Practical Guide to Supportive Care of Patients with Functional Neuroendocrine Tumors

Practical Guide to Supportive Care of Patients With Functional Neuroendocrine Tumors Lowell B. Anthony Supportive care of patients with functional neuroendocrine tumors (NETs) has evolved to include the use of multiple targeted agents to control paraneoplastic states and newer surgical and interventional radiologic techniques to reduce tumor bulk. Challenges encountered by the clinician are the recognition of specific symptom complexes, selecting the relevant laboratory tests and radiologic/scintigraphic scans, and the timing of intervention(s). Individual variables such as the severity of symptoms in the context of primary and metastatic disease sites, tumor bulk, comor- bidities, and previous treatment are factors determining the prioritization of specific treatment regimens for patients with functional NETs. Symptoms such as flushing, secretory diarrhea, hypercalcemia, hyper /hypoglycemia, hypercortisolism, and peptic ulcers should improve with decreasing the elevated amino acid and/or peptide levels produced by NETs. These paraneoplastic symptoms may be accompanied by complaints related to tumor burden such as fatigue, pain, early satiety, anorexia, weight loss, night sweats, and/or symptoms secondary to adverse drug effects such as mucositis, dysgeusia, diarrhea, rash, hypertension, and myelosuppression. Developing a comprehensive continuum of care plan early in disease management assists in controlling the presenting signs and symptoms, and in minimizing disease- and/or treatment-related side effects. This guide serves as a framework to manage the signs and symptoms of metastatic functional neuroendocrine tumors. Semin Oncol 40:45-55 © 2013 Elsevier Inc. All rights reserved. ignificant advances in supportive care occurred disease, and syndrome.5–8 These observations ushered over three decades ago with the development of in a new era in the medical management of functional Sthe somatostatin congeners resistant to degrada- NETs by targeting specific receptors and cell signaling tive enzymes.1 The recognition that specific life-threat- pathways affecting hormonal synthesis and/or secre- ening conditions such as carcinoid syndrome, carci- tion.9 Applying somatostatin receptor autoradiographic noid crisis, and WDHA (watery diarrhea, hypokalemia, imaging technology to the in vivo setting resulted ini- achlorhydria syndrome or Verner-Morrison syndrome, tially in the development of indium-111 pentetreotide vasoactive intestinal peptidoma [VIPoma], or pancre- scintigraphy and more recently, gallium-68 DOTA oc- atic cholera) could be medically controlled by octreotide for the detection and localization of somatosta- treotide acetate when surgical extirpation was not an tin subtype receptors 2 and 5 (sst2, stt5)-expressing 10,11 option dramatically changed clinical management.2–4 tumors. The hormonal-suppressive effects of somatostatin conge- Advances in somatostatin formulations occurred ners extended to other functional NETs such as gastrino- when depot injections became the preferred route of 12 mas, glucagonomas, insulinomas, acromegaly, Cushing’s administration. Within the last 5 years, the introduc- tion of temozolomide-based therapy, oral vascular en- dothelial growth factor (VEGF) tyrosine kinase and Department of Medicine, Markey Cancer Center, University of Ken- mammalian target of rapamycin (mTOR) inhibitors as tucky, Lexington, KY. therapeutic options in the pancreatic subtype of NETs Conflicts of interest: Research grants, advisory board and honoraria from has led to improved control of symptoms as well as the Novartis Pharmaceuticals, Inc, Pfizer Pharmaceuticals, Inc, and Im- 13–15 clone Pharmaceuticals, Inc. underlying disease. This guide to the supportive Address correspondence to Lowell B. Anthony, MD, Professor of Med- care of functional NETs focuses on the management of icine, Department of Medicine, Markey Cancer Center, University of those signs and symptoms encountered in clinical prac- Kentucky, 800 Rose St, CC412, Lexington, KY 40536. E-mail: tice. [email protected] 0270-9295/ - see front matter Medical advances coupled with newer operative © 2013 Elsevier Inc. All rights reserved. techniques and interventional radiology procedures http://dx.doi.org/10.1053/j.seminoncol.2012.11.002 provide for improved symptom control in patients with Seminars in Oncology, Vol 40, No 1, February 2013, pp 45-55 45 46 L.B. Anthony metastatic functional NETs. The challenge is to recog- multiple causes of flushing. A detailed clinical history is nize which symptom or symptom complex is attribut- necessary to establish the presence of two distinctly able to the disease or disease progression versus other different flushing patterns in the perimenopausal fe- etiologies such as adverse drug effects, surgical anatom- male with carcinoid. Carcinoid syndrome flushing usu- ical changes, or other superimposed condition(s). ally is facial, neck and upper chest and sometimes Worsening of either symptoms or signs of the disease accompanied by palmar and plantar erythema. Carci- may simply reflect “tachyphylaxis” or may have more noid syndrome flushing is usually a dry flush and may serious implications such as anatomical progression.16 last from a few seconds to a few minutes for those Despite symptom progression, it is common for pa- primaries arising in the luminal intestinal tract versus tients to continue somatostatin analog therapy at the 30 minutes to hours for foregut primaries such as those same or an alternative dose and schedule as symptoms arising in the lung. remain suppressible, at least in part. With definitive Carcinoid diarrhea is typically secretory in nature, evidence of hepatic disease progression, local regional may be nocturnal, and is not responsive to fasting. treatments such as bland embolization, chemoemboli- Weight loss, dehydration, malaise, electrolyte distur- zation, or radioembolization may be options. Alterna- bances, and cramping can occur, with their severity tively, enrollment in a clinical trial of agents in develop- correlated with tumor bulk. Other manifestations of ment such as bevacizumab, pasireotide in combination carcinoid syndrome may be a facial rash mimicking with cixutumumab (IMC A-12, an insulin-like growth fac- rosacea, cardiac valvular disease (tricuspid insuffi- tor-1 inhibitor), everolimus in combination with bevaci- ciency, pulmonic stenosis), wheezing, and malaise. zumab, and peptide receptor radiotherapy (PRRT) using Flushing, asthma, and secretory diarrheal symptoms lutetium-177 DOTATOC would be recommended (http:// require immediate control by subcutaneously adminis- clinicaltrials.gov/ct2/results?termϭneuroendocrineϩ tered octreotide as the majority of patients respond cancer). within a few days to 1–2 weeks (see Figure 1).3 The Various well-defined clinical syndromes and their severity of symptoms will determine which octreotide presenting symptoms related to hormonal secretion(s) formulation and route of administration is optimal. The from either a primary mass and/or metastases from a subcutaneous route is satisfactory for most patients to well-differentiated or intermediate-grade NET category control symptoms quickly with eventual conversion, with management options are discussed below. Even usually within 2–4 weeks, to the intramuscular or de- though the pancreas and small and large intestines pot monthly formulation, octreotide long-acting repeat- comprise the majority of tumors addressed, functional able (LAR).12 Subcutaneous octreotide should be con- syndromes may also arise from the lung, thymus, or an tinued for 2 weeks after the initial intramuscular LAR unknown primary tumor. injection until therapeutic levels are achieved. Break- through symptoms that occur after conversion to LAR are more common during the week prior to the CARCINOID SYNDROME monthly intramuscular injection and may require sub- Presenting symptoms are generally attributable to a cutaneous dosing depending on their severity and du- well-differentiated (low- or intermediate-grade) NET ration. metastatic to the liver, often present for years prior to Following octreotide initiation, the clinician can fo- diagnosis and typically with an insidious onset. Symp- cus on other individual factors that may contribute to toms may be isolated flushing or diarrhea or the com- symptomatology and disease morbidity such as bowel bination of flushing and diarrhea.17 As early symptoms obstruction, high tumor bulk, or concomitant illnesses are vague and nonspecific, misdiagnosis or a delay in such as irritable or inflammatory bowel disease, hyper- diagnosis may occur even in patients presenting with tension, dumping symptoms from bowel surgery, bile advanced disease.18 Provocative factors for flushing in- acid colitis, and malabsorptive syndromes. As a mesen- clude ethanol, emotional upsets, exercise, eating, epi- teric desmoplastic process is common with intestinal nephrine, and pentagastrin.19,20 The Valsalva maneuver, NETs, chronic abdominal pain and recurrent bowel hepatic palpation during the physical exam, breast obstructions may limit quality of life. compression during mammography, hepatic emboliza- While octreotide controls secretory diarrhea, it in- tion, or resection also may provoke symptoms and duces steatorrhea. With diet adjustment and lopera- even crises in some circumstances.21–23 mide, this steatorrhea is controllable in most patients. Should flushing be an early symptom in a perimeno- For those few patients who experience significant pausal female, confusion with physiologic flushing is weight loss, a trial of pancreatic

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