Neuroendocrine tumors (NET) are rare neoplasms, but with increasing incidence and prevalence
in the last decades. Although they may manifest in the most diverse tissues, the vast
majority of cases will affect organs of the digestive tract and lung. At diagnosis, more than
half of the cases present metastatic disease, and among patients with localized disease, up
to one-third will have recurrence of the disease. Unfortunately, the minority of patients
with metastatic disease are eligible for curative intent. Although there are many types of
NET, they are often studied together as a group because their cells share common histological
findings, have special secretory granules, and the ability to secrete bioactive amines and
polypeptide hormones. Approximately 25 percent of the tumors present functional hormonal
syndromes (situation of great morbidity for these patients), being the carcinoid syndrome,
the most common one. From the molecular point of view, these neoplasias are largely dependent
on the activation of the mTOR pathway and neoangiogenesis. Another striking feature of
neuroendocrine cells is the expression of cell surface hormone receptors whose activation or
blockade may exert an important regulatory function. The discovery of somatostatin, and
consequently its receptors, is one of the major advances in the treatment of this neoplasm.
Due to the increased ability of somatostatin to inhibit the secretion of several hormones,
its antitumor property has long been studied. However, only after the development of
synthetic long-life formulations can their use be used in clinical practice.
Well-differentiated neuroendocrine tumors (G1 and G2 according to World Health Organization
(WHO) classification) present in more than 80 percent of somatostatin receptor cases. In this
population, the use of somatostatin analogues promotes symptomatic improvement of functioning
syndromes in the order of 70 to 77 percent and biochemical improvement around 50 percent .
Regarding antiproliferative activity, two phase III studies evaluated the role of octreotide
LAR and of lanreotide autogel, both somatostatin analogs, in the population of well
differentiated tumors and, almost entirely, somatostatin receptor hyperexpressors when
evaluated by octreoscan. In these studies, the use of somatostatin analogue was associated
with reduced risk of progression or death from 53 percent to 66 percent when compared to
placebo. Currently, this class of drugs is often considered as the first treatment option for
patients with progressing metastatic disease, when the strategy of watchful waiting is not
opted for (because they are tumors of sometimes indolent behavior, some cases are selected
for observation only). In general, there are few options for systemic therapies that are
approved for these tumors in addition to somatostatin analogs (mTOR and antiangiogenic
inhibitors), none of which clearly demonstrate overall survival gain, are costly and none are
available for use in the public health system (SUS). Therefore, it is very important to
develop studies with new therapies for patients with NET, especially, molecularly defined
therapies with greater access to patients. In this context, other anti-hormonal therapies
could be explored in patients with NET, such as the role of the sex hormones estrogen and
progesterone, as well as their receptors. A few studies have evaluated the expression of
estrogen and progesterone receptors in NET and suggest interesting results. One of the
largest series was conducted at the AC Camargo Cancer Center where the immunohistochemical
expression of these receptors was evaluated in 96 patients with NET from various sites. About
35 percent of the cases presented positivity for some hormonal receptor (HR) in the tumor
tissue. Among the HR positive cases, there was no difference between sex, more frequent in
thin, pancreatic and lung tumors and in well differentiated tumors (G1 and G2 by the WHO).
Viale et al. Evaluated the expression of progesterone receptors (PR) in 96 patients with
pancreatic neuroendocrine tumors. Nuclear immunoreactivity for PR was observed in 58 percent
of cases, with no difference in PR expression according to gender, age, or functioning
syndromes. About 163 primary tumors of the gastroenteropancreatic site and 115 metastases
were evaluated by Zimmermann and colleagues for expression of female hormone receptors.
Progesterone receptor was more frequently found in pancreatic tumors and rarely in
non-pancreatic (p <0.001), estrogen receptor was more frequently expressed in non-pancreatic
tumors (<0.001) and in women (p: 0.019). There was no difference between primary site and
presence of metastases. Apparently, HR positive tumors may present a more favorable
evolution. A study evaluated 160 patients with pancreatic neuroendocrine tumors operated for
expression by PTEN immunohistochemistry (negative regulator of the mTOR pathway) and PR.
Approximately 69 percent of the cases were positive for PR and PTEN, 28 percent were positive
for one of the two markers and only 3 percent were negative for both. Combined positivity for
PTEN and PR was associated with metastasis-free survival in stages I and II (p <0.001) and
overall survival in all patients (p <0.001), even after adjustment for other prognostic
variables. Patients with negative PR and PTEN tumors had the shorter survival times when
compared to those who had only one or both markers (p <0.001). 9 Similarly, other author
demonstrated a retrospective analysis of 277 patients with neuroendocrine tumors (95 percent
vs. 76 percent, p <0.05), and a higher survival rate (p <0.05) than in the control group (p
<0.05) 0.015). Even rarer in the literature is the role of antiestrogen therapies as a form
of control of this neoplasia. Case reports point to antiproliferative activity of tamoxifen
in patients with NET and, in some cases, patients presenting more than 12 months of disease
control.11 Reports of control of carcinoid syndrome and even regression of associated
retroperitoneal fibrosis have also been described. However, the only study to assess the
activity of tamoxifen in neuroendocrine tumors dates back to 1984. Sixteen patients were
evaluated clinical benefit in only 19 percent of cases and no radiological response. However,
in this study, no patient was previously selected for HR tumor expression or degree of
differentiation, which the investigators believe limited benefit in disease control.
Therefore, based on the premise that there is a need for research and treatment strategies
for this rare neoplasm; there is clear therapeutic embezzlement in the public heath system
due to the high cost of the treatments approved in the country for this neoplasia; NET are
tumors that may present positivity to estrogen and / or progesterone receptors; evidence
points to the possibility of antiproliferative effect using hormonal therapy, the
investigators propose a phase II study of tamoxifen for patients with well differentiated NET
and positive for HR, estrogen and / or progesterone expression.
Inclusion Criteria:
- Age greater than or equal to 18 years
- Histological diagnosis of well differentiated NET (typical and atypical lung
carcinoids, NET G1, NET G2 of all gastroenteropancreatic sites and pancreatic NET G3
according to WHO 2017 classification) 20 advanced / metastatic, inoperable, with no
possibility of curative treatment
- Immunohistochemical expression ≥ 1 percent for estrogen and / or progesterone receptor
- Disease with radiological progression (at least 10 percent tumor volume growth) in the
last 12 months before day 1 cycle 1.
- No possibility of established treatments due to lack of access, risk of toxicities or
without clinical indication. Patients who meet criteria for watchful waiting (low-dose
disease and non-functioning NET) may be included.
- Measurable disease
- ECOG performance scale 0 to 2.
- Adequate organic function as defined by the following criteria:
- serum aspartate aminotransferase (AST), serum alanine aminotransferase (ALT) ≤
2.5 times the upper limit of local laboratory normality (LSN-LL);
- Total serum bilirubin ≤ 2.0 x ULN-LL;
- Absolute neutrophil count ≥ 1,500 / mm^3;
- Platelet count ≥ 80,000 / mm^3;
- Hemoglobin ≥ 9.0 g / dL;
- Estimated creatinine clearance by the MDRD equation ≥ 30ml / min
- Albumin ≥ 3.5 g / dL;
- INR ≤ 1.5
- Term of free and informed consent signed by the patient or legal representative.
Exclusion Criteria:
- Patients already on tamoxifen, but other prior treatment are allowed
- Patients with aggressive disease requiring cytotoxic therapy or locoregional therapies
(eg hepatic embolization)
- A history of serious clinical or psychiatric illness that, by clinical judgment, may
involve participation risk in this study
- Patients participating in other protocols with experimental drugs.
- Patients with oral food difficulties.
- Patients who underwent major recent surgery less than 4 weeks previously.
- Patients receiving chemotherapy or other oncologic therapy for less than 3 weeks.
- Patients who use oral anticoagulation
- Previous history of deep vein thrombosis or pulmonary embolism in the last 12 months.
- Pregnant or lactating patients.
- Patients with postmenopausal vaginal bleeding with no defined etiology.
- Patients with breast cancer who need to use tamoxifen for this neoplasm
- Another synchronous neoplasm that requires systemic treatment
