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DigestiveTrac DIGESTIVE DISEASES • WINTER 2013

Issue 9

INSIDE THIS ISSUE: NEUROENDOCRINE TUMORS Medical Management of Neuroendocrine Tumors Surgical Removal of NETs is Ideal for Curative Treatment Medical Oncology Offers Approaches for Advanced or Aggressive NETs


Multidisciplinary Team Includes the Following Areas of Specialty:

Dear Colleagues, Rare among malignancies, neuroendocrine tumors can be overlooked or misdiagnosed as another more common disorder. Changing classification and nomenclature have added to confusion that surrounds neuroendocrine tumors, for both physicians and patients. With the death of Steve Jobs due to a pancreatic NET, neuroendocrine tumors have garnered national attention.

Colorectal Surgery: Scott L. Baker, MD, FACS, FASCRS

Tumors of the diffuse neuroendocrine system can occur throughout the body, however, two-thirds occur within the GI tract. Symptoms such as diarrhea and flushing can mimic other disorders, for example, irritable bowel syndrome.

Gastroenterology and Hepatology: Steven Condron, MD, MHES, FACP Cristina Hill Jensen, MD Christopher Hurley, MD Dany Shamoun, MD

Accurate diagnosis is important for effective treatment, and the possibility of saving patients years of suffering and even premature death due to these tumors. Yet diagnosis can be a complex process, and warrants specialty guidance.

General Surgery: Scott L. Baker, MD, FACS, FASCRS Michael Bauer, MD, FACS Wade E. Dosch, MD, FACS David Flanagan, MD Thomas E. Fullerton, MD Michael Person, MD, FACS David A. Strand, MD, FACS Bradley C. Thaemert, MD, FACS Donald J. Wingert, MD, FACS

We at the Avera Digestive Disease Institute hope to share a greater understanding of NETs. Appropriate referral of patients who have unresolved GI symptoms can help them experience significant health improvement. Our multidisciplinary approach includes the medical specialties of gastroenterology, surgery, endocrinology, radiology, pathology, medical oncology, radiation oncology and interventional radiology.

Genetics: Kayla York, CGC, MS

The specialists of Avera Digestive Disease Institute collaborate across medical disciplines to arrive at accurate diagnosis and the most effective treatment plan, whether that involves medical treatment, surgery or chemotherapy.

Hepatology: Hesham Elgouhari, MD, FACP Mumtaz Niazi, MD, FACP

As always, it is our privilege to work closely with primary care physicians for our patients’ best interest and continuity of care. Please feel free to contact us at 605-322-7797 with questions or for more information.

Medical Oncology: David Elson, MD, FACP Mark R. Huber, MD Michael McHale, MD, FACP Heidi McKean, MD Benjamin Solomon, MD Addison R. Tolentino, MD

Sincerely,

Scott L. Baker, MD, FACS, FASCRS Colorectal Surgery Surgical Institute of South Dakota Surgical Director of Avera Digestive Disease Institute

Steven Condron, MD, MHES, FACP Gastroenterology and Hepatology Avera Medical Group Gastroenterology Medical Director of Avera Digestive Disease Institute

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Pathology: Steven P. Olson, MD Bruce R. Prouse, MD Raed A. Sulaiman, MD Radiation Oncology: Barbara Schlager, MD Kathleen L. Schneekloth, MD James Simon, MD Radiology: Sabina Choudhry, MD Brad A. Paulson, MD Research (Cancer clinical trials) Transplant Surgery: R. Christopher Auvenshine, DO Jeffery Steers, MD, FACS Urogynecology: Matthew A. Barker, MD, FACOG


Medical Management of

Neuroendocrine Tumors B

ecause two-thirds of significant neuroendocrine tumors appear in the gastrointestinal tract, gastroenterologists are often consulted in the diagnosis and treatment of these tumors. As neuroendocrine tumors can be difficult to diagnose, classify and stage, a multidisciplinary approach and specialized understanding of these tumors are important for the most appropriate treatment plan and best outcomes. Unlike many cancers that are known due to where they appear in the body – the breast, the colon or the lung – neuroendocrine tumors (NETs) can develop at various locations in the body. These tumors arise from the diffuse neuroendocrine system – cells scattered throughout the mucosa of the gut that secrete hormones that regionally or systemically regulate organ function. Cancerous neuroendocrine cells can flood the body with inappropriate hormones or neurotransmitters. In the GI tract, NETs are most common in the

Raed A. Sulaiman, MD, board-certified Pathologist pancreas, appendix, colon or rectum, but can also appear in the small intestine and stomach, as well as other sites, including lung, and thymus and other glands. There is no one type of neuroendocrine tumor – various types of NETs have different appearances, and can grow differently and affect patients in diverse ways. Since the first discovery of a neuroendocrine tumor 100 years ago, classification of NETs has been challenging and even confusing, and has changed numerous times. The tumors can either be functioning, in that they secrete hormones, or non-functioning. They can be slow growing or aggressive. They can be silent and go undetected for years – perhaps even throughout a person’s lifetime – or cause troubling symptoms. It’s not unusual for these tumors to be found incidentally in an unrelated CT scan, endoscopy or colonoscopy. To help patients better understand their diagnosis, neuroendocrine tumors are often described according to where they appear in the body. For example, Steve Jobs had an islet cell pancreatic neuroendocrine tumor. Among pancreatic NETs alone, there are many types, including insulinoma, gastrinoma, glucagonoma, VIPoma and somatostatinoma. Continued

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“In the past, metastatic neuroendocrine tumors have been referred to as ‘metastatic carcinoid tumors.’ This is really a misnomer, carcinoid being the benign variant of these tumors. Histology alone can’t always predict the behavior of a NET. What predicts malignancy is metastasis.” -Dr. Raed Sulaiman, board-certified Pathologist  However, several criteria are used to assess the biological behavior of NETs, such as tumor size, number of mitoses, the presence or absence of invasion of the muscularis propria, angioinvasion or metastasis. Using these criteria, a site-independent NET classification system considers: n Well-differentiated NET:

classification. In turn, a correct diagnosis and medical understanding of this classification system is important in developing a treatment and/or management plan. Many neuroendocrine tumors are asymptomatic. If symptoms exist, they are often nonspecific and mimic other conditions, such as irritable bowel syndrome (IBS). Symptoms may be related to the secretion of the hormones by the tumor. The range of symptoms may include: n Hyperglycemia or hypoglycemia n Light-headedness or weakness n Flushing n Diarrhea n Persistent pain in a specific area

n Benign

n Loss of appetite/weight loss

n Uncertain malignant potential

n Persistent cough or hoarseness

n W  ell-differentiated NE carcinoma – low-malignant potential

n Thickening or lump in any part of the body

n P  oorly-differentiated NE carcinoma – high-grade malignant

n Unexplained weight gain or loss

n Changes in bowel or bladder habits n Jaundice

n Small-cell type

n Unusual bleeding or discharge

n Large-cell type

n Persistent fever or night sweats

More than 50 percent of NETs have metastasized before they are diagnosed. Because NETs can be difficult to detect until they have grown large or spread, NETs often don’t cause symptoms until they have grown or spread, and NETs symptoms resemble those of more common conditions, NETs may be misdiagnosed, or an accurate diagnosis may be delayed. An accurate pathology report – what’s seen under the microscope and interpreted by the pathologist – is what determines an accurate NET diagnosis and

n Headache n Anxiety n Gastric ulcer disease A combination of serum tests, diagnostic imaging tests and pathology studies are used to confirm a diagnosis. Depending upon the exact diagnosis, physicians then recommend a plan of care, which may include surgery, medication, interventional radiology or medical oncology. In some cases, small NETs can be removed during an endoscopy procedure.

“Our goal is a cure, or optimal management for long-term disease-free living.” 3


What is commonly known as “carcinoid syndrome” refers to the common group of symptoms that occur when NETs produce excess amounts of certain hormones. Carcinoid syndrome symptoms are flushing and diarrhea. A large percentage of NETs, which are classified as well differentiated, are not immediately life threatening, and are slow growing. If slow-growing tumors are located such that surgery is risky or difficult, for example, the pancreas, physicians may recommend an approach of “watchful waiting.” If a neuroendocrine tumor is functioning and secreting the hormones serotonin and kallikrein, then a medication known as octreotide, brand name Sandostatin®, is a common recommended treatment. The effectiveness of the medication and monitoring of the disease progress can be accomplished by serum serotonin and urinary 5-hydroxyindoleacetic acid (5-HIAA) tests. “In the case of neuroendocrine tumors, gastroenterologists consult with patients and referring physicians, and prescribe hormone-blocking medication when appropriate. As part of a multidisciplinary treatment plan, we make immediate referrals to other specialists, including surgeons and medical oncologists,” said Dr. Steven Condron, board-certified Gastroenterologist. “Our goal is a cure, or optimal management for long-term disease-free living.” n

Fa neuroen cts about docrine tumors: • 0.5 perc en

t of all ma lignancie • Incidenc s e is 2.5-5 p e r 100,000 Incidence people. has been decades, r perhaps d ising in past awarenes u s, improv e to increased e d diagn and chan ges in de ostic tools finition. • Prevale nce is esti mated at 100,000 o 35 per r mo have reve re, as autopsy stu dies aled a hig asymptom h incidence of atic NETs .

tment a e r t l a Medicof NETs: name and tide, brtatin® o e r t c O s he Sando crete t that se

rein mors ning tu nin and kallik o i t c n u he • For f ones seroto hibits t n i h c i m hor , wh tostatin in hormones a m o s cs rta he • Mimi retion of ce locks t b d n sec a that owth mor gr ng functions u t s w reti • Slo oms ne-sec hormo cause sympt ge y mana l e v i t c effe used to s for a long e b n a m •C sympto d of time i r pe o

Steven Condron, MD, MHES, FACP board-certified Gastroenterologist

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Surgical Removal of NETs is Ideal for Curative Treatment

A

s is the case with many cancers, surgery is looked to as an ideal treatment for neuroendocrine tumors that have the potential to metastasize or cause troubling symptoms. While successful medical treatment can allow patients to live symptom free for years, surgical removal of the primary tumor is the only curative option. “These tumors can be very indolent for several years, or very aggressive. They are much more variable than other types of tumors, and can behave unpredictably,” said Dr. Michael Bauer, board-certified Surgeon. A full diagnostic workup is needed to determine where the tumor is located, if it has metastasized, and if it is surgically resectable. Because neuroendocrine tumors can be asymptomatic for years, or symptoms might be attributed to another disease, it is not uncommon for detection to occur incidentally through a suspicious spot found during an unrelated imaging test. The typical diagnostic workup includes imaging, tumor markers and nuclear medicine.

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“It is often one of the first imaging tests that individuals undergo to investigate non-specific symptoms or pain.” Sabina Choudhry, MD, board-certified Radiologist Imaging: •

CT is the most common imaging tool, due to its wide coverage. “It is often one of the first imaging tests that individuals undergo to investigate non-specific symptoms or pain,” said Dr. Sabina Choudhry, board-certified Radiologist. Because neuroendocrine tumors are generally vascular tumors, intravenous contrast injection during the arterial phase imaging is effective, especially if a neuroendocrine tumor is known or highly suspected.

Positron emission tomography (PET-scan) is useful in detecting high-grade neuroendocrine tumors as a result of their high proliferative activity.

Magnetic resonance (MR) imaging is not often used for detection purposes but can be used to confirm whether a suspicion is correct in a given area of the body, or to determine metastasis in the liver.

Biochemical tumor markers: •

Plasma chromogranin A: For more than 90 percent of patients with neuroendocrine tumors, this blood level is elevated. It can be used to detect NETs as well as monitor disease progression.


Many patients with carcinoid syndrome have high levels of serotonin in blood and urine. Serum serotonin and urinary 5-hydroxyindoleacetic acid (5-HIAA) are tests used to signal a possible neuroendocrine tumor.

Other biomarkers such as intact parathyroid hormone (PTH), PTH-related protein, calcitonin level, substance-P, vasointestinal polypeptide (VIP), serum insulin level and serum proinsulin level aid in diagnosing neuroendocrine tumors.

Pancreatic polypeptide and neuron specific enolase are useful markers for follow-up in patients with a known diagnosis of neuroendocrine tumors.

The final classification of the neuroendocrine tumor is accomplished at the level of pathology, however, this cannot always predict the tumor activity. Malignancy often is determined only when the tumor metastasizes.

Endoscopic ultrasound: EUS combines endoscopic and ultrasound technology. The endoscope, equipped with ultrasound, is passed into the stomach or small intestine, and then the pancreas is studied via ultrasound through the stomach or intestine wall. EUS can be used to guide a fine needle into the tumor to perform a biopsy during the same procedure.

Nuclear medicine: A nuclear octreotide scan uses radioactive material, indium-111, to detect neuroendocrine cancers. The radioactive material can travel throughout the entire body through the bloodstream, and attaches to any cancer cells in the body. A gamma camera detects the radioactive octreotide and creates images. The scan can show both the primary site and metastases.

Diagnostic options Imaging – CT, PET, MRI Nuclear octreotide scan Endoscopy Endoscopic ultrasound (EUS) Tumor markers

Dany Shamoun, MD, board-certified Gastroenterologist Endoscopy: It’s not uncommon for neuroendocrine tumors to be found in the GI tract during an unrelated endoscopy or colonoscopy – or an endoscopic exam to investigate the cause of unexplained symptoms. “These tumors grow in the submucosa and may appear as a bump, although the tumor itself is not visible,” said Dr. Dany Shamoun, board-certified Gastroenterologist. In such cases, a biopsy can be performed during endoscopy, or if the tumor is small, it can be removed endoscopically. Surgical resection of the tumor and/or the part of the organ affected is the best possible treatment. This can often be performed through minimally invasive procedures, including laparoscope. The type of operation depends upon the location of the tumor. For example, if the tumor is on the appendix, complete removal of the appendix is the course of action. If the tumor is located in the colon or rectum, resection of the affected portion of the bowel is performed. As opposed to adenocarcinoma of the pancreas, which is often deadly, pancreatic NETs are often slow growing and surgically treatable. If the tumor is located on the tail of the pancreas, a distal pancreatectomy, or removal of the lower portion of the

Continued

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pancreas, is indicated. If a tumor is located in the head of the pancreas, a Whipple procedure may be considered. The Whipple procedure, or pancreaticoduodenectomy, is a very intricate, aggressive procedure. It has potential for significant complications and a high mortality rate (up to 12-16 percent). However, when performed by an experienced surgeon in a high-volume center, the Whipple procedure mortality rate is less than 5 percent and is associated with better outcomes for patients. The National Comprehensive Cancer Network (NCCN) recommends that Whipple procedures be performed at a high-volume center that has multidisciplinary consultation and performs more than 15 Whipple procedures annually. Avera McKennan Hospital & University Health Center meets all these criteria and is considered a high-volume center.

Other treatment options Radiofrequency ablation (RFA) Transarterial chemoembolization (TACE) Endoscopic procedures

creating heat that destroys the cancer cells. Transarterial chemoembolization (TACE) involves the use of fluoroscopy, or less commonly CT, to guide catheters through the blood vessels to the liver, and deliver chemotherapy directly to the tumor, as well as inject material such as gel foam, gelatin spheres or metal coils to block the blood vessels that feed the tumor. TACE, performed by interventional radiologists, is only considered if the tumor is not operable. n

Surgical treatment

“Anytime we are

Resection and debulking

presented with a

Laparoscopy and minimally invasive techniques

neuroendocrine tumor, it requires

Open procedures

a multidisciplinary

Pancreatic techniques: Distal pancreatectomy (lower portion or tail), Whipple procedure, or pancreaticoduodenectomy (head)

approach, including gastroenterology, oncology, endocrinology, radiology,

If neuroendocrine tumors cannot be completely removed by resection, the patient may benefit from surgical debulking of the tumor for control of symptoms. Radiofrequency ablation can be used to destroy inoperable primary or metastatic tumors in the liver. In RFA, imaging modes such as ultrasound or CT are used to help guide a needle electrode into a malignant tumor. High-frequency electrical currents are then passed through the electrode,

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pathology, surgery or interventional radiology. Successful surgery hinges on advanced diagnostic modalities and workup to decide the exact classification and location of the primary tumor, as well as metastases.� - Dr. Bauer


Medical Oncology Offers Approaches for

Advanced or Aggressive NETs A

vera medical oncologists consult with Avera Digestive Disease specialists to address neuroendocrine tumors that are inoperable, or those tumors that do not respond to somatostatin analog alone. Dr. Mark Huber, board-certified Medical Oncologist and Hematologist, said chemotherapy approaches differ based on type and aggressiveness of the neuroendocrine tumor.

“Many of the chemotherapy approaches that exist are specific to neuroendocrine tumors of the pancreas.” -Mark Huber, MD, board-certified Medical Oncologist and Hematologist

The latest advances have come in the form of targeted therapies – treatment that targets the cancer’s specific genes, proteins or the tissue environment that contributes to cancer growth and survival. This type of treatment blocks the growth and spread of cancer cells while limiting damage to normal cells. Continued

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Sunitinib (Sutent速) attacks both blood vessel growth and other targets that stimulate cancer cell growth. When used to treat patients with pancreatic NETs that have spread outside of the pancreas, it has been shown to slow tumor growth and help patients live longer. This drug is a pill that is taken once a day to treat pancreatic NETs. The most common side effects are nausea, diarrhea, changes in skin or hair color, mouth sores, weakness and low blood-cell counts. Other possible effects include fatigue, high blood pressure, heart problems, bleeding, hand-foot syndrome and low thyroid hormone levels. This drug is approved by the FDA to treat NETs that cannot be removed with surgery or have spread outside the pancreas. Everolimus (Afinitor速) works by blocking a cell protein known as mTOR, which normally promotes cell growth and division. When used to treat patients with pancreatic NETs that have spread outside of the pancreas, it has been shown to slow tumor growth. Everolimus is a pill taken once a day. Common side effects of this drug include mouth sores, an increased risk of infections, nausea, loss of appetite, diarrhea, skin rash, fatigue, weakness, fluid buildup and increases in blood sugar and cholesterol levels. A less common but serious side effect is damage to the lungs, which can cause shortness of breath or other problems. This drug is approved by the FDA to treat NETs that cannot be removed with surgery or have spread outside the pancreas. Everolimus can be used alone or in combination with somatostatin analogs.

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According to the American Cancer Society, standard chemotherapy has limited value in treating neuroendocrine tumors. When chemo is used, the preferred drugs are doxorubicin and streptozotocin. Streptozotocin alone generates response rates of 30 percent to 40 percent. It is more effective for islet cell tumors than other NETs. When combined with 5-fluorouracil the response rate rises to up to 65 percent for a duration of about two years. Other chemo drugs that have been helpful in treating these tumors include dacarbazine (DTIC), and temozolomide. Some recent studies have found that combining temozolomide with thalidomide or with capecitabine can be helpful. n


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INSIDE THIS ISSUE: NEUROENDOCRINE TUMORS Medical Management of Neuroendocrine Tumors Surgical Removal of NETs is Ideal for Curative Treatment Medical Oncology Offers Approaches for Advanced or Aggressive NETs

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Digestive Trac • Winter 2013, Issue 9