THE EVOLVING LANDSCAPE OF NEUROENDOCRINE TUMORS

Introduction: Recent
Advances in the Genetics, Diagnosis,
and Treatment of Neuroendocrine Tumors

N euroendocrine tumors (NETs) represent an ex-

tremely heterogeneous group of tumors, which
share expression of neuroendocrine markers and
the ability to secrete bioactive amines/peptides. Histori-
cally, the rarity of these cancers, coupled with their
differentiated tumors.8 –10 It is worth noting, however,
that the optimal cutpoints for proliferative rate remain
the subject of ongoing debate.11 For years NETs were
bundled with other tumor types arising in the same
organ, as no formal tumor-node-metastasis (TNM)-
variable clinical manifestations and natural history (eg, based staging systems existed.12 In response to growing
related to site of origin, hormone production, prolifer- evidence that NETs are characterized by distinct tumor
ative index) was perceived as a major barrier to clinical biology and patterns of spread, the American Joint
investigation. Progress was slow, with few advances Committee on Cancer (AJCC) recently incorporated
over a 30-year period, except for the development of staging systems specific for different types of NET.8
streptozocin-based chemotherapy for pancreatic neu- As discussed by Öberg in this edition of Seminars,
roendocrine tumors (PanNETs) and somatostatin ana- the genetics of most NETs remain a mystery, although
logs for symptom control in carcinoid tumors.1,2 In the recent data suggest that nearly 30% of patients with
past decade, the field has evolved dramatically, leading pheochromocytoma/paraganglioma have underlying
to new treatment options for patients with medullary germline mutations in succinate dehydrogenase path-
thyroid carcinoma and PanNETs, innovative clinical way genes (including a sizeable subgroup of patients
development paradigms, and revised tumor classifica- with apparently sporadic tumors).13 Similarly, RET mu-
tion schemes.3– 6 Perhaps most importantly, the identi- tations occur in the majority of medullary thyroid can-
fication of novel therapeutic targets, coupled with the cers and, as in paraganglioma and pheochromocytoma,
demonstration that accrual to NET trials is feasible, has the precise mutation dictates the phenotype.14 A famil-
led to enhanced interest by academic researchers and ial syndrome of small bowel carcinoid has recently
the pharmaceutical industry in developing novel ther- been identified, but the genetic drivers are not consis-
apies for these diseases. As a result, we have witnessed tent across families.15 Furthermore, work by Jiao et al
a dramatic increase in the number of clinical trials suggests that ⬎80% of sporadic PanNETs have muta-
available to patients (including studies focused on ge- tions in genes encoding for proteins implicated in chro-
netics, biomarkers, diagnostics, imaging, therapy, nat- matin remodeling (eg, MEN1, DAXX, ATRX).16 The
ural history, and supportive care).7 In this issue of clinical significance of these findings remains uncertain
Seminars in Oncology, recent advances related to un- but is an area of intense interest, particularly since
derstanding and treating NETs will be reviewed, as will ⬍15% of PanNETs harbor mutations in components of
areas of unmet need and as yet unanswered scientific the mammalian target of rapamycin (mTOR) path-
questions. way.16 Despite these advances, many questions remain
Perhaps one of the most significant recent develop- regarding the precise genetic alterations underlying
ments in the field is the recognition that carcinoid most sporadic NETs, as well as the optimal surveillance
tumors and PanNETs vary with respect to underlying and treatment of patients suffering from inherited can-
tumor biology and response to therapy, paving the way cer syndromes. Several ongoing studies offer hope that
for separate paths for clinical investigation for these these issues will be addressed in the coming years.
diseases. Modern classification schemes have emerged In terms of therapy, liver-directed strategies con-
(reviewed by Klimstra in this issue), which emphasize tinue to play a significant role in the treatment of
the value of the proliferative index as a means of patients with liver-dominant well-differentiated NETs
distinguishing between well-differentiated and poorly (reviewed by Wang and colleagues in this issue). How-
ever, the relative merits of ablation, resection, emboli-
0270-9295/ - see front matter
zation, transplant, and liver-directed radiation therapy
© 2013 Elsevier Inc. All rights reserved. remain unclear, as randomized trials are lacking.17,18
http://dx.doi.org/10.1053/j.seminoncol.2012.12.001 Without such studies, patient, physician, and institu-

Seminars in Oncology, Vol 40, No 1, February 2013, pp 1-3 1

2 E.K. Bergsland

tional preferences will continue to influence choice of Given the chronic nature of most NETs, along with
intervention in patients with unresectable disease. their predilection to secrete hormones and bioactive
With regard to resectable primary or metastatic tumors, amines, the ability to prevent and/or palliate symptoms
there continues to be no randomized data to support is of paramount importance. As reviewed by Anthony
the use of adjuvant therapy, despite the emerging evi- in his “Practical Guide to the Supportive Care of Pa-
dence for active agents in the setting of advanced tients with Functional Neuroendocrine Tumors,” physi-
disease. cians must be aware of the various symptom complexes
The systemic therapy for carcinoid continues to be a associated with functional tumors and anticipate the trig-
major challenge (summarized in the article by Pavel, gers (eg, surgery in a carcinoid patient) and treatments
Kidd, and Modlin). Beyond somatostatin analogs, no specific to individual hormones and/or bioactive amines.
standard therapy exists and additional treatment strat- SSTa play a pivotal role in the control of hormone-medi-
egies are desperately needed.19 Furthermore, the re- ated symptoms.25 Novel SSTa are under study, as are
sults of the RADIANT-2 trial underscore the limitations other innovative strategies such as the use of a trypto-
related to imaging in NETs (reviewed by Leung and phan hydroxlase inhibitor to block serotonin ex-
Schwartz in this issue), given the loss of power and cess.26,27 In short, many patients enjoy a good quality of
informative censoring that occurred due to discordant life with maneuvers to decrease symptoms. Recogniz-
assessments between local and central reviewers.20 ing that radiographic progression can be extremely
However, progress is likely in the near future, as evi- indolent (measured over many years in some cases),
denced by the numerous ongoing and recent trials defining the optimal timing for initiation of anti-tumor
exploring new imaging modalities, novel somatostatin therapy in well-differentiated tumors continues to be a
analogs (SSTa), peptide receptor radiotherapy (PRRT), key concern, and is at the root of ongoing efforts to
vascular endothelial growth factor (VEGF) inhibitors, identify predictive and prognostic biomarkers.
mTOR inhibitors, and other therapeutic strategies. To
this end, the randomized phase III trial of bevacizumab Emily K. Bergsland, MD
versus interferon in patients with high-risk carcinoid UCSF Helen Diller Family Comprehensive
tumors (Southwest Oncology Group [SWOG]-0518) re- Cancer Center
cently closed, and the results are eagerly anticipated. San Francisco, CA
The article by Toumpanakis and Caplin provides a Guest Editor
detailed discussion of next generation of SSTa, for use
alone (for symptom control or tumor treatment) or in
the context of PRRT.
REFERENCES
1. Kvols LK, Moertel CG, O’Connell MJ, et al. Treatment of
Unlike carcinoid, significant advances have been made
the malignant carcinoid syndrome. Evaluation of a long-
in PanNETs over the last few years, culminating in the US acting somatostatin analogue. N Engl J Med. 1986;315:
Food and Drug Administration approval of both everoli- 663– 6.
mus and sunitinib for progressive disease (reviewed by 2. Moertel C, Lefkopoulo M, Lipsitz S, et al. Streptozocin-
Kulke in this issue). Unfortunately, the role of chemother- doxorubicin, streptozocin-fluorouracil or chlorozotocin
apy continues to be controversial, as traditional streptozo- in the treatment of advanced islet-cell carcinoma. N Eng
cin-based regimens have been plagued by an unfavorable J Med. 1992;326:519 –23.
risk to benefit ratio.21,22 Temozolomide-based chemotherapy 3. Wells S, Robinson B, Gagel R, et al. Vandetanib in pa-
regimens are of great interest, but definitive studies have tients with locally advanced or metastatic medullary thy-
roid cancer: a randomized, double-blind phase III trial.
not yet been performed.23
J Clin Oncol. 2012;30:134 – 41.
Targeted agents appear to hold great promise for
4. Raymond E, Dahan L, Raoul JL, et al. Sunitinib malate for
treatment of medullary thyroid cancer (MTC), as indi- the treatment of pancreatic neuroendocrine tumors.
cated by the recent FDA approvals of vandetanib and N Engl J Med. 2011;364:501–13.
cabozantanib in this disease. In contrast, progress in 5. Yao JC, Shah MH, Ito T, et al. Everolimus for advanced
the treatment of paraganglioma and pheochromocy- pancreatic neuroendocrine tumors. N Engl J Med. 2011;
toma has been limited. Strosberg discusses the treat- 364:514 –23.
ment of rare NETs in his article entitled, “Update on the 6. Schoffski P, Elisei R, Muller S, et al. An international,
Management of Unusual Neuroendocrine Tumors: Pheo- double-blind, randomized, placebo-controlled phase III
chromocytoma and Paraganglioma, Medullary Thyroid trial (EXAM) of cabozantanib (XL184) in medullary thy-
roid carcinoma (MTC) patients with documented RE-
Cancer, and Adrenal Cortical Carcinoma.” Advances in
CIST progression at baseline. J Clin Oncol. 2012;30:
the treatment of high-grade NETs also have been slow, abstract 5508.
thus the disease continues to be treated according to 7. National Cancer Institute, Search for Clinical trials. 2012.
small cell lung cancer guidelines, despite predictably poor http://www.cancer.gov/clinicaltrials/search.
outcomes (as outlined by Smith and Reidy-Lagunes in this 8. Edge S, Byrd D, Carducci M, et al. AJCC cancer staging
issue).24 manual. 7th ed. New York: Springer; 2010.
Introduction 3

9. Klimstra DS, Modlin IR, Coppola D, et al. The pathologic growth in patients with metastatic neuroendocrine
classification of neuroendocrine tumors: a review of no- midgut tumors: a report from the PROMID Study Group.
menclature, grading, and staging systems. Pancreas. J Clin Oncol. 2009;27:4656 – 63.
2010;39:707–12. 20. Pavel ME, Hainsworth JD, Baudin E, et al. Everolimus
10. Rindi G, Arnold R, Bosman F, et al. Nomenclature and plus octreotide long-acting repeatable for the treatment
classification of neuroendocrine neoplasms of the diges- of advanced neuroendocrine tumours associated with
tive system. Lyon: IARC Press; 2010. carcinoid syndrome (RADIANT-2): a randomised, place-
11. Sorbye H, Welin S, Langer SW, et al. Predictive and bo-controlled, phase 3 study. Lancet. 2011;378:2005–12.
prognostic factors for treatment and survival in 305 pa- 21. Cheng PN, Saltz LB. Failure to confirm major objective
tients with advanced gastrointestinal neuroendocrine antitumor activity for streptozocin and doxorubicin in
carcinoma (WHO G3): the NORDIC NEC study. Ann the treatment of patients with advanced islet cell carci-
Oncol. 2013.24:152– 60. noma. Cancer. 1999;86:944 – 8.
12. Klimstra D, Modlin I, Coppola D, et al. The pathologic 22. McCollum AD, Kulke MH, Ryan DP, et al. Lack of efficacy
classification of neuroendocrine tumors: a review of no- of streptozocin and doxorubicin in patients with ad-
menclature, grading, and staging systems. Pancreas. 2010; vanced pancreatic endocrine tumors. Am J Clin Oncol.
39:707–12. 2004;27:485– 8.
13. Gill AJ, Benn DE, Chou A, et al. Immunohistochemistry 23. Strosberg JR, Fine RL, Choi J, et al. First-line chemother-
for SDHB triages genetic testing of SDHB, SDHC, and apy with capecitabine and temozolomide in patients
SDHD in paraganglioma-pheochromocytoma syndromes. with metastatic pancreatic endocrine carcinomas. Can-
Hum Pathol. 2010;41:805–14. cer. 2011;117:268 –75.
14. Raue F, Frank-Raue K. Update multiple endocrine neo- 24. Strosberg JR, Coppola D, Klimstra DS, et al. The NANETS
plasia type 2. Fam Cancer. 2010;9:449 –57. consensus guidelines for the diagnosis and management
15. Cunningham JL, Diaz de Stahl T, Sjoblom T, et al. Com- of poorly differentiated (high-grade) extrapulmonary
mon pathogenetic mechanism involving human chromo- neuroendocrine carcinomas. Pancreas. 2010;39:799 –
some 18 in familial and sporadic ileal carcinoid tumors. 800.
Genes Chromosomes Cancer. 2011;50:82–94. 25. Modlin IM, Pavel M, Kidd M, et al. Review article: soma-
16. Jiao Y, Shi C, Edil BH, et al. DAXX/ATRX, MEN1, and tostatin analogues in the treatment of gastroenteropan-
mTOR pathway genes are frequently altered in pancre- creatic neuroendocrine (carcinoid) tumours. Aliment
atic neuroendocrine tumors. Science. 2011;331:1199 – Pharmacol Ther. 2010;31:169 – 88.
203. 26. Wiedenmann B, Pavel M, Seufferlein T, et al. The effect
17. Mayo SC, de Jong MC, Pulitano C, et al. Surgical manage- of telotristat etiprate on clinical and biochemical re-
ment of hepatic neuroendocrine tumor metastasis: re- sponses in patients with symptomatic carcinoid syn-
sults from an international multi-institutional analysis. drome: preliminary results of an ongoing phase II, mul-
Ann Surg Oncol. 2010;17:3129 –36. ticenter, open-label, serial-ascending dose study. J Clin
18. Pitt SC, Knuth J, Keily JM, et al. Hepatic neuroendocrine Oncol. 2012;30:abstract e14564.
metastases: chemo- or bland embolization? J Gastrointest 27. Kvols L, Wiedenmann B, Oberg K, et al. Safety and
Surg. 2008;12:1951– 60. efficacy of pasireotide (SOM230) in patients with meta-
19. Rinke A, Muller HH, Schade-Brittinger C, et al. Placebo- static carcinoid tumors refractory or resistant to oc-
controlled, double-blind, prospective, randomized study treotide LAR: results of a phase II study, Pro Am Soc Clin
on the effect of octreotide LAR in the control of tumor Oncol. 2006; abstract 171.