Fig. 12.1
CT scan of patient with ileal NET and bulky lymph node metastases
Twenty percent of ileal NETs are multicentric and even though this data does not change the surgical strategy, the resection should not be too close to the tumor. This is not a problem when a high lymphadenectomy is performed, because in this case an extended resection is mandatory.
Some lesions can have important peritumoral fibrosis involving the mesentery root and the retroperitoneum, leading to occlusion, hydronephrosis, and chronic pain. In these patients, surgery must be performed in highly experienced centers.
In referral centers, minimally invasive resection is the procedure of choice. The laparoscopic technique provides the same oncologic outcome as open surgery, with all the advantages of a minimally invasive approach. During the surgical procedure, in candidates for therapy with somatostatin analogs, a simultaneous cholecystectomy is recommended to prevent cholelithiasis.
Curative surgery allows patients with stage I and II 5- and 10-year survival rates of 100% and more than 95% and 80% for patients with stage III disease.
In stage IV patients, medical therapy is the mainstay, but surgery still has an important role. Since abdominal complications remain one of the major causes of death, debulking surgery should always be considered. How surgery, in metastatic patients, can influence oncological outcomes is still debated [7, 8].
Even if a complete surgical resection of the I-NET is performed, recurrence can occur in about 35% of cases [9]. For liver recurrence, surgical resection is the best option, but this is feasible in fewer than 20% of cases. For unresectable liver metastases, local treatment (chemoembolization, thermoablation) can be used, together with systemic therapy like somatostatin analogs or chemotherapy.
12.1.2 12.1.2 Medical Treatments
Somatostatin analogs (SSAs) in I-NETs have their main indications in (a) symptomatic and (b) non-functioning advanced forms [10].
a) In the case of symptomatic disease, like the carcinoid syndrome [10, 11], it is recommended to start immediately the treatment with SSAs [12–14]. The first formulation providing symptom control is short-acting octreotide subcutaneously (s.c.). Since the 1990s, long-acting formulations have replaced the quick-release formulations in the long-term control of carcinoid syndrome. About 40% of patients with carcinoid syndrome under treatment with the maximum dose of long-acting SSAs are not fully controlled. In these cases, the clinician may consider an increase in dose, a reduction of the dosage intervals or the addition of s.c. octreotide (rescue) [15].
In a phase II trial, pasireotide, a multireceptor-targeting SSA with high affinity to all somatostatin receptors (SSTRs) except SSTR type 4, was administered to patients with carcinoid syndrome refractory to SSAs. The trial demonstrated a benefit in controlling the symptoms of carcinoid, following failure with a standard dose of octreotide LAR [16]. However, this drug is not currently approved by the Italian Medicines Agency (AIFA).
Interferon-alpha (IFN-alpha) controls the symptoms of carcinoid syndrome in 40–70% of patients, but it is a second-line therapy because its use is associated with substantial adverse effects including fever, fatigue, anorexia and weight loss, autoimmune diseases and myelosuppression [17].
Telotristat etiprate, an oral serotonin synthesis inhibitor is a potential novel option that significantly reduces diarrhea in patients with refractory carcinoid syndrome [18].
b) In non-symptomatic I-NETs, SSAs can be considered in progressive disease due to their anti-neoplastic activity [19, 20]. The efficacy of SSA therapy (octreotide and lanreotide) in non-functioning I-NETs with progressive disease has been demonstrated in two placebo-controlled trials. Fig. 12.3 summarizes the treatment of advanced locoregional disease or distant metastases from I-NETs. Data from a study with ultrahigh-dose octreotide pamoate at 160 mg i.m. every 2 weeks for 2 months followed by the same dose once monthly seemed to show some promise [21]. A high-dose formula of octreotide has been reported to stabilize hormone production and tumor growth in 75% of patients with advanced midgut carcinoid tumors and stabilize progressive disease for 6–24 months [22].
Fig. 12.3
I-NET G2 in a 65-year-old woman. 68Ga PET images pre and post 177Lu-DOTATATE peptide receptor radionuclide therapy (PRRT)
Among the new targeted therapies, everolimus, an oral inhibitor of the mammalian target of rapamycin (mTOR), can be recommended in advanced I-NETs in the case of disease progression as a second- or third-line therapy, after failure of SSAs and/or IFN-alpha or peptide receptor radionucleotide therapy (PRRT) [23]. Everolimus was the first targeted agent showing a robust antitumor activity across a broad range of neuroendocrine tumors, with acceptable tolerability. On June 2016, the European Medicines Agency (EMA) approved everolimus for the treatment of unresectable metastatic gastrointestinal NETs.
There are not enough data to support the use of other targeted drugs including bevacizumab, sorafenib, pazopanib or axitinib in either pancreatic or nonpancreatic NETs.
In metastatic disease, whether or not symptomatic, concomitant locoregional/ ablative therapy, where feasible, is recommended. In the absence of any large comparative trials of the different locoregional or ablative therapies (bland embolization, chemoembolization, radioembolization, radiofrequency ablation or microwave destruction), the choice of treatment is based on individual patient features (e.g., size, distribution, number of liver lesions, vascularization, proliferative index) and local physicians’ expertise. Fig. 12.4 summarizes the medical treatment options for advanced/metastatic I-NETs.
Fig. 12.4
Treatments of advanced locoregional or metastatic I-NETs. IFN, interferon; PRRT, peptide receptor radionuclide therapy; SSA, somatostatin analog; SSTR, somatostatin receptor
12.1.3 12.1.3 Chemotherapy
Like other neuroendocrine carcinomas (NECs), poorly differentiated I-NETs are both biologically and morphologically identical to small and large cell NECs of the lungs. Therefore, patients are usually advised to go for a palliative chemotherapy that corresponds to the medical treatment of small cell carcinoma of the lungs. The objective response rate is ≥50% and classic chemotherapy using cisplatin/etoposide (Moertel regimen) [24] is recommended. Alternative regimens substituting irinotecan for etoposide [25] or carboplatin for cisplatin [26] are thought to be acceptable options.
The optimal duration of chemotherapy has not been clearly defined and there is no established second-line therapy. Encouraging results using either 5-FU i.v. or capecitabine orally combined with oxaliplatin or irinotecan are reported, considering this schedule of treatment as an option [27].
12.1.4 12.1.4 Peptide Receptor Radionuclide Therapy
Peptide receptor radionuclide therapy (PRRT) of I-NETs has recently benefited from the publication of a phase-III pivotal study of PRRT with 177Lu-DOTATATE (Lutathera) for the treatment of midgut NETs [28]. This was the first multicenter randomized protocol to have tested, on 229 patients, the toxicity and efficacy of PRRT with 177Lu-DOTATATE versus a double standard dose of long-acting octreotide therapy. The study showed a 65.2% rate of progression-free survival (PFS) at 20 months (95% confidence interval [CI], 50.0 to 76.8) in the active arm (177Lu-DOTATATE) versus 10.8% (95% CI, 3.5 to 23.0) in the control arm. The response rate was 18% versus 3% (p <0.001). Tolerability was recorded up to a maximum of 9% of transient hematological toxicity, without any renal toxicity. A myelodysplastic syndrome was reported in 2% of the population. These data strongly support the effectiveness of PRRT with 177Lu-DOTATATE in NETs (Fig. 12.3). As the registration of 177Lu-DOTATATE is pending, this therapy can be currently performed only in experimental protocols.
PRRT is indicated both for I-NETs and for other NETs and, since the first applications of PRRT, good tolerability and effective symptomatic response have been recorded for both syndromic symptoms and pain relief. These data, also evident from the use of 90Y-DOTATOC, have been recently confirmed in a study on 90 patients with metastatic carcinoid tumors, 22 of which intestinal. This study showed that symptomatic response had an impact on survival because PFS was significantly longer in those who had improvement of diarrhea [29].
Our group recently published data from a prospective phase-II study on the toxicity and efficacy of PRRT with 177Lu-DOTATATE in 43 patients with I-NETs previously operated or inoperable and in progression after the first line of therapy [30]. Patients were treated with a personalized activity of the radiopharmaceutical in relation to the presence or absence of risk factors for kidney or bone marrow toxicity. The efficacy data showed a disease control rate (DCR) of 84% and a median PFS of 36 months (95% CI, 24–n); the median overall survival (OS) was not reached after a median follow-up of 38 months (range 11–59). In the same study, patients treated with different activities (18.5 vs 26 GBq) showed comparable DCR and PFS. The toxicity was minimal thanks to the extra care given to patients with risk factors.
In another study we evaluated the prognostic value of FDG-PET and found confirmation of a significantly greater reduction in PFS (24.5 months vs. 42 months with p = 0.025) in positive patients than in those with normal glucose metabolism, as previously highlighted [31]. In a further study, we enrolled 26 consecutive patients with advanced NET and in progression after a PFS of at least 12 months, following a previous 90Y-DOTATOC treatment in a prospective phase-II study [32]. All patients who had preserved blood chemistry parameters, were treated with 177Lu-DOTATATE administering an activity comprised between 14.8 and 18.5 GBq in 5 cycles performed 6 + 2 weeks apart. With a median total activity of 16.5 GBq in 5 cycles, we achieved a DCR of 84.6% and a median PFS of 22 months (95% CI, 16 months-not reached) compared to 28 months (95% CI, 20–36 months) after 90Y-DOTATOC. The tumor burden and the number of metastases were important prognostic factors. Toxicity was modest for both the bone marrow (1 patient G2 and G3) and the kidneys (1 patient with one with G2 and G3).
177Lu-DOTATATE PRRT offers significant advantages over other therapies, it is effective and should be closely considered in planning treatment for patients with advanced I-NET [33].
12.2 12.2 Appendiceal Neuroendocrine Tumors
12.2.1 12.2.1 Surgery
Appendiceal NETs (A-NETs) represent 7% of all NETs and 11% of gastroenteropancreatic NETs (GEP-NETs). They normally arise from the same cells as the ileal NETs, except for the rare goblet cell carcinomas (GCCs) and adenoneuroendocrine carcinomas.
In the majority of cases, the diagnosis is obtained as an incidental finding after appendectomy performed for acute appendicitis. One appendix out of 200/300 appendectomies contains a small A-NET. In these cases, a postoperative evaluation is made to decide if a second surgical step is needed. The parameters to be evaluated are the tumor dimension and signs of lymphatic involvement and are the same that substantiate the indication for right hemicolectomy in the few cases of preoperative diagnosis of appendiceal NET. Serosal, vascular, lymphatic or perineural invasion alone does not constitute an inclusion criterion for right hemicolectomy.
More than 95% of A-NETs are <2 cm [3] and appendectomy itself is the only surgical treatment needed, because the metastatic rate (lymph nodes or liver) is low (<1%). According to some authors, for tumors between 1 and 2 cm, the surgical strategy (appendectomy alone or second-stage right hemicolectomy) has to be evaluated patient by patient on the basis of deep mesoappendiceal invasion (>3mm), positive margin, microscopic lymphatic or venous invasion [34]. Nevertheless, when the size of the primary tumor is >2 cm the metastatization rate is 30–60% and right hemicolectomy is indicated in order to achieve adequate lymphadenectomy.
In females with GCCs, regardless of age, bilateral salpingo-oophorectomy is also advocated. In cases with peritoneal dissemination, cytoreductive surgery and intraperitoneal chemotherapy may offer prolonged survival.
12.2.2 12.2.2 Medical Treatment
There is no evidence of the effectiveness of treatment with SSAs in patients with metastatic A-NETs, due to their rarity. In a recent study, patients with A-NETs were pooled together with patients with I-NETs and the appendix cases cannot be extrapolated [37].
In the RADIANT-4 study only one patient with A-NET in the treatment arm with everolimus was reported. Therefore, medical therapy has a limited role in A-NETs and it is confined to the very rare cases of carcinoid syndrome associated with metastatic disease [38].
12.2.3 12.2.3 Chemotherapy
In cases of high tumor grading, GCC or mixed adenoneuroendocrine carcinomas (MANEC) should be suspected, but usually the cases of a “true” neuroendocrine carcinoma (G3 NEC) of the appendix are very rare [39].
NECs of the appendix have very poor outcomes because of frequent lymph node and hepatic metastases, rapid progression and a 1-year survival rate <50% [5]. Because NEC could be misinterpreted as acute appendicitis, it should be considered in the differential diagnosis with immunohistochemical analyses. Appendiceal NEC (grade 3, Ki-67 >20 %) requires a right hemicolectomy and, like adenocarcinoma, adjuvant or intraperitoneal chemotherapy [39, 40]. Because of their clinical and biologic characteristics, de facto similar to those of small cell lung cancer (SCLC), the European Neuroendocrine Tumor Society guidelines [23] recommend that metastatic appendiceal NEC should be treated in a similar way to SCLC (i.e., with etoposide [24] or irinotecan, associated with platinum compounds such as cisplatin or carboplatin [26, 41]). Although objective remission rates are high (40–67%), median PFS is limited within 4–6 months [42].
12.3 12.3 Colorectal Neuroendocrine Tumors
12.3.1 12.3.1 Surgery
Colorectal NETs (CR-NETs) are fewer than 1% of all colorectal tumors. Up to 40% of all CR-NETs occur in the cecum and right colon, although this may result from tumors of the appendix extending from the base in the cecum. More than 60% of them are located in the rectum and the diagnosis is mostly incidental during screening endoscopy (1/2500 procedures). Colonic NETs (C-NETs) have a peak incidence in the seventh decade of life, have a male/female ratio of 2:1, and most of them are small, non-functioning tumors.
C-NETs are treated in a similar way to adenocarcinoma of the colon. Well-differentiated C-NETs, <2 cm in diameter, should be treated endoscopically.
Surgery is the only therapy that can cure large colon and rectum NETs (>2 cm) and it is also indicated in cases of incomplete endoscopic resection, deep tumor invasion through the muscularis propria and G3 tumors [43] The surgical options are divided into two types: laparoscopic resections (colectomy, sigmoidectomy and resection of the rectum) and local excision (transanal).
Rectal NETs (R-NETs) are diagnosed at a much younger age than colonic carcinoids, (average age, 48 to 52 years) and about half are asymptomatic; symptoms, when present, are discomfort, mild pain, change in bowel habits, and bleeding. R-NETs are frequently far from the sphincters and can be treated endoscopically or surgically. The treatment of R-NETs is based on the size of the primary tumor. Lesions <1 cm have a low metastatic rate (<3%) and can be completely removed with a transanal excision. Lesions between 1 and 2 cm in diameter have a high metastatic rate, about 10–15% [43–45]. In these cases the endoscopic treatment can be performed if the tumor has a low mitotic index and if there is no ultrasound evidence of deep invasion up to the muscularis propria [46]. Histologic features such as lymphovascular invasion, high mitotic rates, and high Ki-67 should be considered as adverse prognostic factors, but further studies are needed to demonstrate if these factors contribute to recurrence in low risk R-NETs. For tumors >2 cm surgical resection is mandatory, because the incidence of regional metastases is 60–80% [47].
Related posts:
Classification of Abdominal Neuroendocrine Tumors
Sporadic Gastroenteropancreatic Neuroendocrine Tumors
Neuroendocrine Tumors Biomarkers
Management of Gastric Neuroendocrine Tumors
Pathological Analysis of Abdominal Neuroendocrine Tumors
Management of Liver Metastases from Gastroenteropancreatic Neuroendocrine Tumors
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