Management of Neuroendocrine Tumors

7/26/2019 Management of Neuroendocrine Tumors

1/3

Management of Neuroendocrine Tumors: NETs of LungOriginMarianne Pavel, MD; Piero Ferolla, MD, PhD

Faculty and Disclosures

CME Released: 05/13/2011; Valid for credit through 05/13/2012

CME Information

Download Audio

Download Slides

An estimated 25% to 30% of all neuroendocrine tumors (NETs) have their origin in the bronchialtract and lungs.[1,2]Although lung NETs account for fewer than 1% of all pulmonary neoplasms,

the incidence of these neoplasms has risen precipitously since the mid 1970s (Figure).[3]

Figure.Rising incidence of neuroendocrine tumors of the lung (United States, 1973-2005).From Yao JC, et al. J Clin Oncol.2008;26(18):3063-3072.[3]

Differential DiagnosisLung NETs vary widely in their pathology, from low- and intermediate-grade NETs (typical andatypical carcinoid, respectively) to aggressive and rapidly fatal small cell lung cancer(SCLC).[1,4]Histologic differentiation of these tumors can be challenging and is critical to effectivetreatment (Table).

Table. Neuroendocrine Tumors of the Lung

Tumor Type Diagnostic Criteria

Typical carcinoid < 0.5 cm< 2 mitoses per 2 mm2(10 HPF*)

No necrosis

Carcinoid morphology

Atypical carcinoid 2-10 mitoses per 2 mm2(10 HPF) or necrosis (punctate)

Carcinoid morphology

Large cell neuroendocrinecarcinoma

11 mitoses per 2 mm2

(10 HPF), median 70 per 2 mm2

(10HPF)Necrosis (large zone)

Neuroendocrine morphology (organoid nesting, palisading,

rosettes, trabeculae)Cytologic features of a non-small cell lung carcinoma

Small cell carcinoma 11 mitoses per 2 mm2(10 HPF), median 80 per 2 mm2(10
http://www.medscape.org/px/trk.svr/742300?exturl=http://img.medscape.com/images/742/300/NETs_LungOrigin_742300.mp3http://www.medscape.org/px/trk.svr/742300?exturl=http://img.medscape.com/images/742/300/NETs_LungOrigin_742300.mp3http://www.medscape.org/px/trk.svr/742300?exturl=http://img.medscape.com/images/742/300/NETs_Lung-Origin_742300_2.ppthttp://www.medscape.org/px/trk.svr/742300?exturl=http://img.medscape.com/images/742/300/NETs_Lung-Origin_742300_2.ppthttp://www.medscape.org/px/trk.svr/742300?exturl=http://img.medscape.com/images/742/300/NETs_Lung-Origin_742300_2.ppthttp://www.medscape.org/px/trk.svr/742300?exturl=http://img.medscape.com/images/742/300/NETs_LungOrigin_742300.mp3


2/3

HPF)

Necrosis (large zones)

Scant cytoplasm, finely granular nuclear chromatin, absent or

faint nucleoli

*10 high-power fields (HPF) in a microscope with field of view of 0.2 mm 2

From Travis WD.Annals of Oncology. 2010;21(Supplement 7):vii65vii71[2];Bertino EM, etal. Cancer. 2009;115:4434-4441.[4]

Although NETs of the lung arise from cells capable of producing serotonin andadrenocorticotropin hormone, hypersecretion of bioactive amines is comparatively rare in typicaland atypical carcinoids of the lung.[1,4]Symptoms characteristic of carcinoid lung NETs --including obstructive pneumonia, atelectasis, and wheezing -- are more commonly the result ofcentral airway obstruction due to tumor mass.[4]

TreatmentSurgery is the primary treatment for typical and atypical carcinoid lung NETs. Up to 64% ofpatients with atypical carcinoid lung NETs present with lymph node metastases, and 5-year

survival ranges from 61% to 88%. In contrast, lymph node metastases are present in fewer than15% of cases of typical carcinoid lung NETs, and 5-year survival exceeds 90%.[2]

Lung NETs are typically underrepresented in clinical trials of NET treatments. In recent years,only a phase 2 retrospective study of the dacarbazine derivative temozolomide[5]and the phase3 RAD001 in Advanced Neuroendocrine Tumors Trial 2 (RADIANT-2)[6]have reported resultsspecific to lung NETs. Ekeblad and colleagues performed a retrospective analysis of 36 patientswith histologically confirmed metastatic or inoperable malignant NETs treated with oraltemozolomide (100-200 mg/m2/d for 5 days every 28 days). The study group included 10patients with typical carcinoid NETs and 3 with atypical carcinoid NETs. After a median follow-up of 7 months (range, 217 months), 31% of patients with lung carcinoids had stable diseaseand 31% showed a partial radiologic response. The most frequently reported adverse event was

grade 1-2 stomachache (N = 6), and 4 patients required dose reductions due to hematologictoxicity.[5]

In RADIANT-2, which evaluated the impact of combination therapy with the oral mammaliantarget of rapamycin (mTOR) inhibitor everolimus and the somatostatin analogue octreotide LARin patients with advanced NET and carcinoid symptoms, only 6.9% of patients in theexperimental arm and 2.3% of patients in the control arm were diagnosed with lung NETs.Patients were randomly assigned to receive octreotide LAR 30 mg intramuscularly every 28days plus everolimus 10 mg per day (N = 216) or octreotide LAR plus placebo (N = 213).

Although treatment with everolimus plus octreotide was associated with longer progression-freesurvival overall -- 16.4 months vs 11.3 months in control patients (P= 0.026) -- patients withlung NETs had more favorable outcomes with octreotide plus placebo.[6]

SummaryThe role of targeted therapy for typical and atypical carcinoid lung NETs remains incompletelydefined, with data from relatively few clinical trials to help guide clinical decision making. Recentin vitro studies indicate that somatostatin receptors are overexpressed in metastatic typicalcarcinoid tumors of the lung[7]and that the mTOR is found in most lung NETs -- with higherexpression in typical and atypical carcinoids.[8]In addition, a recent preclinical study of theimpact of the mTOR inhibitor everolimus found that it suppressed the viability of typical andatypical carcinoid lung cells in culture.[9]Further research is needed to clarify the role of


3/3

somatostatin analogues, mTOR inhibitors, and other targeted therapies on these diverse andclinically challenging tumors.

In the accompanying discussion, Drs. Marianne Pavel and Piero Ferolla review a case thatillustrates the challenges inherent in the management of patients with lung NETs.

Documents

Management of Neuroendocrine Tumors