The Carcinoid Cancer Foundation is pleased to announce that Jaydira Del Rivero, MD, is the NET expert for CCF’s Ask the NET Expert program during March 2022. Launched last month, the Ask the NET Expert is a web-based program* for the neuroendocrine tumor community featuring a different NET expert each month who will answer your questions.
A medical oncologist and endocrinologist, Dr. Del Rivero is the Director of the Neuroendocrine Tumor Program as well as a research scientist in the Developmental Therapeutics Branch at the National Cancer Institute of the National Institutes of Health in Maryland.
Dr. Del Rivero is the Principal Investigator of the Natural History Study for Neuroendocrine Neoplasm and Adrenocortical Cancer to provide the basis of further development of therapeutic interventions, prevention/screening guidelines, endpoints for future clinical trials, and patient-reported outcome measures. Dr. Del Rivero’s current research is focused on the development of novel treatment approaches and targeted therapies for endocrine malignancies such as advanced gastroenteropancreatic neuroendocrine tumors (GEP-NETs), adrenocortical cancer and pheochromocytoma/paraganglioma.
Dr. Del Rivero serves on the Board of Directors of the North American Neuroendocrine Tumor Society (NANETS) and currently serves as co-chair on the Guidelines Committee.
Clinical trials with which Dr. Del Rivero is currently involved are:
- Tissue Procurement and Natural History Study of Neuroendocrine Neoplasms (NENs) including Adrenocortical Carcinoma (ACC)
- A Prospective, Multi-Institutional Phase II Trial Evaluating Temozolomide Vs. Temozolomide and Olaparib For Advanced Pheochromocytoma And Paraganglioma
Questions and Answers
Question: How common are ovarian carcinoids? The ovary has grown, but did not respond to a GA-68 Dotatate PET scan. Is it still possible to be a neuroendocrine tumor metastasis?
Answer: A primary ovarian neuroendocrine tumor (meaning that the tumor started in the ovary) is very rare and it is less than 2% of gynecological cancers and even more rare when they are ovarian carcinoids (it can also be other types of neuroendocrine tumors). If it is not positive on a 68Ga-Dotatate scan, I would recommend seeing a gynecologist for further evaluation and even resection of that mass. If surgery is done, I would also recommend doing exploration of the small bowel since approximately 10% of patients with small bowel neuroendocrine tumors have ovarian metastasis. I am happy to help with that at my institution and please email at firstname.lastname@example.org
Question: I am a spouse of a NET patient (primary NETs in ascending colon and numerous METs in the liver) and lately I have observed quite a negative shift in his mood and mental health. Are there any correlations with NETs and /or high serotonin levels and mood and mental health? Long term effects of elevated serotonin levels on mental status? He is receiving a monthly Lanreotide injection – is there any evidence of this causing things like obsessive thoughts, increased suspicion, insecurity, distrust, isolation behavior and general anger? Thank you for your time.
Answer: There is no data of a relationship of higher levels of serotonin and mental health or causing depression. We usually say it is not likely since the serotonin (produced by the tumor) in the circulation does not cross the blood brain barrier. This means, it does not go to the brain and alter any chemicals associated with mood and depression. However, a depressive score in carcinoid patients is attributable to the stress of diagnosis and adaptation to this chronic disease. In rare occasions, lanreotide could potentially be associated with depression but to my knowledge, there is no association with obsessive thoughts as describe above.
Question: I have stage 4 neuroendocrine cancer — functioning well-differentiated ileum primary. Lymph nodes and gallbladder removed; heavy hepatic tumor burden is inoperable. I have been taking Prozac for slight depression; is there a different antidepressant I should be taking? I read an article about which ones were best for carcinoid syndrome but now I can’t find it.
Answer: Prozac is an SSRI (serotonin reuptake inhibitor) and it is safe to use in patients with neuroendocrine tumors with and without carcinoid syndrome. Please see this article: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5970966/pdf/nihms953515.pdf
Question: I had a carcinoid tumor in the upper lobe of my lung removed on January 13, 2022. My initial symptom was coughing all of the time. Now, post op, I am still coughing. Will this cough ever end?
Answer: Thank you for the question. I would recommend discussing it with your surgeon. I am not a surgeon, but my thought is that you are still healing from that surgery. The healing process also depends on what type of surgery was done and if it was an open or robotic surgery.
Question: What is the best treatment for neuroendocrine tumors that have spread to the liver and have also been found in the lymph nodes after a Dotatate Gallium 68 PET Scan, but the primary location could not be found?
Answer: Thank you for this question. Without having the whole clinical picture, it is difficult to provide any guidance or recommendations. However, the management of neuroendocrine tumors varies from patient to patient, and it is personalized, based on the burden/bulk/amount of disease, location of the primary tumor or unknown location, if it is only in the liver or outside the liver, if the tumor express somatostatin receptors, if its functional meaning producing hormones causing symptoms. Moreover, patients with neuroendocrine tumors need to be discussed in a multidisciplinary team including oncology, surgical oncology, nuclear medicine, interventional radiology, radiation oncologist, pathologist, endocrinology to discuss the best course of treatment. The treatment of liver involvement due to neuroendocrine tumors can vary from patient to patient with treatment options available including surgery, ablation/embolization, and systemic therapies.
Question: Is there is correlation between high levels of Pancreastatin and uptake on Gallium 68 or if neuroendocrine tumors with high levels usually don’t show up on Gallium 68?
Answer: Pancreastatin is a diagnostic biomarker in neuroendocrine tumors and is found in many cells of the neuroendocrine system. It is a precursor or fragment of Chromogranin A and may not affected by proton-pump inhibitors (like omeprazole, pantoprazole) like chromogranin A is. To my knowledge, there is not association of pancreastatin levels with uptake on 68Ga-dotatate, some studies may report association with survival, but more studies are needed.
Question: I often hear specialists say that pancreatic NETs tend to grow at faster rate than other primary sites. With that being said, does that mean a PNET with a ki67 of 1% will grow faster than a small intestine NET with a ki67 of 1%?
Answer: Thank you for your question. Not necessarily. Ki67% is a marker of cellular proliferation and how the cells are able divide under the microscope. Pancreas NET usually have a higher Ki67% at diagnosis hence the discussion why may grow a bit faster. Small intestine NET often have a Ki67% <3% whereas Pancreas NET as discussed above may have a higher Ki67% at diagnosis and often >10%.
Question: My dad died from carcinoid tumors at 73 years old. I have Crohn’s, pulmonary sarcoidosis and chronic daily migraine. I’m wondering if Crohn’s and carcinoid tumors are related and if carcinoid cancers are hereditary.
Answer: There is no clear evidence of patients with Crohn’s disease and carcinoid tumors. There was an article that mentioned that correlation (below), however, more studies need to be done to determine is this a causality or if there is a true correlation and more studies needs to be done. In terms if carcinoid tumor is hereditary, there is a condition recently discovered called familial small intestinal neuroendocrine tumors and people with this condition have a higher risk of developing carcinoid tumors in the small intestine. However, it is very rare, and it runs in the family (meaning if your father also has brothers, sisters of his parents diagnosed with carcinoid tumor). If it does not run in the family, then it is not hereditary.
Question: What is the smallest size of tumor PET/CT can detect?
Answer: “PET scans may play a role in determining whether a mass is cancerous. However, PET scans are more accurate in detecting larger and more aggressive tumors than they are in locating tumors that are smaller than 8 mm a pinky nail (or half of a thumb nail) and/or less aggressive cancers. The size of smallest tumor mass that can be found at PET is constantly improving.”
Question: If you have no evidence of disease and have no carcinoid symptoms do you need to be on octreotide or lanreotide? If you are not on the injections how often should you be scanning?
Answer: Thank you for this question. Without having the whole clinical picture, it is difficult to provide any guidance recommendations about when to use somatostatin agonists such as octreotide and lanreotide. However, I am happy to review your case more in detail. Somatostatin agonists have two functions: 1) control the symptoms due to hormone excess of any functional neuroendocrine tumor (meaning hormone-producing tumor); 2) slow down the growth of the tumors. It is possible that your doctor is recommending either lanreotide or octreotide the slow down the growth of your tumors.
Question: Should either octreotide or lanreotide be prescribed for patients with functional gastrointestinal tumors in the absence of carcinoid syndrome, and regardless of 5-HIAA value?
Answer: Thank you for this question. Without having the whole clinical picture, it is difficult to provide any guidance recommendations for the use of somatostatin agonists (either lanreotide or octreotide). However, I am happy to review your case more in detail. Somatostatin agonists have two functions: 1) control the symptoms due to hormone excess of any functional neuroendocrine tumor (meaning hormone-producing tumor); 2) slow down the growth of the tumors. Carcinoid syndrome is due to excess of serotonin from the small bowel neuroendocrine tumors. However, pancreatic neuroendocrine tumors can also produce hormones (more common is non-functional, meaning no symptoms related to hormone excess) such as gastrinoma (producing gastrin), insulinoma (producing insulin) among others and in those patients the use of somatostatin agonists is also recommended.
Question: What exactly is the pancreastatin blood test looking for and how should results be interpreted?
Answer: Pancreastatin is a diagnostic biomarker in neuroendocrine tumors and is found in many cells of the neuroendocrine system. It is a precursor or fragment of Chromogranin A and may not be affected by proton-pump inhibitors (like omeprazole, pantoprazole) like Chromogranin A is.
Question: I’ve a question about the 68 Gallium Dotatate PET scan. I had one performed approximately five years ago and my tumors lit up. I thought this would indicate my tumors were secreting SSRT2 and thus potentially NET. My official diagnosis is SDHB Deficient GIST. My father and aunt died of paragangliomas. Could my Gist tumors have neuroendocrine aspects to them? (Since that PET scan I’ve had three surgeries for GIST tumors one of them at NIH (the only surgeon I could find who’d say yes to surgery). My oncologist of 13 years told me I was inoperable.
Answer: Gastrointestinal stromal tumors (GIST) have been reported to express somatostatin receptors and a few cases reported with positive 68Ga-Dotatate scan. It will also be important to screen for pheochromocytoma and paraganglioma since they are also avid on 68Ga-Dotatate scan.
Question: Is carcinoid hereditary?
Answer: There is a condition recently discovered called familial small intestinal neuroendocrine tumors and people with this condition have a higher risk of developing carcinoid tumors in the small intestine. However, it is very rare, and it runs in the family. If it does not run in the family, then it is not hereditary. Otherwise, I can say that small intestine neuroendocrine tumors producing carcinoid syndrome is sporadic and not familial or hereditary. Less than 17% of pancreas neuroendocrine tumors are associated with familial cancer predisposition syndromes such as von Hippel Lindau, multiple endocrine neoplasia type 1, neurofibromatosis type 1.
Question: I’ve been prescribed Xermelo. The serotonin level in my monthly blood tests have been consistently well below even the lowest range of normal. I have had clinical depression (decades ago) and I would prefer to not have it again. It is said that carcinoid diarrhea (I certainly have diarrhea) is caused by too much serotonin which is produced by the tumor, yet that doesn’t seem to apply in my case. I have never gotten a straight answer on this – can you explain?
Answer: If the question is “does excess of serotonin causing depression,” there is no data that there is a relationship of higher levels of serotonin causing depression. We usually said it is not likely since the serotonin in the circulation does not cross the blood brain barrier that goes to the brain and alter any chemicals associated with mood and depression. However, a depressive score in carcinoid patients can be attributable to the stress of diagnosis and adaptation to this chronic disease.
Question: I did serotonin, indole acetic acid, and Chromogranin A tests and based on the results I suspect the presence of carcinoid in my body but nothing appears on scans. Can these tests confirm its presence in the body? Also, how long before a tumor goes from one stage to another and how long does it take for a carcinoid tumor to spread?
Answer: Thank you for this question. Without having the whole clinical picture, it is difficult to provide any guidance or recommendations. I would consider obtaining a 68Ga-Dotatate or 64Cu-Dotatate scan.
Question: Serotonin jumped to 1510 and Chromogranin to 324. One carcinoid tumor in the liver has increased from 2.1 x 1.8 to 2.5 x 2.2 cm. Is this growth causing the increased cancer markers and is it time to visit an interventional radiologist for bland embolization? Or is ablation the better one?
Answer: Thank you for this question. Without having the whole clinical picture, it is difficult to provide any guidance or recommendations. However, obtaining a 24-hr 5HIAA urine test could be helpful; you can discuss with your local physicians. It is important to be seen or consult a NET expert to discuss further recommendations.
Question: How do amines play into carcinoid syndrome?
Answer: High-amine foods, like alcohol, cured meats, and aged cheeses, can trigger the release of serotonin from the carcinoid tumor and can lead to carcinoid symptoms/syndrome. In patients with carcinoid syndrome, these foods can affect by increasing the blood pressure, causing palpitations and flushing. READ MORE
Question: I was diagnosed with a pancreatic neuroendocrine tumor with metastases to the liver. I am supposed to start CAPTEM. I also have a naturopath who prescribed artemisinin. Do you have any information on artemisinin and neuroendocrine tumors?
Answer: To my knowledge, there is no information of the use of artemimisin in neuroendocrine tumors. It would be very important to discuss it with your oncologist about artemisinin. We also don’t know what side effects may cause in relationship with neuroendocrine tumors and in combination with other drugs like CAPTEM.
Question: How many times can PRRT, peptide receptor radionuclide therapy, be given?
Answer: PRRT with Lutathera is a radioactive drug that works by binding to a part of a cell called a somatostatin receptor found in the neuroendocrine tumor. After binding to the receptor, the drug enters the cell allowing radiation to cause damage to the tumor cells. A total of four doses/cycles pf Lutathera is given every 8 weeks. However, new studies are emerging demonstrating the efficacy of re-treatment. How many more cycles it is unclear, however, some data recommended 2 extra cycles.
Lutathera-Based PRRT Retreatment Shows OS Benefit With Acceptable Safety in NETs
Dr. Strosberg on Retreatment With Lutathera in Advanced NETs
Question: If an atypical carcinoid tumor of the lung ends up spreading to the bones does it metastasize slowly or would it move quicker like any other cancer? I suspect it would be slow. I have been studying this cancer for 8 years since my husband has it, always trying to stay ahead. I really can’t find any information on this scenario. Also, how do you know besides scans if this cancer is getting worse since it sometimes seems to hide? Thank you for any information on these questions.
Answer: Most common site of metastasis from a lung neuroendocrine includes liver, bone and within both lungs. However, we don’t have robust evidence to determine the prognosis of only bone metastasis related to atypical lung NET. Further studies are needed to understand better the biology of bone metastases in lung NET.
Atypical lung NET is more avid on FDG PET scan than on dotatate scan (more than half of patients with atypical lung NET are negative for dotatate scan). FDG PET can also be complementary to the CT scans to determine the burden of disease.
Question: My questions have to do with repurposed drugs. 1. Would SSRI, metformin or cannabis compounds possibly help in treatment of midgut NET? 2. Should the use of ARBS be avoided?
Answer: To my knowledge, there is no prospective data of the use of SSRI, metformin, and cannabis in the treatment of midgut NET. However, 3 studies with metformin are reported in clinical trials.gov, however, no results are reported to determine any efficacy.
For the second question, if you are referring to the use of ARB and the risk of cancer, it is not known in NET. However, a recent paper (below) discussed an increase risk of lung cancer with long term ARBs with increasing cumulative exposure.
Question: Why is it that some patients can have surgery or ablation or other surgical treatments for innumerable liver metastases and others cannot?
Answer: The management of neuroendocrine tumors varies from patient to patient, and it is personalized, based on the burden/bulk/amount of disease, location of the primary tumor, if it is only in the liver or outside the liver, if the tumor express somatostatin receptors, if its functional meaning producing hormones causing symptoms. Moreover, patients with neuroendocrine tumor need to be discussed in a multidisciplinary team including oncology, surgery, nuclear medicine, interventional radiology, endocrinology to determine the best course of treatment. In regard to your question, multiple liver metastasis can be treated differently based on my comment above described.
Question: Curious on the current follow up recommendations or markers to look for history of carcinoid (appendix) with diameters 2mm or larger with no signs of metastasis. Is 5HIAA still the recommended test?
Answer: The most common presentation of neuroendocrine tumor of the appendix is acute appendicitis. Infrequently, they can present as a vague abdominal pain located in the right lower part of the abdomen as a result of possible bowel obstruction. Carcinoid syndrome is a much rarer presentation, and it usually occurs after we see metastasis. For carcinoid syndrome is recommended to measure 5HIAA which can be obtained from a 24-hour urine collection or from blood. No markers is recommended for tumors less than 2 cm in size.
Question: If and when will lanreotide be in a pill form? I’m tired of the shots.
Answer: Somatostatin agonists such as lanreotide and octreotide LAR (long acting) have 2 functions:
- Control symptoms due to excess of hormone
- Anti-tumor activity, meaning it can slow down the growth of tumors.
Mycapssa is octreotide capsules and is currently being studied for patients with carcinoid syndrome symptoms due to neuroendocrine tumors, meaning to control symptoms due to hormone excess. We do not know the anti-tumor activity of this oral form of octreotide and for that purpose we recommend the monthly injections of sandostatin or lanreotide.
Amryt Announces Successful Bioavailability Study for Mycapssa® (octreotide capsules)
Question: My NETs have traveled to the eye muscles. I was treated with radiation which has now caused radiation retinopathy and I am being treated for this. There is so little information out there regarding this condition. I have lost a lot of vision in one eye and may at some point have to have surgery to remove some of the tumor which would destroy my eye muscles. I need advice on 1) a good optometrist to help me be able to see as good as possible and 2) a specialist that has had experience in this field.
Answer: NET with eye involvement is an uncommon presentation, but it is reported. I agree there is limited information about eye involvement due to NET. An ophthalmologist who specializes in retinal diseases would be helpful.
Question: I was diagnosed late with poorly-differentiated large cell NET of the esophagus (at/near stomach) and metastasis to the liver. Carboplatin was the only treatment offered and I have had all four sessions. I had my DNA analyzed and no trials available (I had psoriasis as a child). I am thus looking for further treatment options.
Answer: Thank you for this question. I would recommend discussing with your oncologist the combination ipilimumab and nivolumab immunotherapy. Ipilimumab plus nivolumab demonstrated a 44% radiographic response (tumor shrinkage) in patients with high-grade or poorly differentiated neuroendocrine carcinoma.
Clinical trials available (links below)
- BAY1895344 Plus Topoisomerase-1 (Top1) Inhibitors in Patients with Advanced Solid Tumors, Phase I Studies with Expansion Cohorts in Small Cell Lung Carcinoma (SCLC), Poorly Differentiated Neuroendocrine Carcinoma (PD-NEC): NCT04514497 https://clinicaltrials.gov/ct2/show/NCT04514497
- Testing the Combination of XL184 (Cabozantinib), Nivolumab, and Ipilimumab for Poorly Differentiated Neuroendocrine Tumors: NCT04079712 https://clinicaltrials.gov/ct2/show/NCT04079712
- A Phase I/II Trial of Lurbinectedin with Berzosertib, an ATR Kinase Inhibitor in High Grade Neuroendocrine Carcinoma: NCT04802174 https://clinicaltrials.gov/ct2/show/NCT04802174
Question: I had an octreoscan that showed 2 spots. But the PET scans are not seeing anything. My blood work is all over the place. Symptoms are flushing, diarrhea, nausea, heart problems, seizures, and headaches. I can no longer drive or work because I get dizzy all the time and seizures are happening about 1 a week. I don’t know what else to do. All the doctors Just keep passing me off to others. Any advice would be wonderful. Thank you
Answer: Is the PET scan with dotatate (either 68Ga-dotatate or 64Cu-dotatate) scan? The capacity for octreoscan to detect tumors is inferior to dotatate scan. Dotatate PET scan is the one with most sensitivity to detect tumors. I would recommend obtaining hormonal evaluation including serotonin, 5HIAA. Based on the symptoms maybe consider discussing with your local providers about mastocytosis. However, it is difficult to provide guidance without understanding the full picture. I hope this helps.
Question: Are there any recommendations/intervals for lab work that should be monitored by PCP for individuals on somatostatin analogs (vitamin levels, thyroid function etc.)? After someone has been on this medication for a while, is high blood sugar to be expected? Wondering if the medication affects pancreatic function itself or if some other reason for high blood sugars.
Answer: Somatostatin analogs can cause high blood sugar and underactive thyroid. My recommendation is to check thyroid function test every 6 months. Niacin deficiency can occur in association with carcinoid syndrome. Vitamin D deficiency and B12 is also observed and is recommended to check those levels and replete accordingly.
Question: Is there any information available on pregnancy and its effect, if any, on a lung carcinoid or a NET given the hormonal commonality?
Answer: Great question. To my knowledge there is no association between pregnancy and hormones with neuroendocrine tumors.
Question: Lung carcinoids that are usually typical low grade and had no involvement anywhere in the body. Are these less likely to come back? Is it possible to not ever see it come back? If they do, in how many years do they usually come back? What is the data that has been collected?
Answer: If the typical lung carcinoid is completely resected, no lymph node involvement and clear margins, it has a very low probability to recur. Recurrence (meaning that the tumor has come back) is more common in patients with atypical lung carcinoid. I personally like to follow up my patients with surveillance scans after surgery.
Question: For someone with history of small bowel net that was removed 2.5 years ago but now has had a recurrence with metastasis to the liver, would you recommend lanreotide as the first option for treatment? Being told the situation is inoperable at this time.
Answer: Somatostatin agonist such as lanreotide is considered the first line of treatment. However, my recommendation is to discuss neuroendocrine tumor patients with a multidisciplinary team including oncology, surgery, nuclear medicine, interventional radiology, endocrinology to determine the best management. The management of neuroendocrine tumors is personalized, based on extension of the tumors; how much liver involvement since some patients may benefit from liver directed therapies or surgery; if the tumors express the somatostatin receptors with positive dotatate scan; if the tumors are functional meaning if the tumors produce symptoms from excess hormone.
Question: What factors go into determining dose of octreotide especially when it is not for symptoms of carcinoid syndrome?
Answer: Somatostatin agonist such as lanreotide and octreotide LAR (long acting) have 2 functions:
- Control symptoms due to excess of hormone
- Anti-tumor activity, meaning it can slow down the growth of tumors.
The dose for lanreotide is 120 mg every 4 weeks and octreotide LAR (long acting) is 30 mg every 4 weeks (the dose of octreotide LAR can be increased up to 60 mg every 4 weeks)
Question: Have there ever been studies on NET to determine any similar patterns in patients or risk factors, that could determine possible causes?
Answer: Great question. We still don’t know any specific association for the predisposition of sporadic neuroendocrine tumors. <15% of NETs are associated with cancer predisposition syndrome such as MEN1 (multiple endocrine neoplasia type 1), VHL (von Hippel Landau), NF1 (Neurofibromatosis Type 1). The NIH is running a natural history study to determine if there are any causes (environmental, genetic, etc.) for the formation of NETs.
*The opinions expressed by NET experts, as well as the questions posed, haven’t been created or suggested by the Carcinoid Cancer Foundation, and CCF doesn’t endorse or promote any of the views or information expressed by the NET experts. You should not rely on the opinions expressed by the NET experts but should seek guidance and direction from your own medical advisors regarding any choices you make regarding your health and treatments.