Management of Advanced Small Bowel Cancer

Opinion statement

Small bower cancer is a rare disease, despite its incidence is increasing in the last decade. Both benign and malignant tumors can arise from the small intestine. The main histological cancer types are adenocarcinomas, neuroendocrine tumors, sarcomas, gastrointestinal stromal tumors (GISTs), and lymphomas. Due to the rarity of these malignances, all the currently available data are based on small studies or retrospective series, although recent breakthroughs are redirecting our approach to these patients. Immunotherapy for small bowel adenocarcinomas, several multikinase inhibitors in resistant GIST patients, as well as everolimus and ¹⁷⁷Lu-DOTATATE in neuroendocrine tumors are only few of the novel therapeutic options that have changed, or may change in the future, the therapeutic landscape of these rare cancers. Larger and more powerful studies on the molecular profile of these tumors may lead to a better design of clinical trials, which eventually would provide our patients with more efficacious treatments to improve both overall survival and quality of life.

Introduction

Small bowel cancer is a rare disease that represents 0.6% of all new cancer cases in the USA [1]. Nonetheless, rates for new small intestine cancer cases have been rising by an average of 2.3% each year over the last 10 years [2–4]. In 2018, it is estimated that there will be 10,470 new cases of small bowel cancer and an estimated 1450 people will die of this disease.

Several different histological types of cancer can arise from the small intestine, such as adenocarcinomas, neuroendocrine tumors, sarcomas, gastrointestinal stromal tumors (GISTs), and lymphomas (Table 1). Of note, benign lesions that may arise in the small bowel include adenomas, leiomyomas, fibromas, and lipomas.

Table 1. Features of the main histological types of small bowel cancers.

Histotype	Incidence among small bowel cancers	Main location	Management of advanced disease	Future perspectives
Adenocarcinomas	30–50%	Duodenum	Chemotherapy First line: FOLFOX/CAPOX Second line: FOLFIRI	Immunotherapy and targeted therapy development based on novel molecular profiling data
GIST	10–20%	Stomach (60%), jejunum and ileum (30%), duodenum (5%)	First line: imatinib Second line: sunitinib Third line: regorafenib	Additional multikinase inhibitors (e.g., sorafenib, pazopanib, and ponatinib)
Neuroendocrine tumors	35–40%	Ileum	First line: SSAs, octreotide LAR, and lanreotide Further lines: everolimus, 177Lu-dotatate, chemotherapy	Multitargeted tyrosine kinase inhibitors and PRRT

GIST gastrointestinal stromal tumors, LAR long-acting release, PRRT peptide receptor radiotherapy, SSAs somatostatin analogs

Due to their rarity and the heterogenous clinical presentation, small bowel cancers are often diagnosed in later stages, which are associated with a poor treatment outcome. Moreover, treatment and prognosis differ for each histological subtype and therapeutic strategies should be tailored to each separate class of tumor.

All data available in terms of clinicopathological features, molecular profile, treatment options, and survival outcomes of this neoplasia usually derive from small studies, often retrospective in nature. Larger and more powerful studies are eagerly awaited to expand our knowledge and implement the treatment scenario of these malignancies.

Herein, we aim to provide an overview on the actual body of knowledge on carcinogenesis, risk factors, and treatment of the main histological subtypes of small bower cancer: adenocarcinoma, GIST, and neuroendocrine tumors.

Epidemiology and etiopathogenetic factors

The mean age at diagnosis of a small bowel neoplasm is 65 years old, with sarcoma and lymphoma presenting at a slightly younger age (60 to 62) than adenocarcinoma and neuroendocrine tumors (67 to 68) [5, 6]. Adenocarcinoma has been the most common histologic type among small intestine malignancies, yet in the last few decades, neuroendocrine tumors incidence remarkably increased surpassing adenocarcinomas as the most frequent tumor type of the small bowel [2]. Of note, adenocarcinomas are most frequently diagnosed in the duodenum, while neuroendocrine tumors are most frequently found in the ileum.

A number of factors have been associated with an increased risk of developing a small bowel cancer including alcohol, tobacco, refined sugar and carbohydrates, red meat or smoked food, while a reduced risk has been linked with higher intakes of coffee, fish, fruit, and vegetables [7–11].

Small bowel cancers have been demonstrated to be associated with several predisposing conditions [12], such as inflammatory bowel disease (i.e., Crohn’s disease), coeliac disease, as well as hereditary syndromes: familial adenomatous polyposis (FAP), Lynch syndrome (otherwise called Hereditary non polyposis colorectal cancer or HNPCC), and Peutz–Jeghers syndrome.

Crohn’s disease induces a chronic transmural inflammation of the gastrointestinal tract which eventually may promote carcinogenesis. Cancers related to Crohn’s disease are usually adenocarcinomas of the ileum, with an increased relative risk (RR) of small bowel adenocarcinoma (SBA) in Crohn’s disease estimated in several population-based studies to range from 17 to 41 compared to the general population [12]. A meta-analysis showed a RR of 33.2 (95% CI 15.9–60.9) for small bowel cancer in patients with Crohn’s disease [13].

Moreover, an increased risk of small bowel lymphoma and SBA has been observed in patients affected by coeliac disease [14].

FAP, an autosomal dominant genetic disorder caused by a germline mutation of the APC gene, is a condition characterized by the early onset of numerous adenomatous polyps mainly in the epithelium of the large intestine. Although all patients affected by FAP will eventually develop colon cancer by age 35–40 years, if left untreated, other malignancies may occur. In fact, the prevalence of duodenal adenomas is 50–90% and these patients carry a RR of 330 for SBA or up to a 5% lifetime risk [15].

Lynch syndrome is a hereditary disorder due to the germline mutations of mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2) that lead to microsatellite instability (MSI). Patients with this condition have an increased risk of colorectal and endometrial cancers and less frequently gastric, ovarian, biliary tract, urothelial cancers and SBA. The lifetime cumulative risk of SBA in Lynch syndrome patients remains low: 0.6–1% [16]. Therefore, international guidelines do not recommend to screen Lynch syndrome patients for SBA. However, analysis of the MMR phenotype is systematically recommended in SBA, because it could reveal the presence of Lynch syndrome and thus inform management and surveillance of patients and counseling for their relatives [17].

Finally, Peutz–Jeghers syndrome is an autosomal dominant condition due to the germline mutation of the STK11 gene associated with an increased risk of malignancies. The most common malignancy is colorectal cancer (CRC), followed by breast, small bowel, gastric, and pancreatic cancers. The reported lifetime risk for any cancer varied between 37 and 93%, with RRs ranging from 9.9 to 18 in comparison with the general population [18]. More specifically, the lifetime incidence for SBA is 1.7–13% and rises rapidly in elderly [19, 20].

Interestingly, data suggest that the carcinogenesis of SBA differs from that of CRC. In the former, the nuclear accumulation of β-catenin is most probably due to a gain-of-function mutation in the β-catenin gene rather than a loss of regulation due to the APC mutation, which is found in ~ 80% of all human colon tumors and it is considered one of the main events of CRC carcinogenesis [17, 21]. Due to the small sample size of the few studies that investigated the molecular profile of SBA, it is difficult to draw a definitive assessment of the frequencies of the gene mutations and protein expression involved in SBA carcinogenesis. However, it seems that SBAs are characterized by an overexpression of the p53 protein, vascular endothelial growth factor-A (VEGF-A), and the epidermal growth factor receptor (EGFR), as well a loss of SMAD4 expression [22]. While MSI or MMR-deficient (dMMR) tumors represent around 5% of CRC, the frequency of dMMR phenotype in SBA varies largely based on different studies; therefore, larger series are warranted to improve our knowledge on the biological mechanisms underlying these tumors and to implement the design of therapeutic trials.

Small bowel adenocarcinoma

As aforementioned, SBAs are rare and unique tumors, which are often diagnosed at an advanced stage due a delayed clinical presentation and non-specific symptoms (i.e., abdominal pain, weight loss, nausea and vomiting, occult GI tract bleeding), coupled with a limited sensitivity of conventional radiological imaging for the detection of this type of cancer [2, 17]. Few studies have specifically addressed the optimal management of SBA, and the general approach to the treatment of these tumors is to follow recommendations from expert agreements or by analogy with CRC [23, 24•]. However, more recently, new data are emerging on the molecular characterization of SBA and targeted treatment approaches in the advanced setting.

Overall, the 5-year survival for SBA patients is poor (14 to 33%), decreasing from 50 to 60% for stage I tumors (approximately 6–12% of patients) to 3–5% for stage IV (32–37% of patients at diagnosis) [2, 25, 26]. Among locally advanced SBA (stage III, 21–27%), the degree of lymph nodal involvement represents the main prognostic factor. In fact, the 5-year disease-free survival (DFS) is worse when three or more nodes are involved compared to two or less positive nodes (5-year DFS rates of 37% vs 58%, respectively, P < 0.01) [27]. A number of additional factors have been associated with a poor prognosis in different studies, including older age, impaired performance status, male gender, black ethnicity, a duodenal primary tumor location, poor tumor differentiation, positive margins, inadequate lymph nodal sampling (< 8 or < 10 according to different studies), low serum albumin, high lactate dehydrogenase, and high CEA or CA 19.9 [2, 26, 28–30].

Surgical complete resection (R0) of primary tumor coupled with locoregional lymph node resection represents the only potentially curative treatment for localized disease. On the other hand, primary tumor resection is generally not recommended in the metastatic setting except in case of acute bowel obstruction, perforation, or uncontrolled bleeding. Of note, a retrospective study reported that the relapse pattern after R0 resection of localized SBA is predominantly systemic, with locoregional and distant relapse accounting for 18 and 86% of all recurrences, respectively [31].

The management of advanced SBA (i.e., unresectable or metastatic) is based on systemic treatment, although no randomized studies have been performed to demonstrate a benefit of systemic chemotherapy in patients with advanced disease. In fact, results from several retrospective comparative studies and small patients series in this setting demonstrated a significant benefit for systemic chemotherapy, both in terms of median progression-free survival (PFS) and overall survival (OS) (6 months vs 1 month and 9–19 vs 2–13 months, respectively) [31–37]. Similarly, no prospective randomized data are available to determine which chemotherapeutic regimen is the most effective. However, retrospective series comparing different regimens consistently reported best results in terms of response, survival, and toxicity with the use of 5-fluorouracil/leucovorin plus oxaliplatin (FOLFOX) [38–42]. More recently, several prospective phase II studies confirmed this retrospective evidence, showing response rates of 45–50%, disease control rates of 80–90%, and a median OS of 15–20 months following frontline treatment with either FOLFOX [43, 44] or capecitabine plus oxaliplatin (CAPOX) [45]. The addition of irinotecan to oxaliplatin and fluoropyrimidine appears to be feasible, but its benefit remains unclear. In a recent study, McWilliams and colleagues tested the efficacy of pharmacogenetic-based dosing of irinotecan (according to the UGT1A1 genotype), oxaliplatin, and capecitabine (CAPIRINOX) as first-line therapy in 33 patients with advanced SBA [46]. Results of this study showed overall an objective response rate of 38%, a disease control rate of 81%, a median PFS of 8.9 months, and a median OS of 13.4 months. Hematological toxicity as well as response rates were comparable among different genotype groups. In the second-line setting, the FOLFIRI regimen has shown modest activity in a small series of patients after failure on a platinum-based therapy (objective response rate 20%, disease control rate 52%, median PFS and OS 3.2 and 10.5 months, respectively) [47]. Of note, a recent small phase II study including ten SBA patients showed signs of activity of nab-paclitaxel in the treatment of refractory SBA, with two partial responses and in vivo testing of paclitaxel in a SBA patient-derived xenograft (PDX) supporting the activity of taxanes in this disease type [48]. Although encouraging, these results require further validation.

To date, contrary to CRC, few data are available exploring the benefit of specific biologic or targeted therapies in the treatment of advanced SBA. However, recent findings from a large-scale genomic profiling study of a series of 317 SBA highlighted that 92% of these tumors harbored a potentially actionable genomic alteration associated with available targeted agents or therapeutics under study in clinical trials. Among the most frequent alterations in SBA were HER2 mutation/amplification, EGFR mutation/amplification, MSI, high tumor mutational burden, and PIK3CA pathway activation [49•]. Similar findings were reported in a different exome sequencing study on a population-based set of 106 SBA [50]. Hence, SBA appears to have distinct molecular characteristics and may benefit from targeted therapeutic strategies. Notably, the rates of KRAS and BRAF mutations in SBA were similar to CRC, although BRAF V600E mutations were less common in SBA (10.3% of BRAF-mutated cases) and case reports have described responses to anti-EGFR therapy in patients with KRAS wild-type tumors [51, 52]. Nonetheless, recently published results from a small phase II single-arm trial investigating the efficacy of second-line panitumumab monotherapy in RAS wild-type SBA and ampullary adenocarcinoma failed to show any clinically meaningful activity of this treatment in this setting of patients [53]. A single published trial has tested, at present, the combination of the vascular endothelial growth factor (VEGF) inhibitor bevacizumab with chemotherapy in SBA. In this study, 30 patients with metastatic SBA and ampullary adenocarcinoma were treated with CAPOX plus bevacizumab, obtaining a response rate of 48% associated to a median PFS and OS of 8.7 and 12.9 months, respectively [54]. These results were not significantly different from results of the previous study with CAPOX alone from the same institution [45]. Finally, the high incidence of MSI, ranging from 5 to 45% in different studies, and the higher tumor mutational burden of SBA, alongside data showing high PD-1 and PDL-1 expression in this tumor type, support a potential benefit from immunotherapy [49•, 55]. Pembrolizumab, an anti-PD1 monoclonal antibody, has already been approved by the U.S. Food and Drug Administration (FDA) in May 2017 for the treatment of a variety of advanced MSI-high or dMMR solid tumors including SBA [56]. Results from dedicated ongoing trials investigating treatments with immune checkpoint inhibitors, such as pembrolizumab (NCT02949219) and the anti-PD-L1 monoclonal antibody avelumab (NCT03000179) in refractory SBA, are eagerly awaited.

Limited information and conflicting evidence are available regarding metastasectomy for advanced SBA. Cytoreductive surgery and intraperitoneal chemotherapy (IPC) have been proposed as an alternative treatment option for selected patients in case of peritoneal metastases. Peritoneal involvement characterizes about one third of stage IV patients and is more common with tumors arising from the jejunum or ileum rather than from the duodenum [57]. A review of literature including 15 observational and 3 phase II studies reporting outcome data from first-line systemic therapy or cytoreductive surgery with IPC for advanced SBA concluded that fluoropyrimidine plus oxaliplatin should be regarded as optimal first-line systemic treatment, although in selected patients, cytoreductive surgery plus IPC appeared safe and possibly more effective than systemic therapy as single treatment [58]. In the presented studies investigating cytoreduction plus IPC, median DFS and median OS ranged from 10 to 12 months and from 16 to 47 months, respectively, while grade III–V morbidity rates were 12 to 35%. More recently, outcome data have been published from a multiinstitutional international data registry including 152 patients with peritoneal metastases from SBA treated with cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy (HIPEC) between 1989 and 2016 in 21 institutions [59]. The combined treatment strategy of cytoreduction plus HIPEC achieved prolonged survival for selected patients (median DFS after completeness of cytoreduction [CCR] 0/1 of 14 months, range 1–100 months) with acceptable morbidity and mortality (treatment-related mortality rate 2%, grade 3 or 4 operative complications 19.1%). Absence of lymph nodal involvement, well-differentiated tumor, and peritoneal cancer index < 15 were independently associated with improved OS in the multivariate analysis. Generalization of these results however warrants some caution due to relatively small number of patients included in these studies and the possible significant bias in treatment results by patient selection and treatment heterogeneity across different studies. Furthermore, recently presented results of the randomized multicentric phase III PRODIGE 7 trial, investigating cytoreductive surgery plus HIPEC in association with systemic chemotherapy in metastatic CRC with isolated peritoneal carcinomatosis, showed no benefit from the addition of HIPEC to surgery alone plus systemic chemotherapy in this setting [60].

Sarcomas and GIST

Sarcomas represent around 10–20% of the small bowel cancers [61, 62]. Among all sarcomas arising in the small bowel tract, the vast majority is considered to be gastrointestinal stromal tumors (GISTs). GISTs are hypothesized to arise from interstitial cells of Cajal, the intestinal pacemaker cells, and are the most common mesenchymal neoplasms of the gastrointestinal tract. However, GISTs are rare tumors, with an incidence estimated to be between 6.8 and 20 per million population [63, 64]. They are usually found in stomach (60%), small intestine, jejunum and ileum (30%), duodenum (5%), rectum (2–3%), and colon (1–2%) [65•].

Activating mutations in the c-KIT (CD117) oncogene are seen in about 60–85% of all GISTs [66]. A subset of GISTs lacking c-KIT mutations (about 5–10% of all GISTs) has activating mutations in a related receptor tyrosine kinase, the platelet-derived growth factor receptor alpha (PDGFRA).

Imatinib mesylate (Gleevec®; Novartis Pharmaceuticals Corporation, East Hanover, NJ) was approved by the FDA for the treatment of malignant metastatic and/or unresectable GISTs on February 1, 2002, with the dose for GIST patients of 400 or 600 mg daily [67], based on a study which included 147 patients enrolled at three US centers and one center in Finland [68]. An overall response rate of 38% across the two dose levels and a response duration ranged from 7 to 38 weeks, with a median of 13 weeks, were observed. In 2012, the FDA granted regular approval of imatinib mesylate tablets for the adjuvant treatment of adult patients following complete resection of c-KIT+ (CD117+) GISTs, with the recommended dose of 400 mg/day administered daily for 3 years. The initial approval (2008) was based on a single phase III randomized, double-blinded, placebo-controlled study that enrolled a total of 713 adult patients with a c-KIT+ GIST, and a resected tumor size ≥ 3 cm. Imatinib mesylate, 400 mg orally once daily, was administered for 1 year [69]. In the intent-to-treat (ITT) population, imatinib treatment led to a significantly longer recurrence-free survival (RFS) interval than placebo (hazard ratio [HR] = 0.398; 95% confidence interval [CI], 0.259–0.610; P < .0001) [70]. Following these results, a phase III, multicenter, open-label, randomized adjuvant trial was conducted comparing imatinib treatment for 3 years with imatinib treatment for 1 year in a higher risk population [71]. Three hundred ninety-seven patients were enrolled and patients assigned in the 3-year arm had longer RFS (5-year RFS, 65.6% vs 47.9%, respectively HR = 0.46; 95% CI 0.32–0.65; P < 0.001) and longer overall survival (HR = 0.45; 95% CI 0.22–0.89; P = 0.02; 5-year survival, 92.0% vs 81.7%) compared with those assigned in the 1-year arm, leading to the aforementioned FDA approval in 2012.

Two main therapeutic options are available for patients with advanced GIST who progress on imatinib treatment: either imatinib dose escalation [72] or sunitinib, a multitargeted tyrosine kinase inhibitor (TKI) active against PDGFRα, PDGFRβ, and VEGFR receptors, which has demonstrated a 5-month PFS improvement compared to placebo in a randomized phase III trial [73]. Based on these results, the European Medicines Agency (EMA) and the FDA granted approval for sunitinib (Sutent, Pfizer) in the second-line treatment of GIST at the recommended dose of 50 mg orally once a day over 4 weeks followed by a 2-week rest period.

Finally, regorafenib (Stirvarga, Bayer HealthCare Pharmaceuticals Inc.), an orally active multikinase inhibitor with activity against several kinases including c-KIT, was recently approved by FDA and EMA for the treatment of patients with unresectable or metastatic GIST after failure or intolerance to imatinib and sunitinib [74].

Several other multikinase inhibitors have shown promising results in resistant GIST patients, although data derive mostly from small phase II studies. Therefore, sorafenib, pazopanib, and ponatinib represent valuable options in patients that progressed after all current standard treatments for advanced/metastatic disease (i.e., imatinib, sunitinib, and regorafenib). Moreover, the enrollment of patients in clinical trials is highly encouraged in this setting.

It is noteworthy that about 10 to 15% of GISTs in adults and 85% of GISTs in children are negative for c-KIT and PDGFRA mutations, which are designated as wild-type GIST [75]. This subset of GISTs is known to be resistant to kinase inhibitor therapies (i.e., imatinib), primarily affects young females, is multifocal but indolent, and the primary tumor has generally a gastric location. Wildtype GISTs may have several different driver mutations and may comprise heterogeneous entities, such as succinate dehydrogenase (SDH)-deficient GISTs, BRAF-mutated GISTs, and neurofibromatosis type I-associated GISTs (NF1-GISTs) [76]. In a recent study by Boikos et al. [77], wild-type GIST specimens from 95 patients were classified into 3 molecular subtypes: SDH-competent (n = 11) and 2 types of SDH-deficient GIST (by SDH-B mutation or SDH-C promoter methylation). The authors found that SDH-competent tumors retain SDHB expression and a normal methylation pattern. This subset of wild-type GIST displays tumor and patient demographic features similar to those seen in patients with c-KIT/PDGFRA-mutant tumors and has a more aggressive behavior compared with SDH-deficient tumors. Thus, investigating the molecular subtype of GIST has direct implications for treatment strategies and for the development of new approaches to systemic therapy.

Neuroendocrine tumors

Neuroendocrine tumors (NETs) of the gastrointestinal (GI) tract are rare diseases, but the incidence and prevalence of NETs are steadily rising, possibly owing to detection of early-stage disease and stage migration [78]. Survival for all NETs has improved over time, especially for advanced-stage GI-NETs, and in particular for pancreatic NETs in particular, reflecting major therapeutic improvements [79]. However, molecular data which may explain the clinical heterogeneity of this class of tumors, from indolent to highly aggressive, and divergent treatment responses, are lacking [80].

GI-NETs represent approximately 35–40% of primary small intestinal malignancies [2]. They comprise a genetically diverse spectrum of malignant solid tumors arising from the secretory cells of the neuroendocrine cell system that may produce peptides causing characteristic hormonal syndromes [81]. Therefore, GI-NETs are categorized as “functioning” when patients are clinically symptomatic (carcinoid syndrome) or “non-functioning.”

The majority of NETs occur sporadically. However, they may occur as part of complex familial endocrine cancer syndromes such as type 1 multiple endocrine neoplasia (MEN 1) [82], von Hippel-Lindau Disease [83], and neurofibromatosis type 1 (NF1) [84].

Many advances have been made in recent years for the treatment of patients with metastatic GI-NETs, and here we will briefly report the current therapeutic standard and the most recent trails which led to a change in clinical practice.

Somatostatin analogs (SSAs), octreotide LAR [85] and lanreotide [86], are appropriate initial therapy in most patients with unresectable metastatic midgut NETs for both control of carcinoid syndrome and tumor progression. Generally, SSAs are associated with major improvements in flushing and diarrhea in roughly 75% of patients with carcinoid syndrome. Because of their relatively benign side effect profile, SSAs are typically selected as first-line systemic therapy.

The RADIANT-2 [87] and RADIANT-4 [88] studies evaluated Everolimus (Afinitor®) in functioning and non-functioning NETs of the GI tract and lungs. RADIANT-4 results showed that median PFS improved from 3.9 to 11 months (P < 0.00001) with everolimus compared to placebo. These data led to the approval of everolimus (Afinitor®, Novartis) by the FDA for the treatment of patients with progressive, nonfunctional NETs of the GI tract and lung. An earlier study, the RADIANT-2 trial, randomized patients with progressive NETs and a history of carcinoid syndrome to receive everolimus plus octreotide LAR versus placebo plus octreotide LAR. It was noted that everolimus efficacy appears stronger in non-midgut NETs (which represented the majority of patients on the RADIANT-4 study) compared with midgut NETs (which represented the majority of patients on the RADIANT-2 study).

A large number of metastatic midgut NETs (> 50% in some studies) secrete serotonin and are associated with the carcinoid syndrome [89]. Therefore, the TELESTAR study [90] evaluated telotristat ethyl, a tryptophan hydroxylase inhibitor, in patients with refractory carcinoid syndrome, which has become the treatment of choice in patients with stable radiographic disease and refractory carcinoid syndrome characterized by suboptimal control of diarrhea.

Finally, the NETTER-1 trial [91] evaluated ¹⁷⁷Lu-DOTATATE in NETs of the small intestine and proximal colon (midgut). ¹⁷⁷Lu-DOTATATE is a radiolabeled SSA, a form of treatment also known as peptide receptor radiotherapy (PRRT). In this study, median PFS was 8 months on the high-dose octreotide arm and was not yet reached on the ¹⁷⁷Lu-DOTATATE arm, translating to a 79% improvement in PFS (P < 0.00001).

Although the treatment landscape for GI-NETs patients has been revolutionized and evolved significantly in the last decade, several questions remain unanswered. Further clinical research will be needed to address key issues pertaining to the management of midgut NETs [92].

Conclusion

Small bowel cancers are a heterogenous group of malignancies, which require a dedicated and personalized approach. Many advances have been made for the treatment of adenocarcinomas, GIST, and NETs arising from the small intestine, although more clinical trials are strongly warranted to provide patients with more therapeutic options which may lead to a longer survival and a better quality of life.