Carcinoid Carcinoid Tumors –– Advances in Treatment - Abramson ...

Carcinoid Tumors – Advances in
Treatment
Kenneth H. Yu
Division of Hematology/Oncology, Abramson
Cancer Center, University of Pennsylvania,
Philadelphia, PA

What is Carcinoid
• “KARZINOIDE” – meaning
carcinoma-like, Siegfried Oberndorfer
1907.
• Different from other carcinomas of
the gut, monotonous structure and
generally less aggressive behavior
Oberndorfer, S. Frankf. Z. Pathol. 1: 426-432, 1907
Rindia, G. Klöppelb, G., Neuroendocrinology 2004;80(suppl 1):12–15

Lungs
25%
Liver
Pancreas
Stomach
Small intestine
75%
Appendix
Colorectal

Where do carcinoids come from
• Neuroendocrine cells
• Secrete biogenic amines like neurons
• Secrete polypeptide hormones
• These cells populate the gut and
pancreas

Where do carcinoids come from
• Neuroendocrine cells can develop
mutations in key genes, ultimately
progressing into malignant cells
• We classify carcinoid tumors based
on location and what if anything they
secrete

Carcinoid Tumors
• Stomach
– gastrin
• Pancreas
– islet cell
– insulin, gastrin, , other substances
• Appendix
– most common cancer of this organ

Carcinoid Tumors
• Produce serotonin
• “Carcinoid Syndrome”
– Flushing
– Skin changes (dermatitis)
– Diarrhea
– wheezing, shortness of breath
– heart valve problems

Carcinoid Tumors
• Other presenting symptoms:
– heartburn
– abdominal pain
– weak spells
– weight change
– jaundice
• Tumors often found serendipitously

Carcinoid Tumors
• Diagnosis:
– Blood test: chromogranin A
– Urine test: 24 hour 5-HIAA5
• Imaging:
– CT/MRI/US/PET
– Octreoscan

Chromogranin
• Protein secreted by tumor cells
• Better marker than serotonin
• Level correlates with tumor burden
• Used to monitor response to
treatment
• More convenient than 24 hour urine
5-HIAA

Imaging
• Endoscopic ultrasound
– Good for pancreatic tumors
• CT scan
– Hard to detect small tumors
• Octreoscan
– Very sensitive and specific

Octreoscan
• Many carcinoid tumors have
somatostatin receptors
• Radio-labeled
somatostatin-like
molecules are injected into the body
and can be imaged
• Implications for treatment

Octreoscan
Northern Nuclear Medicine, Tasmania

Treatment
• Once tissue diagnosis is established
and appropriate imaging performed
• No two patients are alike!
• Establish pace of disease
• If resectable → surgery
• Slow growing or stable disease can
be watched without treatment

Treatment
• Octreotide
– Somatostatin analog, binds receptors on
tumor cells
– Effective in reducing hormone secretion,
and thus symptoms
– short and long acting formulations
– even in asymptomatic patients, may
slow tumor growth

Octreotide
• Side effects – reasonably well
tolerated
– transient nausea, abdominal discomfort,
bloating, loose stools, and fat
malabsorption
– gallstones (usually asymptomatic)

Liver directed therapy
• Many patients have disease mostly
involving the liver
• (Chemo)embolization
– larger tumors
• Radiofrequency ablation
– smaller tumors

Chemotherapy
• Reserved for:
– aggressive disease
– progression of tumors through less toxic
treatment options
• No clear standard regimens
– small trials
– heterogenous disease

Chemotherapy
• Single agent
– streptozocin, , doxorubicin, 5-FU5
– dacarbazine → Temodar
• Combinations
– Temodar + thalidomide
• In aggressive tumors
– cisplatin + etoposide

Targeted therapy
• Target pathways specific to tumors
• Less toxic
• Often combined with chemotherapy
to improve effectiveness
• Avastin, Sutent, Sorafenib,
temsirolimus

Avastin (bevacizumab(
bevacizumab)
• Carcinoid tumors are enriched with
blood vessels
• Drugs like Avastin inhibit blood vessel
growth
• Promising data combining Avastin
with octreotide
• Side effects

Sutent (sunitinib
malate)
• Targets pathways that stimulate
tumor growth
• Stable disease in 93 % of patients
with carcinoid tumors
Kulke, M, Lenz, H, Meropol, N, et al. Results of a phase II study with sunitinib malate
(SU11248) in patients with advanced neuroendocrine tumours In: ECCO, 718, Eur J
Cancer Supplements, 2005. p. 204.
• Very well tolerated

Nexavar (sorafenib)
• Inhibits growth signals and blood
vessel formation
• Active, with some patients showing
tumor shrinkage
• Side effects include rash, GI upset,
abdominal pain, hand-foot syndrome,
fatigue
Hobday, TJ, Rubin, J, Holen, K, et al. MCO44h, a phase II trial of sorafenib in patinet with
metatatic neuroendocrine tumors (NET): a phase II consortium (P2C) study (abstract). J Clin
Oncol 2007; 25:199s.

Torisel (temsirolimus)
• inhibits pathways specifically
implicated in carcinoid tumor growth,
and in blood vessel formation
• In early studies, a large number of
patients experienced disease stability
• Well tolerated

Conclusions
• New, biological agents hold great
promise for the treatment of
carcinoid tumors
• Patients with carcinoid tumors
require individualized,
multidisciplinary care