Exocrine pancreatic insufficiency and somatostatin analogs in patients with neuroendocrine neoplasia

1. Introduction

Gastroenteropancreatic neuroendocrine neoplasia (GEP-NEN) is a heterogeneous group of rather rare cancers. Such cancers have different biological behaviors depending on both clinical and pathological features, including primary tumor site, disease staging, tumor grading, and somatostatin receptors’ expression. The presence of these receptors in GEP-NEN patients is the rationale for using the somatostatin analogs (SSAs) octreotide long-acting release (LAR) and lanreotide slow-release (autogel), which are widely recognized as first-line therapy for most GEP-NENs. In fact, in patients with slow-growing, well-differentiated, somatostatin receptor-positive tumors, which represent the most common type of GEP-NENs, both analogs have been demonstrated to be effective in controlling symptoms and inhibiting tumor growth [1,2]. These drugs are well tolerated and have an excellent safety profile. The most commonly reported side effects are abdominal pain, flatulence, diarrhea, constipation, bloating, hyperglycemia, and gallstone development [3]. Although relatively frequent, these symptoms are rarely severe, and, while treatment discontinuation is necessary for a negligible minority of patients, most of them are able to remain under treatment for long periods of time.

Interpreting abdominal symptoms may be tricky in GEP-NEN patients receiving SSAs owing to the possible overlap between aforementioned symptoms and carcinoid syndrome as well as previous surgery, which might result in the small bowel or pancreatic resection depending on the primary tumor site [4]. Furthermore, secretory diarrhea may be present because of short bowel, bile acid diarrhea, or bacterial overgrowth, which are also known to be potential causes for low fecal elastase levels pointing to exocrine pancreatic insufficiency (EPI) [5,6].

The onset of EPI may further confound the clinical picture in patients with NENs receiving SSAs, which may occur owing to the effects of these drugs on pancreatic function, and more specifically, inhibition of the production and secretion of pancreatic enzymes [7]. Although EPI is rarely reported in clinical trials investigating the efficacy of SSAs in GEP-NEN patients [1,2], its prevalence in daily clinical practice seems to be dramatically higher (up to 20%), as highlighted in few studies (Table 1) [7–10].

Table 1. Clinical studies on EPI and SSAs in patients with NENs

Reference	Study design	Population	Diagnosis of EPI	Main findings
Saif [7]	Retrospective	Patients with diagnosis of NEN	Steatorrhea QFFT No pancreatic disease	EPI prevalence 11.6% 100% improvement after PERT
Lamarca [8]	Prospective	Patients with well-differentiated NEN of any anatomical site	Stool FE ^−1 <200 μg/g or by a reduction of ≥21% of baseline value and/or development or worsening of symptoms	EPI prevalence 24% Median time to EPI: 2.9 months
Saif [9]	Retrospective	Patients with advanced well-differentiated GEP-NEN	Clinical signs of malabsorption (steatorrhea and weight loss) QFFT	EPI prevalence 38% Median time to EPI: 6.5 months
Rinzivillo [10]	Prospective	Patients with advanced well-differentiated (G1 or G2) GI NEN	Clinical signs of malabsorption and/or maldigestion (steatorrhea, weight loss, flatulence, and abdominal distention) Stool FE-1 <200 mcg/g	EPI prevalence 20% Glycated Hb predictor for EPI occurrence 100% improvement after PERT

2. EPI and SSAs: weak evidence, heavy problem

To date, a PubMed search for ‘exocrine pancreatic insufficiency AND somatostatin analogs’ retrieves very few studies, usually including retrospective clinical studies with a small number of patients.

A case series on the association between SSAs and EPI was initially published in 2010. The study included a small group of patients with NEN who experienced worsening of diarrhea after octreotide dose escalation and who achieved symptom improvement after initiation of pancreatic enzyme replacement therapy (PERT) [7].

More recently, a prospective observational study including 50 NEN patients reported that 24% developed EPI after a median interval of approximately 3 months after initiation of SSAs [8]. Most patients (60%) had jejunoileal tumors, and two-thirds were nonfunctioning. Although the onset of EPI did not significantly decrease the quality of life scores, a trend toward an increase in abdominal symptoms was observed. This study was the first to suggest that EPI may frequently occur as a potential early side effect in patients with NEN treated with SSAs.

An even higher prevalence of EPI (38%) was reported in a larger series including 110 patients. However, the retrospective design of the study and evaluation of a heterogeneous population of NEN from any site made the finding less reliable in clinical practice [9].

The significant prevalence of EPI in NEN patients treated with SSAs was further confirmed by our own recent prospective study in which 20% of the patients receiving octreotide or lanreotide were diagnosed with EPI with fecal elastase 1 (FE-1) assessment after a median period of 84 months. Further, glycated hemoglobin was identified as the sole predictor of EPI occurrence [10].

Taken together, given the predictable indolent course of the disease and the expected favorable response to SSAs therapy, a consistent proportion of patients with well-differentiated, slow-growing NENs under long-term treatment with SSAs will experience EPI during treatment. Given the well-known negative impact of EPI on patients’ quality of life, nutritional status, and clinical outcome, identifying this condition becomes mandatory when planning an optimal care for NEN patients (Figure 1). Notably, in the specific setting of pancreatic NENs, EPI may be already present before the start of SSAs because of atrophy of the remaining part of the pancreas distal to the tumor. Furthermore, patients with calcitonin-, gastrin-, and VIP-secreting pancreatic NENs can also present with secretory diarrhea due to the presence of the tumor-related specific syndrome.

Figure 1. Proposed algorithm to manage patients with GEP-NENs receiving SSAs. ¹Symptoms of maldigestion/malabsorption of nutrients; physical examination with anthropometry; circulating levels of nutrients including fat-soluble vitamins, proteins and micronutrients [glycemia, glycated hemoglobin, cholesterol, triglycerides, prealbumin, retinol-binding protein, 25-OH cholecalciferol (vitamin D), vitamin A, vitamin K, and minerals/trace elements, including serum iron, zinc, and magnesium]; noninvasive pancreatic functional test (FE-1 test). ²Standard dose of 40.000 PhU with main meals and half dose with snacks (increase dose according to clinical response)

In clinical practice, diagnosing and treating EPI is quite easy. Given its efficacy in evaluating symptoms in patients at risk of pancreatic dysfunction owing to different causes, noninvasive FE-1 is widely considered the standard diagnostic tool for the identification of EPI [11]. A combination of clinical features and biochemical parameters (with particular focus on glycemia, glycated hemoglobin, cholesterol, triglycerides, and D and K vitamins), together with FE-1 values <200 mcg, indicates the presence of EPI. Caution is needed when interpreting vitamin D values, owing to the relatively high prevalence of low vitamin D levels in the European population independent of the use of SSAs or the presence of NEN [12]. In general, malnutrition and fat-soluble vitamin deficiencies, including D vitamin, are relevant clinical problems in patients with NENs, deserving routine assessment in plasma, potential dietary advice, or standard vitamin supplementation [13–15]. The risk of fat-soluble vitamin deficiency and malabsorption, in general, was also reported in patients with acromegaly treated with SSAs, suggesting that it may be directly related to the use of these drugs rather than to the presence of a GEP-NEN [15]. Once diagnosed, EPI may be managed using PERT, which needs to be prescribed at a proper dosage (standard dose of 40.000 PhU with main meals and half the dose with snacks, which can be increased according to the clinical response) [16]. Surprisingly, both physicians and patients with EPI have shown low adherence to these simple rules. A recent survey reported an approximate 50% compliance with PERT administration guidelines [17], thus suggesting a general lack of awareness about EPI and PERT and a strong need to fill these knowledge gaps to provide patients with optimal care.

In addition to starting PERT, owing to the risk of developing specific nutrient deficiencies, vitamin D supplementation and testing for other nutrients, including vitamin B12, should be recommended in these patients. Finally, since the clinical picture of patients with NEN receiving SSA may be influenced by several factors, it seems justified to try PERT without further examinations in patients experiencing symptoms compatible with EPI after the introduction of a somatostatin analog, while proceeding with the specific diagnostic workup to rule out the presence of malabsorption.

3. Conclusions

Owing to the rarity of the disease and its biological heterogeneity, the management of patients with GEP-NENs remains a challenge for physicians. This is further complicated by the complex landscape of the clinical picture of such patients, which may include peculiar tumor-related syndromes in functioning tumors, nonspecific symptoms related to tumor growth, and potential side effects of long-term medical treatments. A multidisciplinary team-based approach is the key aspect of care for this group of patients as it shortens the delay in diagnosis and increases the opportunity for patients to receive the best care [18]. The lack of awareness regarding the potential onset of treatment-related EPI, which can lead to a deterioration in nutritional status, worsening in the quality of life, and prejudicing clinical outcomes in GEP-NEN patients, is no longer acceptable. Thus, the involvement of gastroenterologists and nutritionists in the multidisciplinary management of these patients is strongly advised to increase the chances of providing them with the best care. A prospective large trial from the community of physicians dealing with GEP-NENs is strongly advised to obtain solid data on the real impact of EPI in the management of patients receiving SSAs.

4. Expert opinion

Exocrine pancreatic insufficiency, which occurs in approximately 20% of the patients with GEP-NENs receiving SSAs octreotide and lanreotide, is an underestimated condition. The clinical picture of EPI in these patients may overlap with tumor-related symptoms and common direct SSAs’ side effects, such as diarrhea, abdominal pain, bloating, and flatulence.

Early recognition of EPI is mandatory since it may negatively affect patients’ quality of life, nutritional status, and long-term clinical outcomes. Given the availability of the noninvasive diagnostic tool FE-1, which is widely used in pancreatic diseases other than NENs to identify exocrine insufficiency, the diagnosis of EPI is quite easy. Thus, the FE-1 test should be included in routine laboratory assessments during follow-up evaluations (Figure 1).

Treatment of EPI is based on PERT, which is often prescribed and administered without following the international guidelines that recommend 40.000 PhU with main meals and half the dose with snacks that must be increased according to the clinical response; moreover, it must be prescribed for a lengthy period. Vitamin D supplementattion and testing for other nutrients, including vitamin B12, should be recommended in these patients.

It seems justified to try PERT without further examinations in patients experiencing symptoms compatible with EPI after the introduction of a somatostatin analog while proceeding with the specific diagnostic workup to rule out the presence of malabsorption.

To avoid the predictable side effects of SSA and to provide optimal care for GEP-NEN patients, the involvement of physicians with specific skills on pancreatic dysfunctions and nutritional assessment in multidisciplinary teams dedicated to GEP-NEN patients is strongly advised.

Declaration of interests

F Panzuto received honoraria as speaker from Mylan Italia. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.