The Carcinoid Cancer Foundation launched the Ask the NET Expert web-based program* for the neuroendocrine tumor community in February 2022.
Our NET expert for February 2022 is Satya (Nanu) Das, MD, MSCI, medical oncologist and hematologist at Vanderbilt-Ingram Cancer Center in Nashville, Tennessee. Dr. Das is the lead of the NET program at VICC and is the medical oncology lead for the peptide receptor radionuclide therapy program. His research interests center on gastrointestinal cancer, with a focus on NETs and drug development. He is the principal investigator of several clinical trials in NETs. To learn more about the Lutathera program at Vanderbilt, click here: https://www.vanderbilthealth.com/treatment/lutathera-therapy.
Dr. Das is a the lead author on a recently-published article in JAMA Network Open, “External Validation of a Clinical Score for Patients with Neuroendocrine Tumors Under Consideration for Peptide Receptor Radionuclide Therapy.” This article reports on a Clinical Score (CS), which is the initial prognostic score to help NET patients with well-differentiated neuroendocrine tumors estimate the benefit from peptide receptor radionuclide therapy, PRRT. He also recently led an effort to explore the evolution of the last two decades of neuroendocrine tumor trials on another recently published article in JAMA Network Open, “Comparison of Design, Eligibility, and Outcomes of Neuroendocrine Neoplasm Trials Initiated From 2000 to 2009 vs 2010 to 2020.”
Clinical trials with which Dr. Das is currently involved are:
Testing the Addition of an Anti-cancer Drug, BAY 1895344, to Usual Chemotherapy for Advanced Stage Solid Tumors, With a Specific Focus on Patients With Small Cell Lung Cancer, Poorly Differentiated Neuroendocrine Cancer, and Pancreatic Cancer, https://clinicaltrials.gov/ct2/show/NCT04514497
Evaluating the Addition of the Immunotherapy Drug Atezolizumab to Standard Chemotherapy Treatment for Metastatic Small Cell Neuroendocrine Carcinomas That Originate Outside the Lung, https://clinicaltrials.gov/ct2/show/NCT05058651
Surufatinib in Combination With Tislelizumab in Subjects With Advanced Solid Tumors, https://clinicaltrials.gov/ct2/show/NCT04579757
Belzutifan/MK-6482 for the Treatment of Advanced Pheochromocytoma/Paraganglioma (PPGL) or Pancreatic Neuroendocrine Tumor (pNET) (MK-6482-015), https://clinicaltrials.gov/ct2/show/NCT04924075
Questions and Answers
(the most recent questions are listed first)
Question: I’ve been struggling with unexplained intense abdominal pain/blood loss for about 10 months. I have been to multiple doctors and hospitals. Hoping you can help give me some direction how I might get a medical professional to give me diagnosis and start/advise treatment options.
Answer: I’m sorry to hear that you are struggling. I think the first thing to ensure is that you have a CT scan of your abdomen/pelvis (with contrast) ordered along with a possible colonoscopy if the bleeding is from the colon. That would be what I recommend first. Thereafter, hopefully, your PCP can help determine who to refer you to.
Question: Pancreatic neuroendocrine tumor patient with insulinoma for 10 ½ years. Looking for next tool in the tool box. What are your thoughts on belzutifan?
Answer: There is an ongoing study of belzutifan in pancreatic NETs [NCT04924075]. This is study open around the country in select places including at Vanderbilt. As long as you have received prior everolimus or sunitinib, you would be a candidate for the trial. I think it is a very interesting drug that seems to be well tolerated and active against pancreatic NETs in early clinical experience.
Question: How long can one stay on the immunotherapy, Tecentriq (atezolizumab)? Grade 4, poorly differentiated.
Answer: Typically, as long as immunotherapy is working, we typically continue it for 2 years. If at that point the tumors are still responding, I stop the immunotherapy given that the immune system has already been stimulated (and should continue to control the tumor) even after the drug is stopped.
Question: How would I have genetic testing done? My mother had carcinoid cancer and now I have it. I am concerned about a genetic component. Should I be tested first before having my children tested?
Answer: I think given your family history and personal history, I would recommend that you undergo genetic testing (germline testing through a platform like Invitae). If you test negative, your children do not need to be tested. I would ask your oncologist to order this for you or refer you to a geneticist who can do so.
Question: I had a thyroid NET calcitonin-free variant removed in 1999 that was an incidental finding during a parathyroid adenoma surgery! I’ve had genetic testing including a cancer panel of 134 mutations and only one came up, FANCC vus. No MEN-related health issues in family history. Do individuals have just one NET or is it a chronic illness once you have one?
Answer: Typically, in the absence of a genetic syndrome (as in your case), the incidence of one NET does not increase the likelihood of another NET.
Question: Do NETs cause stress OR do the tumors cause stress?
Answer: NETs typically do not cause stress. However, it is certainly possible that some patients with functional neuroendocrine tumors can experience worsening carcinoid syndrome symptoms with stress (as well as other factors that stimulate adrenaline).
Question: Can you have pain from a tumor on the rib?
Answer: Absolutely. A tumor sometimes in the rib can cause bone pain. If a tumor there is quite painful, sometimes some radiation to the site can relieve the pain. In the short term, a course of dexamethasone can help relieve the acute pain.
Question: I never hear or read anything about non-reactive NETs and the few choice options that are available to us unfortunate patients. Also neck/throat lymph node metastasis, paralyzed vocal chord/chords. Please help with information about treatment options.
Answer: I’m sorry but I’m not sure I fully understand the question. Are you referring to patients with tumors with no somatostatin receptor expression? If so, where did your primary tumor originate? Though you are correct that there are less options for tumors without expression of somatostatin, there still may be treatments (for pancreatic NETs- everolimus, sunitinib; for small bowel or lung NETs- everolimus).
Question: Please expand on the consideration of peritoneal carcinomatosis presence which was included in your recent study to validate a clinical score for NET patients considering PRRT. How much is too much? Or is it relative to the patient’s tumor burden elsewhere also? What are the risks of this type of spread? Etc. Thank you.
Answer: Absolutely. In our clinical score, we gave patients a score of 0 or 1 based on whether peritoneal carcinomatosis was present. We didn’t define quantification for the degree of peritoneal carcinomatosis present in the score. However, given the degree of peritoneal carcinomatosis present, certain patients are more at risk of bowel obstructions with PRRT (which can occur more acutely). This is an individual discussion with your treating oncologist. However, what we have done at VUMC is to identify patients at risk of this at NET tumor board. Once we identify these patients, we pre-treat them with dexamethasone 4 mg twice a day 3 days before, the day of treatment, and 3 days after to prevent flares which can cause bowel obstructions. For more information about the clinical score, here’s our recently published article, “External Validation of a Clinical Score for Patients With Neuroendocrine Tumors Under Consideration for Peptide Receptor Radionuclide Therapy.”
Question: With no previous diagnosis of diabetes, should a patient on lanreotide have an A1C test as a regular maintenance item? Would length of time on lanreotide be a contributing factor, say greater than 5 years?
Answer: This is a really good question. The somatostatin analogs octreotide and lanreotide can cause hyperglycemia over time, particularly with prolonged use. Usually monitor blood glucose levels every 3 months with routine electrolyte panels. If we notice the blood glucose rising, we often recommend an HgbA1c check with their primary care doctor. Routinely, however, I don’t check Hgb A1cs.
Question: Do NETs cause osteoporosis?
Answer: Neuroendocrine tumors can metastasize to the bone which can create bone weakness. They do not cause osteoporosis directly.
Question: How is the SUV for somatostatin receptors determined?
Answer: The SUV for SSTR receptors is defined on a semi-quantitative basis and is measured in relation to organs with high SSTR uptake such as the liver and spleen. I would defer to my colleagues in nuclear medicine about how the SUV for SSTR receptors is determined specifically.
Question: I would like to ask how much success patients have had with lowering/maintaining serotonin levels while taking Xermelo. Thanks so much.
Answer: I think telotristat is a unique drug that blocks the synthesis of serotonin from tryptophan. If a functional tumor producing serotonin is indeed present, this is quite an effective drug at reducing serotonin (5-HIAA levels). In terms of unique drugs, this is one of the most potent drugs at lowering serotonin levels; however, at times the challenge is getting telotristat approved if carcinoid syndrome associated diarrhea is not present.
Question: Why does liver SUV uptake increase from one scan to the next (PET)?
Answer: There is some scan-to-scan variation on Dotatate PET/CT scans with regards to normal liver SSTR SUC uptake. I don’t have a great explanation as to why it changes; however, my understanding is that this is not clinically relevant.
Question: Does diarrhea ALWAYS occur with carcinoid crisis? (and does there have to be liver metastases in syndrome)?
Answer: Diarrhea does not always occur with carcinoid crisis. In fact, during carcinoid crisis, usually flushing, blood pressure changes, light-headedness and shortness of breath are more common occurrences. Liver metastases are usually present when patients have carcinoid syndrome (because the liver has an enzyme called monoamine oxidase which breaks down serotonin to 5-HIAA) however is not absolutely necessary. Patients with bulky functional NETs with enough serotonin secretion can overwhelm the ability of the monoamine oxidase enzyme to break it down, resulting in carcinoid syndrome.
Question: If known NET (mid-gut) tumors have been removed can remaining malignant carcinoid cells cause carcinoid symptoms?
Answer: Yes, sometimes. This can occur when a small bowel NET has multiple lymph nodes which are involved and even surgical removal does not remove all the microscopic disease. In that case, these small microscopic cells can still result in excess serotonin secretion.
Question: Can NET be a cause or closely linked to hyperadrenergic POTS?
Answer: I would defer to my endocrine colleagues for further specifics however in general traditional NETs are not usually associated with adrenergic excess. Rarer NETs such as paraganglioma/pheochromocytoma can be associated be adrenergic excess and produce symptoms similar to POTs. I don’t believe there is a direct cause.
Question: Primary in duodenum. Numerous mets to liver. Diagnosed 4 years ago. Recent MRI shows an enlarged lymph node of 1.6cm superior to the pancreatic head. Should there be great concern?
Answer: I think tempo of disease progression is the key in this situation. If that lymph node has slowly grown over time, it may not be of significant concern. If that lymph node emerged over a short period of time, it may be worth further interrogating (by getting a Dotatate PET to see if it represents involvement from the NET). I have seen patients with small bowel NETs with peri-pancreatic lymph node involvement however.
Question: How do SUV (uptake) numbers relate to familiar size measurements (i.e. cm, mm) of a mass seen on a Dotatate PET scan?
Answer: SUV uptake does refer to concentration of somatostatin receptor uptake on tumors. It does not correlate with mass size (so very small tumors can still appear very bright on a Dotatate PET). However, the Dotatate scans usually have an accompanying CT or MRI component which can provide information about tumor size.
Question: Does the immunotherapy Yervoy and Opdivo protect against COVID?
Answer: This is a really interesting question. Though the checkpoint inhibitors Yervoy (ipilimumab) and Opdivo (nivolumab) activate one’s immune system by activating T-cells (which are truly virus fighting cells), I don’t believe there is any data to suggest that being on immunotherapy is protective against COVID. Rather, in some patients early during the pandemic who got COVID (prior to vaccines being available), patients on immunotherapy could get severe lung inflammation.
Question: Do you think that CAPTEM is the most appropriate treatment for a mid-gut NET, grade 3, KI67 20%-30% with multiple metastasis to the liver?
Answer: I think it is definitely a reasonable treatment option, however if your tumors are somatostatin receptor expressing (by Dotatate), starting on a somatostatin analog (lanreotide/octreotide) is also reasonable. If you have a lot of disease in the liver, however, I would favor starting with CAPTEM first given the grade 3 nature of the tumor.
Question: My husband’s surveillance imaging is a copper scan every 6 months. He is a grade 2 PNET that was not fully resectable. I’ve heard frequently during CCF’s Facebook Live Luncheon with the Experts programs that surveillance imaging can be with CT or MRI imaging. He has no liver lesions thus far. Could this be an option? Also, I’ve heard about research studies at Vanderbilt University. How would we see if we could participate?
Answer: I don’t believe he needs a copper Dotatate scan every 6 months. A CT scan or MRI (as long as the residual tumor is visible which it appears to be) every 6 months is very reasonable. We don’t have a research study in this setting at Vanderbilt however have several treatment trials down the road for him (patients with pancreatic NETs) should he need them.
Question: How does one differentiate between atypical lung carcinoid and small cell lung carcinoma? I was first diagnosed with the latter, then the former.
Answer: It is based upon appearance of the tumor tissue under the microscope. Small cell carcinoma is usually characterized by small round blue cells with very high mitoses and Ki-67 (usually more than 70%). Atypical lung NETs have lower Ki-67% and mitoses and don’t have the same morphology as small cell. I would try to ask you oncologist to have the pathology reviewed to ensure the diagnosis.
Question: My wife has had chronic diarrhea for just over 2 years. She has gone through all the GI tests and treatments with no relief. She has elevated pancreastatin, CgA, and serotonin (5-HIAA by 24-hour urine test). No NET was visible by Cu-64 DOTATATE imaging. Sandostatin didn’t work to relieve diarrhea. Our oncologist is pretty sure she has an unknown primary. How do we make it known? How do we find it?
Answer: This is a very challenging circumstance. In this case, there are a number of biochemical clues (particularly the elevated 24-hour urine 5-HIAA as the other biomarkers sometimes can be falsely elevated due to medications) that suggest that a serotonin-producing NET is indeed present. Sometimes, a capsule endoscopy can reveal a small tiny NET which is not visible otherwise. If this test is negative, unfortunately managing the diarrhea (Imodium, Lomotil, possibly cholestyramine) and imaging every 6 months with CT or MRI to assess for the presence of the NET is the best approach.
Question: Is 24-hour urine an important marker?
Answer: I believe this is referring to the 24-hour urine 5-HIAA test. For some types of NETs (mostly functional midgut NETs) along with other NETs which can secrete serotonin causing carcinoid syndrome, this is a very important marker which assess the secretory activity of a tumor. I have moved away from the 24-hour urine 5-HIAA due to the inconvenience of collecting it and now collect if for certain patients through plasma 5-HIAA. The plasma 5-HIAA has demonstrated equivalent performance to the urine 5-HIAA.
Question: NED (no evidence of disease) patients with symptoms aren’t given consideration/taken seriously until a scan or blood and urine tests CONFIRM the NET has returned. Knowing what we know that by then the tumor has metastasized, why does MDT (multidisciplinary team)/oncology STILL ignore patients’ symptoms e.g.: palpitations/arrythmia, nausea, gut issues especially constipation over diarrhea, poor digestion, migraines, general sense of malaise. It seems the art of listening to the patient has been lost and scans are the only tool to diagnose neuroendocrine tumors (an all too familiar story on a patient’s journey the first time around; repeating it the second time causes unnecessary distress).
Answer: Unfortunately, I can’t answer this question. This is still a more common occurrence than we’d like to acknowledge. I would recommend trying to see a NET specialist if a loved one is going through this cycle as providers who care for patients with these tumors are much more attune to some of these symptoms.
Question: I was diagnosed with LUNG NET and had surgery in 2013. What is the recommended protocol for checkups post-surgery? What blood work, what scans, how often? I am not willing to ASSUME there will be no reoccurrence so want to stay on top of it all. Thank you!
Answer: So, this truly depends on the grade of your tumor. If it was a typical lung NET, getting scans (CT chest +- abdominal imaging) every 6 months at least for the initial 5 years is what I typically do. Thereafter, I move to annual scans until year 10. If it was an atypical lung NET, getting scans (CT chest +- abdominal imaging) every 3 months is what I do at least for the initial 5 years. Typically, I repeat a CBC and CMP at every visit. If your NET was associated with an elevated hormonal level pre-operatively (5-HIAA, histamine), I would also repeat lab tests for these at those intervals.
Question: How do you treat NETs of the eye, head and neck?
Answer: It depends on whether they originated there or metastasized there. We have seen metastases to the orbit and head/neck area from small intestinal and pancreatic NETs. If the NETs are originating in those locations, it is important to ensure they are not a traditional NET versus a rarer type of NET such as a paraganglioma. It also depends on the somatostatin receptor (SSTR) expression of these tumors. If they are SSTR expressing, somatostatin analogs or PRRT may be treatment options. It would also likely be valuable to get input from ophthalmology or ENT to ensure other measures don’t need to be done given those are quite small real estate regions.
Question: I’m scheduled for PRRT. I am having reservations about the associated sickness and side effects versus a success rate of 58%.
Answer: This is a valid concern however PRRT, particularly when administered with the compounded amino acids arginine and lysine is very well tolerated. Apart from mild fatigue and sometimes tumor site associated soreness, most patients tolerate it very well. Also, there are 2 dose levels (100 mCi and 200 mCi). If the 200 mCi dose level is not well tolerated, we certainly reduce the dose level to 100 mCi (we have data that suggests that reduced dose amount does not impact anti-tumor activity of lutetium Dotatate). Furthermore, lutetium Dotatate in the NETTER-1 trial reduced risk of disease progression by 80% for patients. It also improved quality of life across nearly every major quality of life metric as well. Though the treatment has some side effects, we think of the benefit from the therapy as far out weighing these detrimental aspects.
*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.