Clinical Advances in Hematology & Oncology
December 2013, Volume 11, Issue 12
Commentary
Evolving Understanding and Management of Poorly Differentiated Neuroendocrine Tumors
John D. Hainsworth, MD, Sarah Cannon Research Institute, Nashville, Tennessee
Poorly differentiated neuroendocrine tumors (PDNETs) are known to arise from a wide variety of sites. These sites include the lung, pancreas, gastrointestinal tract, urinary bladder, prostate, cervix, uterus, and parotid gland, although primary sites other than the lung are rare. PDNETs are often grouped together as “extrapulmonary small cell carcinomas” because in addition to their histologic similarity, this group of tumors shares biologic and clinical characteristics. All are rapidly growing neoplasms with the potential for early metastasis; the majority have distant metastases at the time of diagnosis. Secretion of bioactive peptides, frequent in various low-grade neuroendocrine carcinomas (eg, carcinoids, islet cell tumors), is uncommonly associated with PDNETs, and somatostatin receptor scintigraphy (octreotide scan) is usually negative.
PDNETs are also distinct from low-grade neuroendocrine tumors in their initial sensitivity to traditional cytotoxic chemotherapy. The high response rate to platinum-based therapy was first described in anaplastic carcinoid tumors arising in the gastrointestinal tract; in contrast, platinum-based regimens were inactive against typical carcinoids and pancreatic neuroendocrine tumors.1 Subsequently, responses to platinum-based therapy have been reported in PDNETs arising in a variety of sites, and in PDNETs of unknown primary site.2-4
Neuroendocrine tumors have traditionally been assumed to have a common origin, with a spectrum of biology ranging from carcinoid-type tumors (indolent) to PDNETs (aggressive). However, the molecular biology of neuroendocrine tumors is just beginning to be elucidated, and evidence currently suggests that PDNETs represent a completely different tumor type. Small cell lung cancer, the best studied high-grade neuroendocrine tumor, is characterized by multiple molecular abnormalities; deletions of chromosome 3p are the most common, but deletions of several other chromosomes (eg, 5q, 10q, and 17p) are also frequently seen.5,6 A similar spectrum of chromosomal abnormalities has been described in PDNETs arising from other sites,6 suggesting similarities in molecular biology among these tumors in addition to their clinical similarities. In contrast, well differentiated carcinoids share none of the molecular abnormalities that are common in PDNETs, suggesting a different carcinogenesis.7
The patient described by Sorscher8 had a PDNET arising in the pancreas; he had a typical clinical course, as evidenced by the presence of advanced metastatic disease at diagnosis, initial sensitivity to platinum-based chemotherapy, and subsequent progression of treatment-resistant disease. As pointed out by Sorscher, newer targeted therapies, including agents with activity against low-grade neuroendocrine tumors, have had limited evaluation in PDNETs. Octreotide, a standard part of therapy for low-grade neuroendocrine tumors, has not been systematically studied in PDNETs, although a recent case report described a patient with a pancreatic PDNET and a positive octreotide scan who had benefit with single-agent octreotide.9 Concurrent use of octreotide with chemotherapy is listed as a treatment option in the National Comprehensive Cancer Network guidelines for such tumors, with only anecdotal supporting evidence. However, since the large majority of PDNETs have negative octreotide scans, this treatment has limited applicability.
Clinical evaluation of other targeted agents has been limited to small cell lung cancer, owing to the rarity of other PDNETs. In small cell lung cancer (as in other PDNETs), multiple pathways that are potential targets of currently available therapeutic agents are overexpressed, including the PI3K/mTOR pathway. However, current evidence indicates that most of these abnormalities are “bystander” abnormalities, rather than key drivers of the malignant process. In a single phase 2 trial, everolimus (Afinitor, Novartis)—an mTOR inhibitor with activity against low grade neuroendocrine tumors—had limited activity against small cell lung cancer.10 Inhibition of the c-Kit pathway, which is frequently overexpressed in small cell lung cancer, has also been ineffective.11 Given the marked differences in molecular biology between PDNETs and low-grade neuroendocrine tumors, the failure to identify therapies effective in both types is not surprising.
No substantial improvements in the therapy of small cell lung cancer or other PDNETs have occurred in over 20 years. To improve the therapy of these neoplasms, critical “driver” molecular abnormalities must be identified and exploited. A number of candidates are currently in early clinical testing. Owing to the similar spectrum of molecular abnormalities, it is likely that new targeted drugs that are highly effective against small cell lung cancer will also have activity in the treatment of other PDNETs.
References
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