the root cause of carcinoid crisis. Although a high incidence of NETs patients with metastases experience CS and carcinoid crisis, the most appropriate prevention of carcinoid crisis appears to mirror efforts to prevent and treat distributive shock. Administration of intravenous fluids and vasopressors are now being considered, with additional research needed to elucidate the best treatment for this condition.³¹ Currently, guidelines recommend a 250-mcg intravenous dose of octreotide prior to surgery and intraoperatively (maximum daily dose of 1 mg) to mitigate a crisis.^19,35

THERAPEUTIC APPROACHES IN THE TREATMENT OF GEP-NETS

Treatment of GEP-NETs depends on tumor site, tumor stage, and patient symptoms. Management options include surgery, radiologic intervention, adjuvant and neoadjuvant chemotherapy, SSAs, and newer biological agents. Surgery is the treatment of choice for patients with resectable disease and is the potential cure for locoregional, well-differentiated tumors. Patients with metastatic disease can also be considered for resection of the primary tumor for disease palliation. For patients with unresectable disease, the primary goals of therapy include symptom management and tumor control.^19,35

Surgical management approaches continue to undergo changes for new GEP-NETs and for disease recurrence.³⁷ Upon evaluation of the tumor’s functional characteristics, size, and metastatic involvement, a non-invasive or invasive approach can be selected. Exceptions to surgery can be made for patients with comorbidities, high surgical risk, or extensive metastatic disease.³⁸ Even with adequate surgery, there is a risk of residual disease, and, especially in patients whose disease was not originally detected, disease progression is an ongoing concern. Follow-up including serial imaging and biomarker testing may be warranted according to the risk of lymph node involvement. An initial nomogram considering Ki-67, tumor size, invasion of adjacent organs, and lymph node status is being used as a tool to assess risk of recurrence after surgery.³⁷

Medication management of metastatic GEP-NETs is difficult, but therapy options have improved in recent years.^1,3,4,7 Depending on the site of tumor origin and the need for adjuvant therapy, there are several pharmacologic treatment modalities for tumor control. SSAs (both octreotide and lanreotide) are used to help manage symptoms and improve quality of life, and they may have some antiproliferative effects.³⁹ Molecular targeted therapies, peptide receptor radiotherapy, systemic cytotoxic chemotherapy, and liver-directed therapy are also options for consideration. 

Somatostatin analog therapy

SSA therapy is considered the standard of care for metastatic GEP-NETs.³ Somatostatin is a peptide hormone that binds to differential somatostatin receptor (SSTR) subtypes. This binding inhibits the secretion of several hormones that affect growth, thyroid function, serotonin activity, gastrin production, vasoactive intestinal peptide activity, and glucagon release.⁴⁰ Additionally, somatostatin binding reduces gallbladder contraction, blood flow in the gastrointestinal tract, and gastrointestinal motility. Somatostatin’s discovery in 1973 was the basis for the development of octreotide, an SSA, because of somatostatin’s limited in vivo functional half-life of 1 to 3 minutes, which limits its clinical utility. The use of SSAs in the treatment of GEP-NETs is based on research that showed high representation of SSTRs on GEP-NETs and data supporting its hinderance of tumor growth.^11,41 As a result, SSAs were developed and octreotide acetate (Sandostatin, Novartis) received FDA approval in 1987 as a treatment option for certain neoplasms. Octreotide’s structure contains 8 amino acids, which allows it to resist degradation and offers an improved half-life of 2 hours.^7,41

Although octreotide’s development was a breakthrough in GEP-NET treatment, the still-limited viability led researchers to develop the long-acting-release (LAR) formulation, octreotide LAR (Sandostatin LAR, Novartis). Its microsphere encapsulation allows administration via the intramuscular (intragluteal) route every 28 days. The slow-dissolving polymer gives octreotide LAR a predictable pharmacokinetic profile and steady-state kinetics. Once administered, octreotide levels plateau in approximately 30 days and steady-state levels are reached after 3 injections.¹¹

PROMID, the first phase III trial to evaluate the antiproliferative effects of an SSA, randomized 85 patients with well-differentiated GEP-NETs to receive octreotide LAR 30 mg every 4 weeks or placebo. The study met its primary endpoint (time to progression) with significant improvement in time to progression (14.3 vs. 6 months; p=0.000072).⁴² This trial validated current utilization of SSAs and, although it did not alter FDA-approved labeling, it resulted in octreotide LAR being recommended for controlling tumor growth in patients with recurrent or unresectable GEP-NETs regardless of functional status.¹¹

Lanreotide (Somatuline, Ipsen Biopharmaceuticals, Inc.) was approved by the FDA in December 2014 for the treatment of unresectable, moderately- or well-differentiated, locally advanced or metastatic GEP-NETs. Administration is via deep subcutaneous injection. The CLARINET trial randomized 204 patients with non-functioning, SSTR-positive, well-differentiated GEP-NETs to receive lanreotide 120 mg every 28 days for 96 weeks or placebo. The primary endpoint, progression-free survival (PFS), was improved for those receiving lanreotide. Risk of disease progression was reduced by 53% within the evaluation period.⁴³

Octreotide and lanreotide have the same mechanism of action. Common side effects for the SSAs include diarrhea, abdominal pain, cholelithiasis, flatulence, and injection site pain.⁴⁴ Once SSA therapy has been initiated, therapy should be continued until disease progression or toxicity. However, because of the minimal side effect profiles associated with SSAs, frequent discontinuation and restart of therapy is not advised.⁴⁵ Rescue doses of immediate-release octreotide (150-250 mcg 3 times per day; maximum daily dose of 1 mg) may be required for initial therapy or breakthrough symptoms prior to administration of the next long-acting dose. Further dose increases of the depot SSAs, administration of continuous-infusion octreotide, or reduction in the interval of administration (28 to 21 or 14 days) can be considered, although prospective evaluations of these strategies are scarce.¹⁹

Resistance to SSAs continues to be an area of evaluation. Mechanisms of resistance include: 1) truncated sst5-receptor variants, 2) desensitization in the number of SSTR sites, 3) development of functioning mutations of SSTR sites, 4) activation of intracellular pathways, and 5) overexpression of tyrosine kinase receptors.⁴⁴

Molecular targeted therapies

Other medication options should be considered if SSAs fail in the treatment of GEP-NETs. Everolimus (Afinitor, Novartis), a mammalian target of rapamycin (mTOR) inhibitor, prevents cell proliferation and metabolism of cancer cells.^46,47 The RADIANT 2, 3, and 4 studies evaluated everolimus as monotherapy and in combination with octreotide (RADIANT 2) in multiple categories of GEP-NETs.^48-50 RADIANT 4 resulted in the 2011 FDA approval of everolimus 10 mg daily for advanced, progressive, well-differentiated GEP-NETs.⁵⁰ Common side effects of everolimus include oral ulcers, rash, diarrhea, hyperglycemia, hyperlipidemia, pneumonitis, and immunosuppression. Dose reductions and supportive therapy can allow most patients the ability to tolerate everolimus for an extended treatment period.⁴⁰

GEP-NETs are marked by vascular involvement, and vascular endothelial growth factor (VEGF) ligand and its receptors, as well as VEGF circulation, are associated with tumor growth.⁵¹ Sunitinib (Sutent, Pfizer), a multi-targeted VEGF receptor tyrosine kinase inhibitor, targets VEGF receptors and platelet-derived growth factor receptor. Oral administration of 37.5 mg daily is FDA approved (2011) for advanced, progressive, well-differentiated pancreatic NETs. Side effects include diarrhea, constipation, mucositis, nausea, skin discoloration, palmar-plantar erythrodysesthesia (hand-foot syndrome), fatigue, decreased appetite, and hypertension.⁴⁰

Currently, there are no studies comparing everolimus and sunitinib. Patient comorbidities, such as diabetes and hypertension, may guide prescribing patterns. Other VEGF inhibitors (bevacizumab) and tyrosine kinase inhibitors (pazopanib, axitinib, sorefanib, and cabozatinib) have been investigated in phase II and III trials; however, none have resulted in alterations to established therapies.^40,52

Peptide receptor radiotherapy

Radiolabeled SSAs, also known as peptide receptor radionuclide therapy (PRRT), combines a radionuclide isotope, an SSA, and a binding chelator. PRRT affinity correlates with SSTR expression.⁵³ In 2018, the FDA approved ¹⁷⁷Lu-dotatate (Lutathera, Advanced Accelerator Applications) for SSTR-positive GEP-NETs. The radioisotope is delivered to the tumor cells once it is affixed to the SSTRs on the tumor cell. The beta emission from Lu-177 induces cellular damage by forming free radicals.⁵⁴

The NETTER-1 trial enrolled patients with metastatic, progressive midgut NETs and showed improved response rates and PFS for patients receiving ¹⁷⁷Lu-dotatate versus octreotide LAR.⁵⁵ Additionally, PRRT provided a positive impact on quality of life. The treatment regimen consists of 4 cycles of 200 mCi over 30 to 40 minutes every 8 weeks for a total of 4 doses. Retreatment has been shown to be beneficial.⁵⁶ The most common side effects include acute kidney injury, hematologic toxicity, and gastrointestinal disturbances. In order to minimize occurrence of kidney injury, a compounded or commercial amino acid infusion should be administered before, during, and after the ¹⁷⁷Lu-dotatate infusion.⁵² Aggressive antiemetic prophylaxis with a 5-hydroxytryptamine receptor antagonist with or without a neurokinin 1 receptor blocker is also advised. Lastly, ongoing support with SSAs for patients receiving ¹⁷⁷Lu-dotatate needs to be considered both prior to and after receiving therapy.¹⁹

PRRT is the subject of ongoing research efforts to improve efficacy and minimize side effects. Combination therapy with cytotoxic chemotherapy, chemosensitizing agents, and dosimetry-guided therapy may reduce toxicities.⁴⁰ Researchers are reviewing additional receptor-targeted agents and nanoparticles that may improve the effectiveness of PRRT and reduce its harmful effects.⁴⁰

Systemic cytotoxic chemotherapy

The utilization of cytotoxic chemotherapy in GEP-NETs has had modest results and is generally reserved for patients with progressive, poorly differentiated disease and those who have experienced failures to other treatment options.^7,19 Streptozocin-based chemotherapy has been used in pancreatic GEP-NETs for decades, and it has been used in combination with 5-flurouracil (5-FU) and doxorubicin for improved response.⁵⁷ Recent phase I and II trials have combined the oral equivalent of 5-FU (capecitabine) and the oral alkylating agent temozolomide for improved PFS and overall survival compared to temozolomide alone.⁵⁸ Additionally, oxaliplatin-based regimens have been used and continue to be an area of research in association with biomarkers for alternative therapies for patients with refractory disease.⁵²

Poorly differentiated GEP-NETs with non-pancreatic (bladder, prostate, cervix, esophagus, larynx, and kidneys) involvement are histologically similar to small-cell lung cancers. Options for therapy include guideline-directed small-cell lung cancer treatments, which consist of platinum-based (cisplatin or carboplatin) therapy with etoposide or irinotecan.^7,19 The addition of paclitaxel in combination with the platinum-based etoposide therapy improved response rates (15%) in a phase II trial, but adverse events (e.g., febrile neutropenia) makes the dual-therapy option preferred.¹⁹ Patients who progress after this therapy have limited therapeutic options remaining.⁴⁰

Liver-directed therapy

Hepatic metastases from GEP-NETs are common in a patient’s initial presentation.⁵⁹ Surgical resection for metastatic GEP-NETs of the liver can prolong survival (median, 9 years) and quality of life; however, it is rarely curative and is associated with a 95% rate of recurrence. Surgical debulking is associated with symptom relief and increased survival (median, 4 years). With the increase in available systemic therapies, surgery is considered in cases of tumors refractory to medication management, tumors larger than 1 cm in size, and tumors displaying rapid growth over a 6-month period.^19,40,60 Liver transplantation has shown promising 5-year survival rates; however, it is still considered investigational based on associated risks and recurrence rates.^19,60

Transarterial embolizaton (TAE), including transarterial chemoembolization (TACE) and transarterial radioembolization (TARE), target blood flow to the metastasized tumor within the liver.⁵² The occlusion of the hepatic artery (normal hepatic cellular blood supply is from the hepatic portal vein) targeted with TACE blockade with or without chemotherapy (i.e., TAE) may improve symptomology and reduce tumor size. Response rates vary from 50% to 96% with a duration of response ranging from 4 to 18 months.^61,62 Neither modality of embolization therapy has shown superiority, but consideration of side effects must be considered with each therapy.^7,19

TACE, as an alternative therapy option, has changed over the past decades with formulations manufactured to provide occlusion and delivery of specified chemotherapy. Older TACE methods include an ethiodized oil product with 1 or more chemotherapy agents (lyophilized powder from only): In the United States, doxorubicin hydrochloride and mitomycin are the most common. The combined emulsion is added to a contrast dye and administered into the hepatic artery. This administration leads to a higher local drug concentration in the targeted tissue (20 times higher than intravenous administration), but exact concentration within the tissue is not measured.⁷

Depending on the manufacturer of the product, newer TACE products use microspheres, polyvinyl alcohol, gelatin sponges, or collagen particles as the embolizing agent.⁶³ The use of drug-eluting beads is a common approach that allows the sequestered chemotherapy to be delivered to the target sites. This new approach has been shown to reduce adverse effects and increase delivery of the medication. Consideration should be given to optimal bead size, as smaller beads (100- to 300-mm diameter) are associated with fewer complications.⁶⁴ Regardless of embolization route, it is seen as an effective approach for GEP-NETs with hepatic involvement; however, due to the lack of comparison studies, the optimal approach remains undetermined.^7,19

ROLES OF THE ONCOLOGY PHARMACIST IN THE MANAGEMENT OF GEP-NETS

The primary goal of a pharmacist is to provide high-quality, safe, and cost-effective patient care. The rational use of medications should include evidence-based prescribing and deprescribing according to indication, efficacy, safety, duration, cost, and suitability for patient care. Such medication-driven advocacy reinforces other support given in the overall management of GEP-NETs, including a multidisciplinary approach to care, medication-related clinical testing and monitoring, patient adherence support, adverse event monitoring, improvement of patient experiences, and successful transitions of care.⁶⁵

The diagnosis and treatment of GEP-NETs requires careful, thorough evaluation by pathology, radiology, gastroenterology, endocrinology, nuclear medicine, oncology, and surgery experts, as well as pharmacists,^11,12,66 and many clinical team members, including physicians, nurse care managers, and others, spend large amounts of time ensuring successful therapy for patients with GEP-NETs. The overall goal of a multidisciplinary team for GEP-NETs management is improving access to and delivery of care. Secondary goals can include: 1) reducing morbidity and mortality, 2) improving patient experience, 3) enhancing coordination of care, 4) providing access to evidence-based treatment options, and 5) reducing costs of care.¹²

Treatment initiation and monitoring

Recent qualitative data suggest that, due to the complex nature of GEP-NETs, confusion occurs for many patients throughout the course of their therapy and this confusion confers a significant impact on patients’ lives.^67,68 Throughout the continuum of care, pharmacists must partner with the interdisciplinary team responsible for successful treatment of GEP-NETs in an effort to mitigate some of the confusion and stress patients will face. For example, before treatment even begins, pharmacists can help design the medication therapy regimen: Interdisciplinary protocol development includes pharmacist engagement in collaboration with the physician or advanced practitioner, which optimizes patient care.¹² Further, pharmacists may be credentialed and privileged to initiate, continue, modify, or discontinue medication therapy based on state scope-of-practice laws and health system policies.

Pharmacists can assist in organizing, implementing, and continually re-evaluating the selected treatment protocol. As discussed, the symptomology of GEP-NETs and medication-related testing and monitoring are priority considerations for treatment decisions,¹² and, due to the longitudinal nature of GEP-NETs, symptom management must be considered across the provider, institution, and overall healthcare system that manage the patient. Moderate-to-severe symptom assessment can inform ongoing comprehensive strategies for patient-centered care for GEP-NETs.¹¹ Protocols should include goals of therapy and outline the data elements required for patient assessment. These data elements may include reported medication adherence, reported adverse events, laboratory results, hospitalizations and emergency department visits, and responses to patient self-assessment questions. 

Patient self-assessment questions help the team better understand the patient’s quality of life and personal health goals. Pharmacists are well positioned to use a combination of validated assessment tools, as well as customized questions, to assess quality of life, treatment-specific side effects, and patient-specific treatment goals. Such questions may measure the number of missed days of work or consider the patient’s ability to participate in activities with family and friends. Clinical protocols may also include scripts for patient encounters and education sessions.⁶⁹

Patient education

Provision of patient education is a critical element of pharmacy patient care services and education programs have been shown to improve patient outcomes. Pharmacists provide education about each patient’s treatment plan, including risks and benefits; offer clear instructions regarding how to properly take medication; and develop follow-up plans to assess for adherence, tolerability, and adverse effects.⁶⁵ Further, evaluating for potential barriers to adherence and developing an intervention plan can ensure that patient outcomes are maximized.⁷⁰ Pharmacists can ensure that patient education programs include a variety of educational methods and provide information in verbal and written formats. Consideration must be given to patient health literacy levels and preferred languages. As part of patient education, patients should be empowered to understand their medication regimens and actionably engage in their own care.

Patient education can be provided by a variety of methods, including face-to-face communication, telephone communication, real-time or recorded video communication, or printed materials. The method of education chosen should be individualized for each patient based on geographic location, patient mobility, patient health literacy, disease state, and medication therapy. Use of multiple education methods should be strongly considered to enhance patient retention of information. For example, written materials could be sent to a patient’s home with a follow-up phone call from a pharmacist to review the written materials and answer patient questions.^67-72

Patient education materials may include written handouts, videos, visual aids, and demonstration tools. Additionally, non-profit organizations, such as the American Cancer Society and the National Comprehensive Cancer Network create patient education materials that are disease-state specific; public use of the materials is allowed. Lastly, pharmacists can provide multi-lingual written materials to meet the language needs of the patient populations served. Ongoing research, including evaluations of web-based support programs, is designed to address the specific educational needs of GEP-NETs patients.^71-72

Interdisciplinary partnerships and patient support

Partnerships can be forged beyond the traditional interdisciplinary team. Overall, positive impacts on patient care are achieved when all providers, facilities, and caregivers establish effective communication strategies with patients—and with each other—and promote joint efforts focused on the same goal of maximizing patient outcomes. The healthcare facilities supporting patient care (including academic institutions, community care clinics, and critical access centers) and accredited specialty pharmacies should be used to support the needs of patients with GEP-NETs. Regardless of the facility type, point-of-care access should improve a patient’s overall satisfaction and quality of life by providing all services at one time and minimizing patient care inefficiencies. Published examples of patient-centered pharmacy services are numerous, including models in oncology, anti-inflammatory conditions, and infectious diseases.^73-76

As an element of patient education and interdisciplinary partnerships, medication adherence is supported by the pharmacist in conjunction with the rest of the team. Medication adherence, which can be calculated by several different methods, is directly associated with achievement of the intended outcomes of medication therapy, and, to optimize the effectiveness of therapy, it is imperative that patients adhere to their treatment regimens.^77,78 Barriers to medication adherence include lack of literacy, incomplete patient knowledge, complex patient expectations, adverse effects of therapy, and cost.⁷⁹ Pharmacists can provide ongoing medication adherence assessments to improve overall outcomes: In a recent study, patients who were called by a pharmacist twice per month had better adherence rates than patients who did not receive support.⁸⁰

Lastly, pharmacists can assist with supporting the overall patient experience. Evidence has indicated that positive patient experience is associated with higher levels of patient adherence to treatment and better clinical outcomes. Multiple patient experience tools exist, but, to be valuable, such assessment tools must be psychometrically sound and implemented using standard protocols.⁸¹ Questionnaires are typically administered by written mailing, email messaging, or phone, but some questionnaires may be completed on tablets or computers in a pharmacy for patients picking up medications in person. Different methods of survey administration can produce different results, so survey administration should be standardized.⁸²

Managed care and specialty pharmacy considerations

As new GEP-NET therapies are discovered, resource utilization for treatment must be considered, and payors are an important participant in this process.^83,84 In 2015, the American Association of Retired Persons Public Policy Institute found that the average annual cost of specialty medication therapy was nearly $52,500. This represented a 10% increase from the annual average specialty medication cost in 2014.⁸⁵ As the cost of medications continues to increase, patients, especially those who are uninsured or underinsured, are challenged with affording medications to treat their chronic, complex medical conditions. 

For GEP-NET therapies requiring outpatient or specialty pharmacy patient care services, selecting a partner is critical. Accredited specialty pharmacy locations are assessed using process metrics, clinical outcomes, and patient experience data. Pharmacists leading specialty pharmacy services must develop a thoughtful strategy for assessing desired outcomes that includes data collection, analysis, and reporting. Many payors require specialty pharmacies to meet specified clinical outcomes to be included in the specialty pharmacy network, and some payor contracts are based on reimbursement rates for achievement of clinical outcomes.⁶⁹

Prior authorization

In many cases, pharmacists will navigate the prior authorization (PA) process. The Centers for Medicare and Medicaid Services define PA as, “a decision by your health insurer or plan that a health care service, treatment plan, prescription drug or durable medical equipment is medically necessary.”⁸⁶ (PA, precertification, prior approval, and pre-authorization are synonymous terms used to describe an insurance authorization process.) Each managed care organization has specific guidelines and criteria for medication reimbursement and requirements for PA vary according to organization. In order to gain approval for many GEP-NET therapies, such as everolimus, pharmacists can provide the necessary justifications, such as indication, previous failed treatments, and references to support the chosen regimen, as part of the PA process. Pharmacist involvement can improve efficiency and reduce the time between when the prescription is written and when the patient starts taking the regimen. 

Patient assistance programs

Patients, caregivers, and healthcare professionals less familiar with medication access programs sometimes confuse PA and Pharmacy Assistance Programs (PAPs). PAPs “provide financial assistance or free drug product (through in-kind product donations) to low income individuals to augment any existing prescription drug coverage.”⁸⁷ PAPs may cover the full cost of the medication, the co-pay of the medication, or some other partial amount of the medication cost.

It is important to clearly distinguish between a PA and a PAP for patients and caregivers. If a PA is approved by a patient’s insurance, it means that the insurance will cover some cost of the medication based on the patient’s coverage. The patient may still be responsible for a co-pay, which is calculated according to the patient’s ability to pay and insurance coverage. The co-pay could be substantial and PAPs may be used to cover all or part of the patient co-pay in some situations. Additionally, some PAPs may cover the full cost of the medication if the PA is denied. In these cases, the patient usually must appeal the initial PA denial. PAP coverage may be used if the appeal is denied on the basis of the individual manufacturer’s program specifications.

Medication access

There are 3 main types of patient medication access support programs: (1) manufacturer-provided PAPs, (2) medication funding from a charitable organization, and (3) charitable care funding provided by the health system. Depending on the patient’s eligibility, some patients may receive medication access support through more than one of these assistance programs.

Charitable organizations also provide funding for medications. Patient eligibility for funding from a charitable organization may be based on patient characteristics (e.g., past or present military service), the disease state (e.g., cancer, cystic fibrosis), or the medication. In some cases, the funding provided by charitable organizations is the result of a donation provided by a pharmaceutical manufacturer’s foundation. Some charitable organizations have an annual amount of funds reserved for use. Once these funds are used, additional funding is not available for the remainder of the calendar or fiscal year, so timing of when funds are requested can impact if patients receive support. 

Many non-profit hospitals, health systems, and clinics also offer charitable funds. Patient eligibility is often based on insurance coverage and income, and the exact criteria and funding available are specific to each institution. Pharmacists, pharmacy technicians, case managers, or social workers are typically responsible for screening patients for eligibility and facilitating allocation of funds.

Navigating PAPs is often complex and confusing for patients and caregivers. Pharmacists can provide navigation support to help GEP-NET patients access needed medication. Consideration should be given not only to initial affordability but also to long-term sustainability of medication access according to the intended treatment duration.⁶⁹

CONCLUSION

The diagnosis and treatment of GEP-NETs have undergone substantial advances over the past decade. Future opportunities exist to improve patient care by leveraging the multidisciplinary team, encouraging international collaborations, integrating classification systems, fostering global surgical and therapeutic research, and ensuring patient-centered experiences.

Update: July 1, 2020 The U.S. Food and Drug Adminstration (FDA) granted accelerated approval to pembrolizumab for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high [≥10 mutations/megabase (mut/Mb)] solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options. This approval was based on the results from the KEYNOTE-158 study – a multicenter, non-randomized, open-label study with primary outcomes of overall response rate (ORR) and duration of response (DoR).  The ORR with patients with tumor mutational burden-high was 29% (95% CI: 21-39), with a 4% complete response rate and 25% partial response rate. The median DoR was not reached, with 57% of patients having response durations ≥12 months and 50% of patients having response durations ≥24 months. Reference: Marabelle A, Fakih MG, Lopez J, et al. Association of tumour mutational burden with outcomes in patients with select advanced solid tumours treated with pembrolizumab in KEYNOTE-158. Ann Oncol. 2019;30(suppl 5):11920.

Update: March 4, 2020 Surufatinib was granted Orphan Drug designation by the FDA for the treatment of pancreatic neuroendocrine tumors.  The phase III SANET-ep trial enrolled 198 patients and was halted early after meeting its primary endpoint of median progression-free survival of 9.2 in the surutafinib arm versus 3.8 months with placebo. [https://www.clinicaltrialsarena.com/news/chi-med-sanet-ep-surufatinib-trial/]

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