GI Cancers: Neuroendocrine Cancer Update

Specialty Pharmacy TimesMay/June 2014
Volume 5
Issue 3

Clinical trial results show that several new combination therapies offer great promise for the treatment of challenging neuroendocrine tumors in the gastrointestinal area.

Clinical trial results show that several new combination therapies offer great promise for the treatment of challenging neuroendocrine tumors in the gastrointestinal area.

The 2014 Gastrointestinal (GI) Cancers Symposium held in January 2014 highlighted 5 studies in its initial press release presenting new therapy options and improvements to existing treatments for a variety of GI related malignancies.1 CAPTEM (capecitebine [CAP] and temozolomide [TEM]) is a regimen investigated in an ongoing Phase II clinical trial targeting a new therapy option for advanced, well-differentiated neuroendocrine tumors (NETs). CAP, the prodrug for fluorouracil as a pyrimidine antimetabolite, and TEM, a prodrug with alkylation properties, shows synergistic qualities when used in combination for this therapy. Additionally, these new combination therapies of established oral oncolytics highlight a future engagement opportunity for specialty pharmacy in a class of neoplasms known to be challenging to therapy.2

Neuroendocrine Tumors and Therapy Approaches

NETs are classified according to organ origination, histology, and activity. Since the 1970s, the incidence of NETs has grown 4-fold, with approximately 8000 new diagnoses within the gastrointestinal area each year in the United States. The reason for the increase is unknown, but as with many other malignances it has been attributed to improved diagnosis and patient management within today’s health care environment.3 Common risk factors include behavioral risk factors (smoking, alcohol consumption, and nutrition), genetic/medical risk factors (family history of cancer and diabetes), and occupational factors.4

Treatment of NETs depends on tumor site, tumor stage, and patient symptoms.5 Surgery is the treatment of choice for patients with resectable disease and is the potential for cure for locoregional 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. NETs that hypersecrete hormones are known as functional tumors and can cause symptoms such as diarrhea and flushing. Medications, such as somatostatin analogs, are used to help manage these symptoms and improve quality of life. Somatostatin analogs, such as octreotide, may also have some antiproliferative effects but the evidence is modest and further investigation is needed.

Depending on the site of tumor origin, there are several pharmacological treatment modalities for tumor control.5 Systemic cytotoxic chemotherapy, including streptozocin-based therapies and temozolomide-based therapies for pancreatic NETs and capecitabine or dacarbazine for carcinoid NETs are 1 option. Cytotoxic chemotherapy has only produced moderate benefit and can be associated with undesirable adverse effects. Biological target therapies are another option.

Everolimus, a mammalian target of rapamycin (mTOR) inhibitor and sunitinib, a multitargeted vascular endothelial growth factor receptor tyrosine kinase inhibitor, are approved by the FDA for the treatment of pancreatic NETs, and everolimus is also recommended for carcinoid NETs. Additionally, interferon alpha, an immune modulator, is another systemic therapy that has been used as salvage therapy for carcinoid NET, but has limited use due to intolerable side effects. Table 1 includes a summary of current pharmacological and non-pharmacological treatment recommendation for the most common subtypes of NETs—carcinoid and pancreatic—by the National Comprehensive Cancer Network (NCCN).5

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The interim analysis of a Phase II trial studying the regimen CAPTEM in patients with different types of NETs reported promising results.2 Twenty-eight patients with moderately or well-differentiated metastatic NETs who had progressed on a long-acting somatostatin analog or were ineligible for a somatostatin analog, were treated with the following regimen: capecitabine 1500 mg/m2 per day orally divided into 2 doses with a maximum dose of 2500 mg per day on days 1 through 14 and temozolomide 150 mg to 200 mg/m2 per day orally divided into 2 doses on days 10 through 14, given in a 28-day cycle.

The overall response rate was 43%, and 54% of patients had stable disease. Response rates (complete and partial responses) were 41%, 100%, and 45% for carcinoid, pituitary, and pancreatic NETs, respectively, at the interim analysis. The median progression free survival for all subtypes was reported at >20 months and the median overall survival was >25 months. The most common grade 3 and 4 toxicities were lymphopenia, hyperglycemia, thrombocytopenia, and diarrhea.

The authors demonstrated in this on-going clinical trial that capecitabine is able to potentiate the effects of temozolomide in multiple subtypes of NETs. The response rates reported in this investigation are greater than responses shown with other treatments and the regimen was associated with tolerable adverse effects. Subsequently, the CAPTEM regimen appears to be a promising therapy for patients with moderately to well-differentiated metastatic NETs that have progressed while using a sandostatin analog.

Role of the Specialty Pharmacist Within the Health System

Therapy selection for the treatment of NETs is linked to the utilization of identified medication therapies. The pharmacist’s role includes a myriad of responsibilities related to medication management, patient management, financial management, and logistics management (Table 2).6,7 Historically, the specialty pharmacy provider offers robust care models with centralized services addressing many of these distinct services that can simultaneously meet the needs and preferences for the payer, provider, and most importantly the patient.

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An additional partner to consider in the management of these patients, is the health system responsible for the care the patient. Regardless of the facility type (eg, critical access hospital community hospital, academic medical center, integrated delivery network), pharmacists in some situations are partners with the physician at the point of treatment decision, being equal part patient and prescriber advocate. In this situation, the pharmacist can be the primary caregiver assisting with navigating the therapy options that may be dictated by the pharmacy or medical benefit. These health care facilities are ideally situated at the point of care to improve the patient’s overall satisfaction when providing all services at a time when minimizing patient care inefficiencies can impact their quality of life.

In many cases, the pharmacist will navigate the prior authorization process. Each managed care organization has specific guidelines and criteria for medication reimbursement. In order to gain approval for regimens such as CAPTEM, pharmacists can provide the necessary justification such as indication, previous failed treatments, and regimen references. The involvement of the pharmacist could improve efficiency and reduce the time between when the prescription is written and when the patient starts taking the new regimen.

The pharmacist also helps the patient navigate through their complex treatment regimen. The pharmacist provides education about the treatment plan including risks and benefits, offers clear instructions regarding how to properly take the medications, and develops a follow-up plan to assess for adherence and tolerability. Evaluating for potential barriers of adherence and developing an intervention plan can ensure that patient outcomes are maximized.8

In summary, the pharmacy profession will be challenged with an increased awareness of upcoming critical trials such as CAPTEM that may alter traditional therapies to the oral environment. Furthermore, consideration of other partnerships in managing specialty pharmacy needs should include the patient’s health system provider. SPT


  • 2014 symposium highlights treatment of advances for multiple GI cancers [press release]. American Society of Clinical Oncology website. Published January 14, 2014.
  • Fine RL, Gulati AP, Tsushima D, et al. Prospective phase II study of capecitabine and temozolomide CAPTEM for progressive, moderately, and well-differentiated metastatic tumors. J Clin Oncol. 2014:32(suppl 3; abstract 179).
  • Yao JC, Hassan M, Phan A, et al. One hundred years after “carcinoid”: epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol. 2008;26(18):3063-3072.
  • Hassan MM, Yao JC. Global epidemiology of neuroendocrine tumors. In: Yao JC, Hoff PM, Hoff AO, eds. Neuroendcrine Tumors. New York, NY: Humana Press; 2011:1-10.
  • NCCN clinical practice guidelines in oncology—neuroendocrine tumors (version 2.2014). National Comprehensive Care Network. Accessed April 16, 2014.
  • Concept series paper on specialty pharmaceuticals. Academy of Managed Care Pharmacy.
  • Adherence to oral therapies for cancer: helping your patients stay on course toolkit. Oncology Nursing Society.
  • Ruddy K, Mayer E, Partridge A. Patient adherence and persistence with oral anticancer treatment. CA Cancer J Clin. 2009;59(1):56-66.

About the Authors

Scott W. Savage, PharmD, MS, received his Doctor of Pharmacy degree from the University of North Carolina at Chapel Hill, and master’s degree with a PGY2 residency certificate in health system pharmacy administration from The Ohio State University Medical Center and The OSU College of Pharmacy.Currently, Scott serves as the associate director of pharmacy over the UNC Shared Services Center Pharmacy, which houses operations for retail (specialty and central fill), medication assistance program, supply chain management, compounding, and pharmacy benefit management services. Additionally, he is an assistant professor of Clinical Education for UNC’s Eshelman School of Pharmacy.Prior to joining UNC, Scott served in leadership and management roles in other academic medical centers and a community based hospital. He is an active member of NCPA, ASHP, and AMCP. He enjoys developing and implementing new approaches to integrating pharmacy services in all facets of patient care. Additionally, he enjoys time at home with his family, UNC and Ohio State sports, and running.Aimee Faso, PharmD, BCOP, CPP, is a clinical pharmacist practitioner at the University of North Carolina Hospitals and Clinics and an adjunct professor with the division of pharmacy practice at UNC Eshelman School of Pharmacy.

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