**8. Management**

Multidisciplinary teams (MDTs) have an important role in deciding the treatment of these tumors as they are slightly rare.

Treatment options range from curative surgery to palliation with medical therapies including somatostatin analogs, chemotherapy and targeted treatments [67].

Conservative management is indicated for incidentalomas, i.e. the tumors which are small, non functional and asymptomatic [68]. Although it is a controversy whether small nonfunctional tumors of under 2 cm should be resected, when they are likely to have less metastatic potential, but a more aggressive surgical approach is recommended for tumors over 2 cm [69].

#### **8.1 Surgery**

Surgery is the only curative treatment option and should be considered in all patients with localized disease as it not only cures the mass related symptoms but also the hormone related effects. Such patients should have their surgery carried out at specialist hepatopancreatobiliary centers. Surgery can be done for curative treatment like radical excision or palliative treatment that aims for symptomatic relief. It can also be used for surgical treatment of complications. The 5-year overall survival rate of resected PNETs is significantly greater than unresected ones, ranging from 77% to 46% [70]. Unfortunately, pancreatic surgery shows significant mortality, ranging from 1% to 10% [71] and morbidity. The perioperative and long-term complications include diabetes, pancreatic exocrine impairment in up to 50–60% patients, even in high volume centers [72, 73].

Careful observation and wait and watch policy can be employed for small non functioning pNET which helps in not only avoiding the pancreatic surgery but also helps curb the operation related complications, as most of the small NF-PanNETs are indolent despite a chance of 10% of nodal involvement [74, 75].

According to the updated ENET guidelines patients having NF-PanNETs ≤2 cm can be safely managed conservatively.

Indications of non operative approach:


In patients with G2 NF-PanNETs greater than or equal to 2 cm, surgery should be recommended. Other factors to be taken into consideration include patient's age, comorbidities, surgical risk, the tumor site, and desire for surgical intervention.

In cases of surveillance, EUS and MRI should be mandatory and to be repeated every 6 months (12 months if no changes are discovered). If an increase of 0.5 cm (or more) in the size of the lesion is seen on the imaging then the patient should be reevaluated for surgery [9].

The studies comparing observation with surgery in pNET are as follows:(**Table 8**).

In contrast to the ENETS guidelines, the American National Comprehensive Cancer Network (NCCN) guidelines recommend surgery to be done in a pNET bigger than 1 cm. Observation is indicated incidentally discovered, low-grade NF-PanNETs smaller than 1 cm. Additional factors for conservative management include the surgical risk, the tumor site, and the patient comorbidities, especially when dealing with small asymptomatic tumor [80]. NCCN states that more aggressive approach (routine surgery) is recommended in tumors greater than 1 cm as some small (<2 cm) high-grade tumors demonstrate frankly malignant behavior (9% to 39%) [81].

*An Overview of Pancreatic Neuroendocrine Tumors DOI: http://dx.doi.org/10.5772/intechopen.96259*


#### **Table 8.**

*Studies comparing observation versus surgery in small pNET.*

### **8.2 Systemic therapy**

In patients with resectable PanNETs, surgery with curative intent (that is, R0 or margins that are microscopically free of tumor) remains the treatment of choice. Unfortunately, as the majority of patients with PanNETs either present with metastatic disease or have disease recurrence within 2 years of surgery, effective systemic therapies are also needed [82].

#### **8.3 Somatostatin analogs**

Somatostatin analogs remain the cornerstone in treatment of advanced neuroendocrine tumors.

Long acting octrotide, lanreotide which bind both SSTR2 and SSTR5 and pasireotide which binds to SSTR1, 3, and 5 are currently approved for clinical use [83].

Trials studying the role of somatostatin analogues (**Table 9**).


**Table 9.**

*Studies showing role of somatostatin analogues in pNET.*

The use of pasireotide, a somatostatin analog was evaluated in a phase III randomized trial targeting SSTR5, in octreotide-resistant patients. It demonstrated no difference in the response rate (RR) compared with long-acting octreotide. The trial was stopped prematurely [86].

Chan et al., studied 1022 patients in 18 trials using more than 30 mg octreotide or 120 mg lanreotide over 28 days in a meta-analysis in 2017 [87]. Pasireotide has shown a more potent antiproliferative effect as compared to octreotide in preclinical data from NCI-H727 cells and from pancreatic NET primary cell cultures [88].

A similar study conducted by Cives et al. recently showed that pasireotide LAR provides better tumor control efficacy (PFS 11 months), when used as first-line therapy in patients with advanced NET [89]. Further, in patients with functionally active advanced GEP-NETs, pasireotide provided an improved tumor control rate at 6 months compared to octreotide [50]. In 160 patients with progressive grade 1 through 2 pancreatic NETs, the COOPERATE-2 trial tested the combination of everolimus and pasireotide vs. everolimus. It was seen that both overall and progression-free survival were similar in both arms (16.8 months vs. 16.6 months), although response rates were higher in the experimental arm [90].


#### **Table 10.**

*Studies showing the role of targeted therapy in treatment of pNET.*

*An Overview of Pancreatic Neuroendocrine Tumors DOI: http://dx.doi.org/10.5772/intechopen.96259*


**Table 11.**

*Studies showing role of cytotoxic chemotherapy in pNET.*
