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Neoadjuvant Therapy for
Neuroendocrine Neoplasms: Recent
Progresses and Future Approaches
Andrea Lania
1,2
*, Francesco Ferraù
3,4
, Manila Rubino
5
, Roberta Modica
6
,
Annamaria Colao
6
and Antongiulio Faggiano
7,8
on behalf of NIKE group
1
Endocrinology, Diabetology and Andrology Unit, Humanitas Clinical and Research Center—IRCCS, Rozzano, Italy,
2
Department of Biomedical Sciences, Humanitas University, Rozzano, Italy,
3
Department of Human Pathology of Adulthood
and Childhood ‘G. Barresi’, University of Messina, Messina, Italy,
4
Endocrine Unit, University Hospital G. Martino, Messina,
Italy,
5
Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO,
IRCCS, Milan, Italy,
6
Endocrinology, Department of Clinical Medicine and Surgery, “Federico II”University of Napoli, Napoli,
Italy,
7
Endocrinology, Department of Experimental Medicine, “Sapienza”, University of Rome, Rome, Italy,
8
Department of
Experimental Medicine, Division of Medical Physiopathology, Sapienza University of Rome, Rome, Italy
Neuroendocrine neoplasms (NENs) are a heterogeneous group of tumors, their treatment
being challenging and requiring a multidisciplinary approach. Though the only curative
treatment is surgery, up to 50% of patients are diagnosed with metastatic disease. In the
last years, neoadjuvant chemo(radio)therapy has become part of the standard of care in
the treatment of different cancer types. However, evidence of its efficacy and safety in NEN
patients has not yet been confirmed in the literature. The aim of the present review is to
perform an extensive review of the scientific evidence for neoadjuvant therapy in patients
with gastroenteropancreatic and thoracic NENs.
Keywords: neuroendocrine tumors, somatostatin (analogs and derivatives), peptide receptor radionuclide therapy,
everolimus, capecitabine, temozolomide, chemotherapy
INTRODUCTION
Although neuroendocrine neoplasms (NENs) are considered rare malignancies, their incidence has
rapidly increased in the last decades. Since several patients are diagnosed with metastatic disease,
curative surgery is usually not an option (1), palliative surgical intervention possibly being effective
in controlling clinical symptoms and improving patient’s quality of life (2–4). Neoadjuvant therapy,
with the aim of reducing tumor size and disease burden, can potentially change the clinical scenario
making it suitable for curative surgery as already demonstrated in other cancer types (5–8). While it
is conceivable that neoadjuvant chemo-and radiotherapy might be effective in NENs (9), reliable
evidence is still lacking in this field and study results are difficult to compare due the heterogeneity
of both neoadjuvant therapies used, and series studied. Moreover, although the available therapeutic
options (i.e., somatostatin analogs, everolimus, chemotherapy, sunitinib, and peptide receptor
radionuclide therapy PRRT) are currently not included in any therapeutic algorithm with specific
neoadjuvant purpose, most of them have been used with this intent, even successfully (9).
Neoadjuvant chemotherapy, radiotherapy, and PRRT have been shown to provide variable
results in terms of tumor down-sizing (10). The aim of the present minireview is to perform an
Frontiers in Endocrinology | www.frontiersin.org July 2021 | Volume 12 | Article 6514381
Edited by:
Antimo Migliaccio,
University of Campania Luigi Vanvitelli,
Italy
Reviewed by:
Daniela Pasquali,
University of Campania Luigi Vanvitelli,
Italy
Dario Giuffrida,
Mediterranean Institute of Oncology
(IOM), Italy
*Correspondence:
Andrea Lania
andrea.lania@humanitas.it
Specialty section:
This article was submitted to
Cancer Endocrinology,
a section of the journal
Frontiers in Endocrinology
Received: 09 January 2021
Accepted: 27 April 2021
Published: 26 July 2021
Citation:
Lania A, Ferraù F, Rubino M,
Modica R, Colao A and Faggiano A
(2021) Neoadjuvant Therapy for
Neuroendocrine Neoplasms: Recent
Progresses and Future Approaches.
Front. Endocrinol. 12:651438.
doi: 10.3389/fendo.2021.651438
MINI REVIEW
published: 26 July 2021
doi: 10.3389/fendo.2021.651438
extensive review of the scientific evidence for neoadjuvant
therapy in patients with pancreatic, gastrointestinal, and
thoracic NENs.
PANCREATIC NEUROENDOCRINE
NEOPLASMS
Pancreatic neuroendocrine neoplasms (pNENs) account for 1 to
2% of all pancreatic tumors and most of them are sporadic and
nonfunctioning. Their incidence has been increasing and
survival rates, although improved, remain poor compared with
other primary sites, with an overall survival of 3.6 years (1).
Often pNENs present with advanced disease at diagnosis and the
treatment of metastatic unresectable pNENs remains debated
and the role of neoadjuvant therapies is still uncertain. However,
among gastrointestinal NENs, data on the possible role of
neoadjuvant therapy are mainly related to pNENs even if the
results seem to be somewhat contradictory and difficult to
interpret due to the extreme heterogeneity of the data and the
incompleteness of the information provided (Table 1). In a large
series of high-grade gastrointestinal neuroendocrine carcinomas,
where pancreas was the most common primary site (361
patients), neoadjuvant or adjuvant therapy resulted in better
overall survival (OS) in patients with early-stage disease
compared with those treated with resection alone. Details of
neoadjuvant therapies were not available, but single and multi-
agent chemotherapy besides radiotherapy were included. The
positive effect of neoadjuvant or adjuvant therapy on OS seems
to suggest the importance of these treatments to lower the
incidence of both micrometastases and possibly to enhance
tumor resection thus lowering the risk of local and systemic
recurrences (26).
Patients who received neoadjuvant or adjuvant therapy had
better over-all survival, suggesting that high incidence of
micrometasta-sis contributes to the poor surgical outcomes. In
TABLE 1 | Neoadjuvant therapies in gastroenteropancreatic NENs.
Year Article type Neoadjuvant treatment Outcome Reference
Pancreas
2019 research article no details available no changes in OS (11)
2008 research article PRRT Partial response and R0 resection (12)
2009 case report PRRT Partial response and R0 resection (13)
2010 case report PRRT Partial response and R0 resection (14)
2011 research article PRRT Stabilization or partial response (15)
2012 case report PRRT Partial response and R0 resection (16)
2015 research article PRRT Better PFS and lower morbidity (17)
2015 research article PRRT Improved PFS (17)
2017 research article PRRT Improved PFS (18)
2018 case report PRRT Partial response and R0 resection (19)
2015 research article chemo Improved survival (20)
2016 research article chemo Improved OS (21)
2017 research article chemo no changes in tumor size (22)
2018 research article chemo Improved OS and RFS (23)
2011 case report chemo, radio R0 resection (24)
2017 research article chemo, radio Stabilization or partial response and R0 resection (25)
2018 research article chemo, radio Low recurrence risk and improved OS (26)
2012 research article chemo, radio No effects (27)
2012 research article PRRT, chemo Radiological response (28)
2020 research article PRRT, chemo Stabilization or partial response (29)
2020 research article PRRT, chemo Improved PFS and OS (30)
Esophagous
2018 case report chemo complete response, complete resection (31)
1989 case report/review chemo almost complete response, complete resection (32)
1995 case report chemo almost complete response, complete resection (33)
1999 case report chemo almost complete response, complete resection (34)
2002 case report chemo partial response, reduced tumor burden (35)
2003 case report chemo partial response, reduced tumor burden (3)
Rectum
2017 research article chemo, radio almost complete response, complete resection (36)
2018 case report chemo reduction of primary lesion/grading (4)
Miscellanea
2009 research article (midgut tumor) PRRT partial response, partial resection (15)
2012 research article (midgut tumor) PRRT partial response, complete resection (37)
2012 research article (midgut tumor) SSA-PRRT partial response, partial resection (38)
2012 research article (duodenal tumor) PRRT partial response (29)
2015 case report (small bowel tumor) PRRT no response (39)
Chemo, chemotherapy; Radio, radiotherapy; PRRT, peptide receptor radionuclide therapy; SSA, somatostatin analogs; OS, overall survival; R0, microscopically margin-negative
resection; PFS, progression-free survival; RFS, relapse free survival.
Lania et al. Neoadjuvant Therapy for NENs
Frontiers in Endocrinology | www.frontiersin.org July 2021 | Volume 12 | Article 6514382
addition, the relatively high proportion of margin-positive re-
section raises the question of whether there is a role of
downstaging with neoadjuvant therapy, aimed at enhancing
resection and lowering risk of systemic recurrence.
Xie et al. recently described the largest group of pNENs in
whom neoadjuvant therapies were used. The study included
4,892 patients who underwent curative-intent surgical
resection. Authors showed that neoadjuvant therapy was
mainly prescribed in patients <65 years, with grade 3 pNENs
localized in the head of the pancreas and associated to the
presence of metastasis. In this setting, Authors did not find
any significant improvement in OS even in patients with grade 1
and 2 pNENs thus suggesting that neoadjuvant therapy should
be used with caution given the lack of conclusive data (11). It is
worth noting that, the main limitation of the Study was the lack
of any detail regarding the type of neoadjuvant therapies used.
PRRT with radiolabeled somatostatin analogues, over the
years, has evolved as an important therapeutic option for the
treatment of inoperable or metastasized, well/moderately
differentiated, NETs, particularly of the GEP (Table 1)(9).
Conversely, neoadjuvant PRRT based on either 177Lu-
octreotate or 90Y-DOTATATE have been shown to provide
variable results as tumor downsizing possibly due to the
heterogeneous inclusion criteria, the variable length of follow-
up and the different response criteria used (10). Kwekkeboom
et al. described a series of 310 patients with pNENs treated with
177Lu-octreotate PRRT. A partial response was observed in four
of them, all undergoing a subsequent R0 resection (12). Similar
results were confirmed by other case reports and small series (13,
14,16,19). Van Vliet et al. described the results of 177Lu-
octreotate as neoadjuvant therapy in 29 patients with borderline,
unresectable or oligometastatic nonfunctioning pNENs (14).
After PRRT, successful surgery was performed in nine patients
and all resection specimens showed fibrosis/sclerosis or necrosis
thus confirming the effects of 177Lu-octreotate on tumor tissues.
As a result, the median PFS was 69 months for patients with
successful surgery and 49 months for the other patients (14). On
the same line, other case reports and case series confirmed a
beneficial effect of neoadjuvant PRRT with 90Y-DOTATATE on
tumor and/or metastases downsizing in patients with pNENs,
thus leading to a successful surgical intervention (15,17). Recently,
Partelli et al. reported a series of 23 resectable or potentially
resectable G1-G2 pNENs who underwent neoadjuvant PRRT
(177Lu-octreotate in three and 90Y-DOTATATE in 20 patients)
comparedto 23 patients who underwentupfront surgicaloperation.
PRRT did result in a reduction of primary tumor size and a
reduction in the number of positive lymph nodes compared with
controls. Interestingly, though both the rates of disease-specific
survival and median PFS from time of diagnosis were similar
between groups, in the subgroup of patients who underwent an
R0 resection, a trend toward a prolonged PFS was observed in the
PRRT group (18).
The administration of chemotherapy prior to surgical
resection is increasingly used for patients with adenocarcinomas
of the pancreas with the aim to improve surgical results. Similarly,
different regimens of chemotherapies have been described as
neoadjuvant treatment in pNENs, all these studies being biased
by their retrospective design and by the heterogeneity of
chemotherapy regimens used (Table 1). Dumont et al.
evaluated the effect of different neoadjuvant chemotherapy
regimens (i.e., 5-fluorouracil, streptozotocin, doxorubicin,
cisplatin, etoposide, and oxaliplatine) on segmental portal
hypertension (SHP), the feasibility of surgery and the
prognostic influence of a complete surgery in 42 patients with
G1/G2 locally advanced pNETs associated to SHP. A complete
resection was achieved in 13 out of 28 cases underwent surgery
and a not statistically significant trend towards improved 5-year
survival was observed in patients with R0 resections compared to
R1/R2 resections and no resection at all (20). A retrospective
analysis of 59 patients with a histologic diagnosis of pancreatic
neuroendocrine carcinomas (pNECs) described five patients who
underwent neoadjuvant treatment with etoposide and cisplatin
before surgery. Four of them had a curative resection and one
patient with stage IV disease remained with residual small liver
metastases (21). A further retrospective observational study
analyzed the efficacy of neoadjuvant 5-fluorouracil (5-FU),
doxorubicin, and streptozocin (FAS) chemotherapy in 29
patients with non-metastatic locally advanced well-differentiated
pNENs. In this series, neoadjuvant FAS did not induce a clinically
significant change inthe size of the primary tumor in upto 90% of
treated patients thus suggesting that localized disease does not
benefit from this preoperative treatment in terms of tumor
downstaging (22). Preoperative FAS treatment has been further
evaluated in a retrospective series of 27 patients with pancreatic
neuroendocrine liver metastases (NELM) who underwent liver
resection. Despite being associated with higher rates of
synchronous disease, lymph node metastases, and larger tumor
size, patients who underwent preoperative FAS had similar
overall survival OS and RFS as patients who did not. Similarly,
in patients who presented with synchronous liver metastases the
median OS and RFS were significantly greater among patients
who received preoperative FAS. Authors concluded that
preoperative FAS could be considered for patients with
advanced synchronous pancreatic NELM (23).
Few data are available on the effects of association of
chemotherapy and radiotherapy as neoadjuvant therapy in
pNENs, all these data being mainly obtained from case reports
(Table 1). A poorly differentiated pNEC metastatic to the breast
and lung was successfully managed with neoadjuvant
chemotherapy (5-FU treatment followed by carboplatin and
etoposide) and radiotherapy, followed by radical surgical
resection (24). Among 33 patients with pNENs undergoing
surgical resection with curative intent, 16 underwent surgery
alone, while 17 underwent adjuvant or neoadjuvant external
beam radiotherapy in addition to surgery. Fluoropyrimidine-
based chemotherapy was delivered concurrently in 14 patients
receiving radiotherapy. Local control in patients receiving
combined modality therapy was like those who had surgery
alone. Although the Authors conclude that the role of
neoadjuvant radiotherapy remains unclear, it has been
hypothesized that patients who underwent radiotherapy had
more aggressive or extensive disease than the surgery alone
Lania et al. Neoadjuvant Therapy for NENs
Frontiers in Endocrinology | www.frontiersin.org July 2021 | Volume 12 | Article 6514383
group thus explaining the lack of any significant effect of
combined neoadjuvant treatments (27).
Capecitabine combined with temozolomide (CAPTEM) has
been frequently used in the treatment of pNENs. In particular,
Strosberg et al. demonstrated that CAPTEM regimen was
extremely effective for treatment of metastatic pNENs,
resulting in an objective response rate of 70% and median PFS
of 18 months (40). These data have been strengthened by a recent
metanalysis confirming that capecitabine combined with
temozolomide is effective for treating patients with advanced
NENs, disease control rate being 72.8% (41). Neoadjuvant
CAPTEM regimen with or without radiation has been
successfully applied in six pNENs with borderline resectable
disease. All patients had radiological evidence of tumor regression
after neoadjuvant treatment (two partial responses and four
stabilization) and all of them could undergo successful resection
of the primary tumor with negative margins in 4/6 patients (25).
The efficacy of CAPTEM regimen in the neoadjuvant setting was
further confirmed by Ostwal et al. who studied 30 patients with
locally advanced pNENs or pancreatic neuroendocrine hepatic
metastases receiving neoadjuvant CAPTEM. Partial response was
observed in 13 of them, while a stable disease was found in 16
patientsthus suggesting that neoadjuvant CAPTEMmight improve
the radicality of the surgical procedure (29).
The association of PRRT and chemotherapy has also been used
as neoadjuvant therapy in pNENs, taking advantage from the
radiosensitising effects of 5-FU. In this respect, the combination
of PRRT with 177Lu-octreotate and 5FU chemotherapy was found
to be effective in five nonfunctioning pancreatic and one duodenum
NEN with inoperable disease, resulting in radiological response in
all pNENs. Only one patient underwent surgery successfully after
treatment and remained12 months postoperatively aliveand free of
disease (28). Finally, combined PRRT and chemotherapy
sandwiching two cycles of CAPTEM between two cycles of
PRRT, has been proposed in neoadjuvant setting. This regimen
resulted in favorable response rates with effective control of
symptoms and longer PFS and OS in NEN patients with
aggressive, both FDG- and SSTR-avid, metastatic progressive
disease (30).
GASTROINTESTINAL NEUROENDOCRINE
NEOPLASMS
As for pNENs, neoadjuvant treatments have been proposed for other
gastrointestinal NENS, data being mainly based on few case reports
(Table 1). Neoadjuvant chemotherapy can be effective in patients
with esophageal neuroendocrine carcinoma (ENEC), which are rare
but aggressive neoplasms. In 2018, Yamamoto et al. reported the case
of a patient with an ENEC who received neoadjuvant chemotherapy
using etoposide and cisplatin. One course of chemotherapy led to
tumor downstaging at endoscopy and to the absence of FDG
accumulation at PET-CT examination. Seven weeks after
chemotherapy, a thoracoscopic esophagectomy was performed and
the histopathological examination of the resected specimen revealed
no residual cancer cells, demonstrating a complete response with
neoadjuvant treatment (31). Other few cases of ENECs treated with
neoadjuvant chemotherapy have been reported (32–35). In three
patients, cisplatin or combinationchemotherapycausedanalmost
complete regression of the neoplasm with evidence of only
microscopic foci of tumor in the resected esophageal specimen
(32–34), while in other three cases treated with carboplatin/
etoposide or combination chemotherapy a significant reduction in
tumor burden was observed (35).
Neoadjuvant chemotherapy or chemoradiotherapy has been
anecdotally reported to be effective also in rectal NENs (Table 1).
In a study reporting on the management of patients with high grade
rectum or anal canal neuroendocrine carcinomas, two cases were
treated with preoperative pelvic chemoradiation. One of them
received radiotherapy followed by consolidative cisplatin/5-FU, low
anterior resection, and postoperative cisplatin/etoposide, while the
second patient received induction oxaliplatin/irinotecan, followed by
radiotherapy, trans anal excision, and additional oxaliplatin/
irinotecan. Both patients had only microscopic foci of residual
carcinoma at surgery (36). In another case report, a 50-year-old
woman diagnosed with a liver mass and a G3 rectal NEN was treated
with two cycles of neoadjuvant chemotherapy with etoposide and
nedaplatin, this treatment being effective in rectal tumor but not liver
metastasis shrinkage. Subsequently, the patient was switched to
irinotecan plus nedaplatin, associated to octreotide LAR 30 mg/
month because of neuroendocrine symptoms and MRI abdomen
scan showed no significant changes in lesions size. Therefore, surgery
was suggested and histopathological examination showed that the
tumor downgraded from G3 to G2 thus suggesting that neoadjuvant
chemotherapy may be effective in reducing primary lesion size and
possibly grading, offering favourable conditions for less demolitive
and more effective surgery.
The possible role of neoadjuvant PRRT and PRRT +
chemotherapy combination was evaluated in small series of
advanced gastrointestinal NENs (Table 1). Sowa-Staszczak et al.
reported on neoadjuvant 90YDOTA-TATE treatment of five
patients with foregut tumors, including three with pancreatic,
and one with midgut NEN. According to RECIST criteria, disease
stabilization was observed in four and partial responses in two
patients, one with pancreatic and the second with the midgut
NEN. In this latter case, tumor size decreased from 11 to 7.2 cm
one month after PRRT. Five months later, a further reduction in
tumor size was observed, enabling qualification for a laparotomy,
which was performed 11 months after PRRT. However, only
partial removal of the tumor was possible due to infiltration of
the large vessels (15). In another study on 89 patients with
disseminated and inoperable gastrointestinal NENs, Authors
described one patient with a midgut tumor who was successfully
treated with PRRT in a neoadjuvant setting, thus enabling an
effective surgical intervention (37). The case of a 43-year-old man
complaining of abdominal pain, vomiting, weight loss and flushes,
who underwent CT examination that revealed upper and middle
abdomen tumor was reported by Sowa-Staszczak et al. (38).
Histopathological examination of tumor specimen obtained
during exploratory laparotomy showed a well-differentiated NET
according to the 2000 WHO classification. The patient received
five cycles of chemotherapy (streptozocin and 5-FU) without any
Lania et al. Neoadjuvant Therapy for NENs
Frontiers in Endocrinology | www.frontiersin.org July 2021 | Volume 12 | Article 6514384
response and then he underwent PRRT with 90Y-DOTA-TATE.
The subsequent CT scan revealed a reduction in tumor size and the
patient wastherefore candidate toa second laparotomy for a partial
excisionof the tumor. Then he was treated with long-acting SSAand
two additional courses of 90Y-DOTA-TATE that induced a further
reduction of tumor size, potentially enabling a further laparotomy
for curativesurgery (38). Barber et al. reported their experience with
PRRT as neoadjuvant treatment in five patients with NENs, one of
them being diagnosed with a locoregional recurrence of a duodenal
tumor. The patient was treated with one cycle of 177 Lu-
DOTATATE, with a partial scintigraphy and biochemical
response (28). On the other hand, Frilling et al. reported the case
of a patientwith a small-bowelwell differentiatedNEN metastasised
to the root of the mesentery, who underwent four cycles of
neoadjuvant PRRT with 177Lu-DOTATATE. A following 68Ga-
DOTATATE PET/CT demonstrated high tracer uptake in the
mesenteric and aortocaval tumor foci with significantly higher
SUV than pre-treatment imaging with no change in size of either
the mesenteric or the aortocaval lesions. The patient then
underwent a modified liver free multivisceral transplantation (39).
Overall, the few reported experiences would suggest that
neoadjuvant chemotreatment can be a successful management
strategy in esophageal NEN, while too little data are available about
chemo/radio-treatment of other non-pancreatic gastrointestinal
NENs in a neoadjuvant setting. However, PRRT seems represent
an option in selected cases in this context.
THORACIC NEUROENDOCRINE
NEOPLASMS
Lung neuroendocrineneoplasms represent approximately 20–30%
of all NENs. Based on clinical, histological and molecular data, lung
NENs are classified in two main categories well differentiated
neuroendocrine tumors (carcinoids) and poorly differentiated
neuroendocrine carcinomas (NECs). Furthermore, lung
carcinoids (LC) are classified in typical (low grade) and atypical
carcinoids (intermediate grade) and lung NECs in large-cells and
small-cells carcinomas (LCNECand SCLC, respectively). Only low-
quality evidence guides the therapeutic management of LC, and
everolimus is the only approved drugs. However currently used
systemic therapeutic options include somatostatin analogues,
alkylating- and oxaliplatin-based chemotherapies and PRRT. Few
data are available on the efficacy of neoadjuvant treatment in
thoracic NENs and all these data come from small series and case
reports (Table 2).
Srirajaskanthan el al. reported two patients with lung NENs
that received a preoperative chemotherapy with 5-FU, cisplatin
and streptozotocin, that induced a good response with
consequently a curative resection, both patients being disease
free at 36 months after surgery (42). A multicentric study by
Daddi et al. reported six of 247 patients with atypical carcinoids
treated with neoadjuvant chemotherapy as an initial diagnosis of
SCLC was performed on fine needle aspiration biopsy. Though
no data on the results of neoadjuvant treatment were clearly
shown, Authors found an association between adjuvant and
neoadjuvant treatments and a worse prognosis. These data do
not support the efficacy of neoadjuvant therapies in terms of
complete regression of the metastatic disease. However, these
treatments might be effective in alleviating clinical signs and
symptoms (43). The same Authors reported five patients with
poorly differentiated NECs who underwent to induction therapy
and surgery without disease recurrence at 5 years, but no
information was available on the chemotherapy regimens
used (44).
More data are available on the role of neoadjuvant therapies in
LCNEC. In the multicenter retrospective study by Veronesi et al.,
15% of 144 patients who underwent surgical resection for LCNEC,
received neoadjuvant chemotherapy (i.e., platin/etoposide,
gemcitabine, vinorelbine and taxol). In this study no association
was found between neoadjuvant chemotherapy and survival except
for stage I patients in whom induction or post-operative
chemotherapy tended to be associated to a longer OS (OS rate at
3 years 100% vs 58%) (45). Sarkaria et al. retrospectively analyzed
100 patients with LCNEC operated at Memorial Sloan-Kettering
Cancer Center. Twenty-four patients received neo-adjuvant
platinum-based chemotherapy and 68% showed a partial
response and 31% were characterized by a stable disease. The
correlation analysis did not show any association between OS and
neoadjuvant or adjuvant chemotherapy. The authors also
TABLE 2 | Neoadjuvant therapies in lung NENs.
Year Article type Lung NENs Neoadjuvant treatment Outcome Reference
2009 case report undefined chemo complete response and resection (42)
2014 research article atypical carcinoids chemo no response, worse prognosis (43)
2004 research article NEC chemo complete resection (44)
2006 research article LCNEC chemo longer OS (stage I) (45)
2011 research article LCNEC chemo longer OS (stage IB-IIA) (46)
2010 research article LCNEC chemo higher 5-year survival rate (47)
2019 research article LCNEC, SCLC chemo higher 5-year survival rate (48)
2018 case report LCNEC chemo downsizing of the tumor, complete resection (49)
2019 case report LCNEC chemo downsizing of the tumor, complete resection (50)
2010 research article LCNEC chemo worse 5-year OS (51)
2015 research article Thymus NENs chemo or radio no effects (52)
2008 case report Thymus NENs chemo downsizing of the tumor, complete resection (53)
NEC, neuroendocrine carcinoma; LCNEC, large cell neuroendocrine carcinoma; SCLC, small cell neuroendocrine carcinoma; Chemo, chemotherapy; radio, radiotherapy;
OS, overall survival.
Lania et al. Neoadjuvant Therapy for NENs
Frontiers in Endocrinology | www.frontiersin.org July 2021 | Volume 12 | Article 6514385
performed a subgroup analysis in patients with completely resected
advancedstage (IB–IIIA) diseaseand, in these patients, neoadjuvant
andadjuvantchemotherapyresultedinanimprovedOS(2vs7.4
years) and 5 years OS rate (37% vs 51%) (46). Saji et al.
retrospectively confirmed a positive effect of perioperative
chemotherapy on survival in 45 patients with LCNEC. In this
study, seven patients received a neoadjuvant chemotherapy
(cisplatin and paclitaxel in four and cisplatin/topotecan in three,
respectively) thus leading to a statistically significant higher 5-year
survival rate (87.5% vs 58%) (47). Similar results were obtained by
Ogawa et al. retrospectively evaluating a series LCNEC and SCLC
who underwent complete resection. Seventy patients (31 with
LCNEC and 32 with SCLC) received perioperative platinum-
based chemotherapy and a significant improvement of the 5-year
OS rates was observed (74.5% vs. 34.7%). Multivariate analysis
revealed that perioperative chemotherapy, sublobar resection, and
lymph node metastasis were independently associated with survival
(48). The efficacy of perioperative chemotherapy in patients with
LCNEC has been further confirmed by some case reports (49,50).
In particular, Mauclet et al. reported a case of a 41-years old women
with a large LCNEC with mediastinal involvement. After an
ineffective first line chemotherapy with cisplatin etoposide,
patient underwent to palliative radiotherapy and second line
therapy with Nivolumab that led to a downsizing of the tumor.
Patient underwent surgery with the complete removal of the tumor
and histology showed an absence of viable tumor cells, while
necrosis and fibrosis were observed (50). Finally, the retrospective
analysis of 63 patients with LCNEC showed that neoadjuvant
platin-etoposide based chemotherapy was associated with a trend
towards a worse 5-year OS rate despite a partial response in 12 cases
was observed. Authors suggested that the negative association
between neoadjuvant chemotherapy and survival could be due to
the fact that only patients with stage III tumors received induction
chemotherapy (51).
NENs of thethymus are very rare tumors, accounting for0.4% of
all carcinoid tumors. Based on WHO 2015, also thymic NENs are
classified in two main histopathological and clinical categories: well
differentiated tumors, typical and atypical carcinoids and poorly
differentiated tumors, small cell and large cell carcinoma. These
tumors could be associated to ectopic hormonal secretion, in
particular adrenocorticotropic hormone secretion or to multiple
endocrine neoplasia type 1. The prognosis of patients with thymic
NENs is poor because of the high incidence of local recurrenceand
distant metastasis and 5-year OS vary from 30–70%. As for other
lung NENs, few data are available on neoadjuvat therapy in thymic
NENs (Table 2). Few data are available on neoadjuvant therapy in
thymic NENs. Filosso et al. reported 25 patients with primary
thymic NENs treated by induction therapy (19 by chemotherapy
and six by radiotherapy), these treatments having no impact on
survival (52). Dham et al. described a clinical case of a 40-year-old
man with unresectable typicalcarcinoid of the thymus. Threeweeks
of treatment with sunitinib 50 mg per day for 4 weeks with 2 weeks
off and octreotide LAR 30 mg very 4 weeks, induced a tumor
shrinkagethat led to curativesurgery of the mediastinal mass andno
evidence of disease recurrence was evident 12 months after
surgery (53).
CONCLUSIONS
Data on neoadjuvant treatment of NEN patients are scanty,
mainly based on inhomogeneous and often incomparable
retrospective studies of limited numbers of patients and
prospective studies are necessary to clarify the role of
neoadjuvant therapy in this clinical setting. Available literature
on pancreatic NEN patients suggests PRRT to be variably
successful as a neoadjuvant approach, as well as chemotherapy
to be more promising in patients with advanced synchronous
pancreatic NELM, while—in the same setting—combined chemo/
radio/PRRT-therapies would not be supported by sufficient
evidence. Neoadjuvant PRRT, chemo or chemoradio-therapies
have been anectodotally reported to be effective in non-pancreatic
gastrointestinal NENs. Among thoracic NENs, neoadjuvant
chemotherapy has been inconsistently reported to be beneficial
in LCNC patients, also in relationship to disease stage, while little
evidence would suggest neoadjuvant treatment to be negligible in
thymic tumors. Therefore, it is advisable to use a neoadjuvant
approach with caution, as the effects on quality of life and long-
term results in terms of prolonged survival remain yet to be
confirmed and the choice of this therapeutic approach should be
discussed for each single patient in a multidisciplinary setting.
AUTHOR CONTRIBUTIONS
AL conceived and authored the final draft of the manuscript. FF,
MR, and RM provided further content, added key references, and
authored sections of the manuscript. AF and AC revised the
manuscript. All authors contributed to the article and approved
the submitted version.
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