The University of Iowa Neuroendocrine Tumor Clinic

Abstract

The Iowa Neuroendocrine Tumor (NET) Clinic was founded and developed by two remarkable physicians, Thomas and Sue O’Dorisio. Tom was an Endocrinologist and close friend and colleague of Aaron Vinik. Both men were pioneers in studies of gastrointestinal hormones and the management of patients with NETs. Sue was a Pediatric Oncologist and research scientist with great expertise in new drug development and clinical trials. She and Tom were leaders in bringing somatostatin analogs and somatostatin-conjugated radioligands to the clinic for the therapy and diagnosis of NETs. All three physicians received lifetime achievement awards for their contributions to the field of NETs. This is the story of how the Iowa NET Clinic developed over the years to become a model for the multidisciplinary management of patients with NETs, culminating in its designation as a European Neuroendocrine Tumor Society NET Center of Excellence, and the receipt of a Specialized Project of Research Excellence (SPORE) grant for the study of NETs from the National Institutes of Health.

Introduction

The period from 1970 to the mid-1990s saw the discovery of multiple gastrointestinal and hypothalamic hormones, including the discovery of somatostatin in 1973.(1) Understanding the remarkable inhibitory effects of this hormone and its analogs on neuroendocrine tumor (NET) hormonal secretions,(2) and subsequently on NET growth,(3) brought a significant advance in the management of patients with NETs who previously had only surgery and limited chemotherapy options.

It was natural, therefore, that young endocrinologists would take an interest in this field and the early careers of both Drs. Thomas O’Dorisio (Tom) and Aaron Vinik (Dr. Vinik) focused significantly on this exciting area of discovery and therapy in endocrinology. Both of these endocrinologists played active roles, often collaboratively, in the development of clinical assays for multiple gut hormonal peptides and neurotransmitters,(4–6) in studies on the pathophysiology of gut peptides,(7, 8) and in clinical trials of somatostatin analogs,(9, 10), amongst other topics. Tom initiated and collaborated in theranostic-related clinical trials, using ⁶⁸Ga-DOTATATE, ⁹⁰Y-DOTATOC and ¹⁷⁷Lu-DOTATATE.(11–13) Dr. Vinik and his wife, Etta Vinik, developed the Norfolk Symptom Scale which was widely used in research studies(14, 15) and used by Tom as a Quality of Life assessment tool in the Iowa NET Clinic. Dr. Vinik was a frequent visitor to the University of Iowa delivering lectures in both clinical and research topics and Tom visited Eastern Virginia Medical School for similar presentations. Dr. Vinik was also an important External Advisor for the NET-focused, NCI-funded Specialized Program of Research Excellence (SPORE) award to the University of Iowa, the first NET-focused SPORE. These endeavors were widely recognized and led to Lifetime Achievement Awards from the North American NET Society (NANETS) to Tom and Sue O’Dorisio in 2017, and Aaron Vinik in 2019). These two endocrinologists leave huge legacies for the care of patients with NETs. A major part of the O’Dorisio legacy continues in the clinical and research accomplishments of the University of Iowa Neuroendocrine Tumor Clinic, which we will describe here.

History

The University of Iowa Neuroendocrine Tumor Clinic story begins with two remarkable physicians, the husband and wife team of M. Sue O’Dorisio MD, PhD (Sue) and Tom O’Dorisio, MD. Sue grew up in Iowa, graduated from Creighton University and received a PhD in Biochemistry from the University of Nebraska. Tom grew up in Colorado, graduated from Regis College then Creighton University Medical School. They moved to Ohio State University (OSU), where Tom began his residency in Internal Medicine and worked as an Assistant Professor of Medicine doing full time research. She decided to go to medical school, and attended OSU from 1981–85, all the while maintaining her NIH funding. She did a Pediatrics residency and Hematology-Oncology fellowship at OSU, finishing in 1990. Remarkably, while still a fellow she had attained the rank of Professor of Pediatrics and Immunology. Tom finished his Internal Medicine residency in 1974 and his endocrinology fellowship in 1977. He then joined the OSU faculty under Ernest Mazzaferri and also worked with Robert Zollinger and continued to follow one of the two patients described in the classic paper on gastrinoma by Zollinger and Ellison in 1955.(16)

The O’Dorisios also began to raise a family of 3 children during this busy period. Both took faculty positions at OSU and began their noteworthy careers. Tom did research on hormones, and raised his own antibodies for calcitonin and others peptides. Sue’s research was on G-protein coupled receptors. They saw many patients with NETs over time, and this became a clinical focus for Tom in his Endocrinology clinics. He used hormone markers to diagnose and follow patients with NETs, and helped to improve existing assays. With the synthesis of octreotide in 1979,(17) Tom finally had a drug with efficacy for treating many of the symptoms his patients had. FDA approval for octreotide was granted in 1988, and the long acting depot form Sandostatin LAR was developed in 1997.(18) Tom became one of the earliest adopters of these drugs to treat his patients, and patients sought him out for his expertise. Meanwhile, Sue was taking care of children with cancer, treating patients with acute leukemia, Wilms tumor, and neuroblastoma, among others. Her laboratory focus on G-protein coupled receptors also included the somatostatin receptor, the target of octreotide, so her interests overlapped significantly with Tom’s. They earned recognition for their expertise with NETs while at OSU, and Tom had developed a specialized clinic devoted to patients with these tumors. They made strong connections with colleagues who had similar interests both nationally and internationally, and frequently gave talks describing their management of NET patients. The clinic’s emphasis was on hormonal treatments for NETs, but was missing the multi-disciplinary components needed to take it to a higher level.

In 1999, Sue accepted the job as Professor and Division Chief of Pediatric Hematology-Oncology at the University of Iowa, and Tom as a Professor in Endocrinology. Tom approached the leadership of the Cancer Center to develop an NET clinic, which was an unusual request from someone in the discipline of Endocrinology, without a formal Oncology background. Since Tom had had an active NET clinic at OSU, our Cancer Center Director (George Weiner, MD) had the great foresight to provide clinic space and nursing support. TMO’s first goal was to recruit a surgeon,and he approached James R. Howe, MD (Jim), a surgical oncologist and endocrine surgeon, and invited him to be the surgeon for the NET clinic. Jim was immediately drawn in by Tom’s enthusiasm and vision and readily agreed to the role. Tom also met with members of medical oncology and nuclear medicine to share his excitement about building the NET program, and his passion was infectious. Tom met with the lead GI pathologist to discuss what was important to include in each report, and to facilitate cutting extra slides from internal and external cases to perform supplemental immunohistochemistry studies and for research. Tom set up an NET patient registry and consent for obtaining blood and tissue samples for research, which was approved by the IRB in 1999 and continues in modified form today. Many patients from across the United States began to come to the Iowa NET clinic, which was further enhanced by the opening of the first trials for peptide receptor radiotherapy (PRRT) in the United States.

Early Clinical Trials

Sue applied for and received Investigational New Drug (IND) approval for ⁹⁰Yttrium(Y)-DOTATOC, a radionuclide with specific activity for NETs, and was awarded an R21 grant in 2001 for a Phase I trial of ⁹⁰Y-DOTATOC therapy in Childhood Solid Tumors expressing somatostatin receptors (SSTRs; primarily neuroblastoma, medulloblastoma, Ewing sarcoma, and osteosarcoma). This was later funded as an R01 from 2005–07. This represented the first use of SSTR-based PRRT in the United States and the radionuclide had to be made on site, requiring significant time and effort from the investigators and Nuclear Medicine personnel. Yusuf Menda, MD (Yusuf) published the results of the Phase I trial in 2010, describing 17 pediatric patients receiving at least one of the 3 cycles of ⁹⁰Y-DOTATOC.(19) They found a 12% partial and 29% minor response rate and no dose-limiting renal or hematological toxicity. The group also received R01 funding in 2012 to investigate dosimetry-based personalized therapy in adult and pediatric patients in a Phase II trial of ⁹⁰Y-DOTATOC, where ⁹⁰Y-PET and Bremsstrahlung imaging were used to determine patient-specific dosages of PRRT.(20) They enrolled 25 adults and children and found that the radiation doses to the kidney were highly variable, and 85% of adult patients had their subsequent cycle doses modified by 20% or more based on dosimetery. This demonstrated the feasibility of this approach, and that without these adjustments, many patients would be either over or undertreated using standard doses.

Meanwhile, David J. Bushnell, MD (David) opened a Phase II trial of the commercially available compound ⁹⁰Y-edotreotide (Novartis; also known as SMT 487) in patients with SSTR positive metastatic tumors (NCT03273712). This trial opened in 2001 and included 18 international sites. Several of the group’s earliest publications were based on observations made on the Iowa patients in this trial, where patients received 120 mCi ⁹⁰Y-edotreotide for 3 cycles, every 6–9 weeks. In 2003, David reported on the hepatotoxicity of ⁹⁰Y-edotreotide in 21 patients. Only 4 of 15 patients with liver metastases had liver enyzme elevation (12 had “diffuse” or >25% liver involvement), suggesting that this PRRT exposure was safe in most patients even with extensive liver involvement.(21) The same year, David reported on a scoring system of responses in these 21 patients.(22) This took into account symptoms, Karnofsky scores, weight changes, and change in health status, where scores could range from −4 (if all four criteria worsened) to +4 (if all improved); favorable responses were considered for scores +2 to +4, stable was −1 to+1, and progression when scores were −2 to −4. Using this scale, 14 of 21 patients had favorable responses, 5 were stable, and 2 had progression. The following year David published a study of the renal protective effects of a commercial amino acid solution in 37 patients receiving ⁹⁰Y-edotreotide.(23) The solution was renal protective, but 62% of patients had emesis, which was likely due to the mixture of several amino acids in this solution. The group later switched to an infusion of just lysine and arginine with significant improvement in symptoms and similar renal protection. The final results of the Phase II trial were published in 2010 by David, where Iowa accrued the largest number of patients in the study.(12) Here 67 of 90 patients (74.4%) had stable disease or some degree of response, and most adverse events were reversible GI symptoms thought to be related to the amino acid solution used to protect the kidneys.

As these trials completed, there was a period of several years where we could not give PRRT at Iowa, between 2006 through 2011. Tom and Sue understood the value of these treatments in NET patients with progressive disease on somatostatin analogues (SSAs) from the European and our own experience with these agents, and many patients were sent to several centers in Europe where they could be treated, predominantly in Basel, Switzerland (⁹⁰Y)(24) and Rotterdam, the Netherlands (¹⁷⁷Lutetium (Lu)).(25) Tom had learned from his European colleagues that this treatment was likely more effective in smaller tumors and when there was less percent liver replacement.(24, 26, 27) Consequently, many patients coming through the clinic were referred to Jim to discuss cytoreduction of their tumors rather than having PRRT, which could be saved for a later time. PRRT started up again in 2012, with the receipt of an R01 grant by Sue and Yusuf on “Image-guided dosimetry and Therapy of NETs”. This used ⁶⁸Gallium (Ga)-DOTATOC scans to select patients who would benefit from ⁹⁰Y-DOTATOC therapy, and INDs from these clinical trials were made available for new drug applications (NDAs) in order to make these tools broadly available to patients in the United States.

Dual Radionuclide Therapy

Another interest of the group was dual therapy of radionuclides to treat NETs. Mark Madsen, PhD published a theoretical paper based on using ¹³¹Iodine (I)-MIBG and ⁹⁰Y-DOTATOC together for NETs.(28) The former binds to norepinephrine transporters (present in over half of patients with SBNET) and the latter binds to SSTRs. They showed that giving both together could significantly increase the tumor dose over that of either agent given alone (50% higher for ¹³¹I-MIBG and 90% for ⁹⁰Y in their model) while staying within dose-limiting toxicity range for the kidney (mostly affected by ⁹⁰Y) and bone marrow (affected more by ¹³¹I-MIBG). Sue and David received R21 funding from 2008–12 to study dual isotope radionuclide therapy with ¹³¹I-MIBG and ⁹⁰Y-DOTATOC with the idea that combination radiotherapy might be an effective strategy for treating children and young adults with neuroblastoma and NETs. This grant also introduced the use of dosimetry to determine patient-specific doses of the radionuclides to improve efficacy and reduce side effects. They published a prospective study of 10 patients with nonoperable metastatic SBNETs, who each had ¹³¹I-MIBG and ¹¹¹In-pentetreotide scans performed.(29) Six patients showed uptake on both scans and dosimetry was used to calculate doses of ¹³¹I-MIBG and ⁹⁰Y-DOTATOC that would be hypothetically given to each patient. They concluded that half the patients would be eligible for dual therapy, and that a Phase I trial should be performed next.

The Advent of SSTR PET/CT Imaging in the USA

Another important contribution to the clinical management of patients with NETs came from replacing standard ¹¹¹In-pentetreotide SPECT scans with the improved resolution, safety, and accuracy of ⁶⁸Ga-DOTATOC-PET imaging. Sue received the IND for ⁶⁸Ga-DOTATOC in 2011, and her protocol received IRB approval in March 2011 to prospectively review the reproducibility and safety of ⁶⁸Ga-DOTATOC scans (NCT01619865), since they were not FDA-approved in the Unites States at this time. ⁶⁸Ga was synthesized from ⁶⁸Ge generators, and linked to DOTA tagged Octreotate molecules. The half life of ⁶⁸Ga is only 68 minutes, requiring that new batches of isotope had to be generated the day of the PET scan. Imaging studies began in June 2012. A trial comparing ⁶⁸Ga-DOTATOC to ¹¹¹In-pentetreotide SPECT was conducted under clinical trial NCT01869725 in 2013. The reproducibility of imaging and SUVs of target lesions were compared between PET and SPECT scans, demonstrating excellent correlation (within 25%).(30) The safety and accuracy of ⁶⁸Ga-DOTATOC scans in 26 adults and young children was published in 2017 where they reported a sensitivity of 88% and specificity of 100%.(31) A third trial examined whether there was a change in management of patients with NETs based on ⁶⁸Ga-DOTATOC scans (NCT01619865). This prospective trial sent questionnaires to clinicians taking care of patients with lung, pancreatic, and small bowel NETs. The results of the ⁶⁸Ga-DOTATOC scans led to major changes in management in 54 of 114 patients (47%), minor changes in 5%, and no change in 47%.(32) Our group also reported that ⁶⁸Ga-DOTATOC PET/CT identified the primary site of NETs in 38% of patients presenting with metastases with an unknown primary.(11) After 4 years of effort and over $400,000 in expenses (with support from the Margie and Robert E. Petersen Foundation), the 1300-page new drug application (NDA) was submitted to the FDA and ⁶⁸Ga-DOTATOC imaging for localization of somatostatin-receptor positive NETs was approved in 2019.(33)

Clinical Consensus Conferences at Iowa in 2017 and 2020

Jim served as NANETS Vice Chair/Secretary from 2016–2018 and Chair from 2018–2020, and with the Board decided to update the previous small bowel (SBNET) and pancreatic (PNET) guidelines from 2010(34, 35) and 2013.(36) Planning for the first meeting focused on developing medical and surgical guidelines for the management of SBNETs. began in January 2016 within the NANETS leadership, and over the next few months areas of controversy were identified and questions and topics to be addressed were prepared. Different consensus models were considered, including the Delphi process and nominal group technique, and a variation of the latter was selected as described below.

To make the conference possible, NANETS worked to get sponsorship from industry to help underwrite expenses, and Sue was also able to secure administrative resources from the Iowa NET SPORE. The course Chairs were designated as Jim (for the surgery section) and Jonathan Strosberg, MD (for the medical section), and 30 faculty agreed to participate. Questions were distributed in advance to collect input and to select the most important topics for research and discussion. The list of participants included many of North America’s experts in NET surgery, medical oncology, endocrinology, pathology, interventional radiology, and nuclear medicine. Each participant was assigned 1–3 questions and delivered a short talk with the rationale for the different points of view to be discussed, with key references examined for each question. All references for all questions were made available to each participant ahead of the meeting. The physicians were separated into sections focused on Surgical and Medical questions, with 7 broad categories and 22 subtopics for the Surgical section, and 8 categories and 22 subtopics in the Medical section.

Each subtopic was presented by one of the panelists to their group, followed by discussion within the groups on the first afternoon, and the following morning votes were taken and responses recorded for each group. In the afternoon, the Surgical section presented their questions, responses and rationale to the Medical section, where the Medical group could raise issues they thought were important to the question for further consideration. Then both sections voted on the Surgical questions. ˇhe process was reversed with the Medical section presenting their questions and responses to the Surgical section, with discussion followed by a vote. After the conclusion of the meeting, each participant was responsible for writing a several paragraph, informed discussion of 1–2 questions including key references. These were sent to the leaders of each section, who assembled them, took the voting into account, and performed final editing to create a consistent manuscript. These draft versions were then circulated to each participant in the Surgical and Medical sections for review and further comment, then were re-edited and re-circulated for final approval.

The end result was two manuscripts which represented expert opinions of the group, since evidence-based guidelines are challenging when most data are derived from retrospective series. These 2 papers were submitted to Pancreas, the official journal of NANETS at that time, and were published in 2017.(37, 38) The Surgical paper has been cited 256 times at the time of preparation of this manuscript, and the Medical paper 222 times. A similar consensus conference was arranged on “The Management of Pancreatic Neuroendocrine Tumors” in Iowa City on July 19–20, 2018, with Jim serving as Chair of the Surgical section and Thor Halfdanarson, MD as Chair of the Medical section. The format was the same as used for the SBNET meeting, with presentations within Surgical and Medical sections and voting, followed by presentation to the other group for input. This culminated in the publication of 2 papers in Pancreas in 2020,(39, 40) with the Surgical paper being cited 238 times and the Medical paper 108 times.

Current NET Clinical Practice at the Iowa NET Clinic

Current Practice of Surgery

Tom was a strong proponent of surgical resection and debulking of neuroendocrine tumors. He challenged Jim to push the envelope on removing as much disease as possible in these patients. What follows below are the surgical perspectives that Jim developed after decades of work with Tom and Joseph Dillon, MB, BCh (Joe).

The primary tumor is the source of nodal, liver, distant, and peritoneal metastases. Tom believed that removing the primary tumor “turns off the spigot”, removing the site of origin of future metastases. This could potentially even be helpful in patients with liver metastases that cannot be effectively cytoreduced, because most patients eventually die of liver replacement.(37, 41, 42) If the primary tumor is left in place, it can also continue to shed metastases and increase liver tumor volume. Numerous studies from large databases have shown improved survival of patients with primary removal even when there is metastatic disease versus leaving the primary tumor in place.(43, 44) This is a controversial topic because these studies likely have selection bias in whose tumor gets resected, and others suggest this approach may not make a difference in asymptomatic patients.(45) Not resecting the primary is worth considering in asymptomatic patients, and especially those with significant medical comorbidities or high volume liver replacement. However, most patients are symptomatic,(46) and in the case of SBNETs, patients may eventually develop obstruction, bleeding, mesenteric fibrosis, or peritoneal carcinomatosis if the primary is left in place. Emergency operations for bowel obstruction are never as thorough as elective resections; they frequently miss additional primary tumors and the nodal dissections performed are usually very limited. A point-counterpoint discussion on this topic was recently published and covers the main points of each argument.(47, 48) There are several important considerations when it comes to removing the primary tumor(s). First, most patients have multifocal disease that will be detected upon careful palpation of the entire small bowel. We found that 56% of patients had multifocal primary small bowel tumors in 107 consecutive SBNET cases, the largest number being 129.(49) Most of the time, the multiple tumors are relatively close to one another and can be removed with a single bowel resection. When there are lesions widely separated which might require removing a lot of bowel, we may just resect small primary tumors without their associated mesentery if they are <3–5 mm in size. We measure the length of the small bowel at each operation and record the sites of each lesions we can make informed decisions regarding the extent of bowel resection. We reported a mean small bowel length of 530 cm, that only one patient had a tumor within 100 cm of the ligament of Treitz, and that 72% of patients had tumors within the terminal 100 cm of the small bowel. Although the laparoscopic approach to removing these tumors has been gaining in popularity, it is still important to palpate the entire bowel through the incision used for the anastomosis to make sure to not miss additional primary tumors.

It is also important to remove involved mesenteric lymph nodes at the time of bowel resection. These can be the source of future metastases, and when present, can also contribute to a mesenteric fibrotic reaction, narrowing of the SMV, and abdominal pain from impaired mesenteric outflow. The majority of these nodes are along the segmental vascular branches supplying the primary tumor, and therefore can be removed with high ligation of the segmental vessels to the portion of bowel harboring the primary tumor(s).(50) However, it is not uncommon that nodes extend even further cephalad along the main trunk of the SMV and SMA, which can be seen on the preoperative CT scan or on a DOTA-PET scan. In many instances, these nodes can be dissected off these larger vessels, but this needs to be done very carefully so as not to compromise inflow or outflow to the bowel. Sometimes these nodes completely encase the mesenteric vessels and are extremely hard and calcified, and a safe plane of dissection cannot be found. In these instances, it is safer to transect the segmental vessels close to their origin by cutting through the nodal mass and leaving the proximal part of the mass in place. One must be aware of possible collateral vessels and try to preserve these wherever possible. Since NETs grow slowly, even patients with unresectable nodal disease can have long-term survival, so compromising blood flow to the remaining bowel may be worse than leaving tumor behind. These tumors have the potential to cause future liver metastases, but this may be an indolent process, and patients can still do very well. It is important to remember that it is not acceptable to lose an SBNET patient at surgery because they may live for years without surgery.

In SBNETs, there are other frequently involved nodes, including aortocaval, left pararenal, retroduodenal, hepatic artery, crural, pericardial, mediastinal, and left supraclavicular nodes. It is unclear what the benefit of resecting these nodes isand many do not cause local problems. We will often try to remove retroperitoneal and peripancreatic/hepatic nodes, especially if they are easily accessible. Getting to pararenal and aortocaval nodes can be difficult and time-consuming, and it usually hard to remove all of the involved nodes from these locations. For larger pericardial nodes, we may open the diaphragm from below, pull them down and dissect them out, trying to stay in the mediastinum and out of the pleural space. Small retrocrural nodes can be hard to find, and exploring the neck for supraclavicular nodes with a high potential for chyle leak generally presents more risk than reward.

General considerations in PNETs begin with the site of the primary tumor, its size, and whether it is functional or non-functional. Larger head lesions will require pancreaticoduodenectomy, which is also effectively removes the regional nodes. Larger lesions in the body or tail require distal pancreatectomy with splenectomy, which also yields a large number of nodes. Nodes along the hepatic artery should be dissected out during open procedures, especially if there is uptake on preoperative DOTA-PET scan. Preoperative CT and PET scans are important to look for other sites of disease, as these can be removed at the same time if they are known about. Smaller lesions in the pancreatic body and tail can be removed laparoscopically, which allows for quicker postoperative recovery, but nodal recovery will generally be lower. Preserving the spleen is preferred if the blood flow can be preserved through the short gastric vessels.(51) Multifocal tumors are common in MEN1 patients and special considerations include enucleating smaller lesions, which is also an option for small head and uncinate lesions, or those at least several mm away from the pancreatic duct. Pancreas surgery has a higher risk of complications than small bowel surgery, so small lesions (<1–2 cm) can often be safely followed if they are non-functional.(39)

Since most of the patients in our clinic present with metastatic disease, Tom and Jim had had to decide upon the approach for patients with liver metastases. Treatment with SSAs or biologic therapy is unlikely to reduce tumor volume, but embolization is an option in many patients. One of the biggest challenges surgically is that most patients have many, bilobar metastases, and therefore anatomic resections are usually inadequate and will remove large amounts of uninvolved liver. Another issue is that even if >90% cytoreduction is achieved, recurrence rates are 94% at 5 years,(52) often due to the presence of micrometastases which may not be seen on imaging.(53) Therefore, achieving R0 resections is usually not possible. For these reasons, cytoreduction of as much tumor as possible seems to be a reasonable approach, as long as certain thresholds of debulking can be achieved. For decades that threshold was considered to be 90%,(54, 55) but there were no data to back that up. More recently, our group and others have shown that achieving 70% cytoreduction can also greatly extend survival.(56–59) We have found that resection of large metastases and enucleation of smaller lesions on the liver surface can be achieved safely. Lesions deeper within the liver that would require larger resections can be treated by microwave ablation and >20 lesions can be treated within a few hours.(59) Therefore, it has been our strategy to remove the primary tumor, regional lymph nodes, and to cytoreduce liver metastases when we believe we can remove >70% of disease. Patients are then treated with SSAs until they meet RECIST criteria for progression, then PRRT may be given. This strategy evolved not only to reduce hormone levels and improve symptoms, but also to reset the clock and improve survival, and to improve the potential efficacy of PRRT, which may work better when there is a lower burden of disease.(24–27)

Peritoneal disease can be another difficult problem to treat surgically, and occurs most commonly in SBNETs when they have grown through the bowel wall (T4 tumors), shedding tumors into the peritoneal cavity. This is another argument for not leaving the primary tumor in place. These patients often have disease in the pelvis, on the diaphragm, in the msesentery and omentum. Pelvic lesions frequently involve the rectosigmoid colon and can lead to large bowel obstruction. Adding rectosigmoid resection to large debulking procedures is sometimes necessary, but increases the risk of the procedure. The presence of many tumor nodules on the mesentery and between bowel loops can lead to obstruction of the bowel, and can be very challenging to fix. Sometimes this requires removing a large amount of small bowel and putting the patient at risk for short gut syndrome. When venous return is compromised, patients may have significant symptoms of cramping and post-prandial pain. Unfortunately, PRRT may not help much in this situation, and can even make things worse.(60) When possible, removing as many tumor nodules as one can, and ablating the many small lesions with cautery or argon beam is a reasonable strategy to try to reduce future complications. Hyperthermic intraperitoneal chemotherapy has been tried in these patients, but did not change overall survival,(61) and therefore is not generally done.

Current and Future Nuclear Medicine Approaches

DOTA PET/CT imaging has a central role in management of NET patients at the University of Iowa. This includes staging and restaging of the disease and identification of the primary tumor, consistent with the published appropriate use criteria.(62) DOTA PET/CT is also used to complement cross-sectional imaging in assessment of response to therapy, particularly if the disease is not measurable by RECIST (such as bone dominant disease). We did not find a high yield for DOTA PET/CT in diagnosis of NETs in patients with symptoms suspicious for NET and reserve the DOTA PET scan for select cases particularly with findings on cross-sectional imaging. We employ ¹⁸F-Fluorodeoxyglucose (FDG) PET/CT in high-grade NETs or in patients with suspected migration to higher-grade NETs, particularly if they are being considered for PRRT. This helps us to identify patients with significant disease burden that is somatostatin receptor negative which would not be expected to respond to PRRT. It also assists with the choice of tumor nodules to biopsy if there is concern with increased tumor grade. Although the interpretation of DOTA PET is primarily qualitative, standardized uptake value (SUVmax) of select lesions are recorded to help with the discussion of PRRT eligibility. Although there is no consensus on the SUVmax threshold to predict favorable response to PRRT, lesions with SUVmax of 15 or higher generally respond favorably to PRRT.(63, 64)

We offer PRRT to patients with NETs which have progressed on SSAs, following the NETTER-1 study and consistent with National Comprehensive Cancer Network (NCCN), North American Neuroendocrine Tumor Society (NANETS), European Neuroendocrine Tumor Society (ENETS) and other guidelines.(65, 66) In addition to imaging-based progression, clinical progression is also considered in the decision to proceed with PRRT, in view of the significant symptomatic control and the positive impact on quality of life that PRRT offers to patients with functional tumors.(22, 67) We administer a 1-liter amino acid solution containing 25 g L-arginine and 25 g L-lysine as part of PRRT for renal protection. Most patients tolerate the PRRT infusion well, although less than 5% of patients develop significant carcinoid symptoms that we treat with short-acting subcutaneous octreotide. If possible, we prefer to wait for approximately 3 hours after the injection of the radiopharmaceutical to administer the octreotide to avoid competition for SSTR2.

We believe that patient-specific dosing considering the radiation dose to normal organs (i.e. dosimetry) may be more effective and safer than administration of a fixed dose of the PRRT. Our group and others have shown that many patients can safely receive higher than standard fixed doses of PRRT if carefully planned with normal organ dosimetry.(20, 68) As we have access to only standard fixed doses of PRRT, we currently employ dosimetry in patients with borderline kidney function (creatinine clearance 30–50 ml/min) to determine if they will be able to tolerate the standard dosage or require a dose modification (to limit the kidney to 23 Gy). Dosimetry initially required multiple imaging visits to determine the renal elimination rate, but we have found that accurate dosimetry can be achieved with imaging at one time point (96 hours post-therapy for ¹⁷⁷Lu-DOTATATE).(69, 70) Randomized trials comparing outcomes and safety of dosimetry-based treatment vs. fixed dose PRRT will be needed for widespread adoption of dosimetry procedures.

The next generation of promising radiopharmaceuticals for PRRT are alpha emitters. Alpha particles are Helium nuclei with a +2 charge with an approximately 10,000 times larger mass compared to beta particles, resulting in a significantly higher linear energy transfer. Direct interaction of alpha radiation with DNA causes double strand breaks that cannot be repaired, resulting in a significantly higher cell kill compared to beta particles.(71) Initial Phase I studies with ²²⁵Ac-DOTATATE and ²¹²Pb-DOTAMTATE have shown promising response rates with acceptable toxicity. At the University of Iowa, we are participating in multi-center trials of ²²⁵Ac-DOTATATE in patients previously treated with PRRT (NCT05477576) and ²¹²Pb-VMT-alpha-NET (NCT06148636) in PRRT naïve patients. We also have an NIH-funded study evaluating the imaging and dosimetry of ²⁰³Pb-VMT-alpha-NET and a Phase I trial of ²¹²Pb-VMT-alpha-NET in patients who have previously been treated with PRRT, escalating the absorbed dose to the organ rather than administered activity (NCT06148636, NCT05111509).

Current Role of the Endocrinologist in the Iowa NET Clinic

The relative roles of endocrinologists (and gastroenterologists) in NET patient care and in NET professional organizations (ENETS and NANETS, respectively) differ significantly between Europe and North America. ENETS was founded mainly by endocrinologists and gastroenterologists and these groups have predominated in their Boards of Directors, Society Chairs and in directors of the ENETS Centers of Excellence. Medical oncologists founded NANETS and predominate as Directors and Society Chairs, consistent with their dominant society membership numbers. These facts make it all the more remarkable that two endocrinologists (Tom and Dr. Vinik) should have received lifetime achievement awards from NANETS for their leadership roles in NET patient care and research.

Many aspects of the NET specialist’s work do not need specialty endocrine training. However, it is helpful to have an endocrinologist involved in the management of some functional tumors. These would include insulinoma-related hypoglycemia, glucagonoma or Cushing’s related hyperglycemia, severe hypercortisolism, and some of the endocrine neoplasia syndromes with potential for malignant and benign secretory lesions (e.g., MEN1, pheochromocytoma/paraganglioma related syndromes). The most common drug therapy for low grade NETs is a hormonal therapy (SSAs) and managing the dosing and side effects of short and long acting SSAs is well within the purview of endocrinologists. Use of SSAs is obviously within the expertise of medical oncologists also, but the oncologist plays a dominant role in advanced NETs and higher-grade disease.

Upon application to come to our clinic, all patients’ tissue samples are reviewed by our expert NET pathologist, regraded and assessed for SSTRs and other marker expression. Patients with high grade or poorly differentiated neuroendocrine carcinoma (NEC) are triaged immediately to the medical oncologist, who determines the need for additional staff to consult with the patient. Patients with lower grade well-differentiated NETs are usually triaged by the endocrinologist to determine appropriate imaging, testing and consultations.

Some patients come to our clinic after having been seen at other high-volume centers. Many have come from their community medical oncologist who has appropriately referred patients with these rare cancers for evaluation and management with the range of therapies available at the University of Iowa. Other patients have themselves sought out a center of expertise because they realize the lack of clinical experience in their own practitioners. Spending time explaining the unique features of NETs and discussing the full range of therapies, including research trials, and assisting in choice of next therapy are features which many patients identify as reasons that they are happy to have come a distance to the University of Iowa NET Clinic. The initial explanation could be given by any expert in NETs, but has developed at Iowa as a frequent role for the endocrinologist for patients with low-grade disease and for the oncologist in those with high-grade well-differentiated or poorly differentiated tumors.

Up to 20% of patients coming to our NET Clinic for an initial visit require appropriate detailed education about their condition, a careful review of the specific characteristics (grade, size, infiltration) of the tumors, along with appropriate initial imaging and resection, but then require no further management. These patients would include those with small (<1cm) rectal, Type 1 gastric, duodenal and appendiceal NETs,(72–74) and require appropriate detailed education about their condition. They are generally seen by our endocrinologist (but could be seen by any experienced NET clinician) to allow the oncologist to focus on those with higher grade or stage NETs. There is another group of patients with very bothersome symptoms, some of which could be consistent with an underlying NET. Many have episodic diarrhea, flushing and multiple other symptoms. Some also have abnormal plasma or urinary NET markers. Evaluation of these complex patients without a biopsy-proven NET diagnosis is generally performed by our endocrinologist.

Pulmonary NETs have been relatively understudied historically. There are less intrathoracic NETs than intra-abdominal NETs. The founders of ENETS and NANETS were gastroenterologists and GI oncologists, respectively. While understanding that many GI NET experts will see patients with lung NETs, we find it helpful in our clinic to have a NET expert who is not GI or lung-focused by training, but who works with GI oncologists, lung oncologists, GI and thoracic surgeons, gastroenterologists, and pulmonologists, routinely attending Tumor Boards for both GI and pancreatic tumors as well as lung tumors. In our clinic, the endocrinologist has adopted that role (although there are multiple other models for appropriate integration of the Lung and GI/Pancreatic NET practices). Additionally, the endocrinologist is a key member of a different team of surgeons, oncologists and endocrinologists caring for patients with pheochromocytoma and paragangliomas. This allows us to offer expert management services for patients with all forms of NETs within the same clinic setting.

NETs remain a rare disease group and access to knowledgeable practitioners in the USA and elsewhere is lacking. Training of new NET experts has been an area of continued focus at NANETS, ENETS and many of the patient-based organizations (e.g., Healing NET Foundation). Clinical NET experts can potentially come from multiple related fields – surgical oncology, medical oncology, endocrinology, gastroenterology, internal medicine, or cardiology, as long as they are practicing in a multidisciplinary care model. There is a role for multiple NET expert providers (including endocrinologists) to allow each provider more time to focus on their unique skills. Additionally, maintaining a broad specialty base to develop NET specialists from increases the available pool of trainees to take care of this patient group.

Current Medical Oncology Practice for patients with NETs and NECs

As a GI cancer focused medical oncologist at the University of Iowa, Chandrikha’s practice encompasses a large variety of patients with other GI cancers in addition to NETs. While cancer management has become increasingly multidisciplinary, the management of NETs perhaps shines as the textbook example of successful interdisciplinary collaboration. The NET clinic at Iowa is set up to facilitate this multispecialty approach in every individual patient. A typical new patient visit to Iowa involves a consultation with the surgical oncologist, medical oncologist and endocrinologist. The pathology has been reviewed and the required imaging interpreted by key NET experts within the respective divisions. This allows the patient to experience a comprehensive approach to the cancer even on their first visit and a recommendation plan based on a real time mini-tumor board within the clinic itself.

In the early 2000s, when the NET clinic was in its infancy at Iowa, drug therapy options for patients with advanced or metastatic NET were limited. Early clinical trials with chemotherapeutic agents such as 5-Fluorouracil, Streptozocin or therapy with interferons had found a place in the treatment paradigm.(75, 76) However, these options were limited in their efficacy and associated with significant toxicity. Beyond SSAs, the medical oncologist had limited therapies to offer patients. As the anti-proliferative activity of SSAs became clear in midgut low grade NETs via the PROMID study,(3) interest in other higher affinity SSAs grew. Iowa was one of the select centers in the USA to enroll patients in a Phase II trial of Pasireotide, a novel multireceptor targeted SSA with high binding affinity to SSTR subtypes 1,2,3 and 5 in patients with advanced NET whose symptoms were refractory to octreotide LAR.(9) With the CLARINET study showing antiproliferative activity of another SSA (Lanreotide), in a broader group with low-intermediate grade enteropancreatic NETs, another tool became available to clinicians to slow the progression of NETs.(77)

In 2011, Everolimus and Sunitinib, drugs targeting the Mammalian Target of Rapamycin (mTOR) pathway and Vascular Endothelial Growth Factor receptor (VEGF), respectively, were FDA approved for the management of pancreatic NETs.(78, 79) Temozolomide, an oral alkylating agent better tolerated than streptozocin, either alone or in combination with capecitabine had also shown high overall response rates in contemporaneous Phase II trials and large case series.(80) Between 2013 and 2015, the University of Iowa also participated in the randomized Phase II trial of pazopanib, a tyrosine kinase inhibitor, in treating patients with radiographically progressive carcinoid tumors.(81) The ⁹⁰Y-DOTATOC PRRT dosimetry guided therapy trial led by Sue and Yusuf was also enrolling at the University of Iowa at the same time. Thus, the medical oncologist at Iowa had more than one FDA-approved therapy option and more than one clinical trial to offer patients, a situation that is unusual for a rare cancer like NET.

As a medical oncologist starting at University of Iowa in 2017, Chandrikha had more options to offer patients than her prior NET medical oncology colleagues (including Daniel Berg, Daniel Vaena, Nancy Sharma, and Thor Halfdanarson). Everolimus had been approved for the management of progressive grade 1 and 2 NETs including those of lung and small bowel origin.(79) The Iowa NET team had made important contributions to the seminal NETTER-1 study evaluating ¹⁷⁷Lu PRRT in progressive grade 1 and 2 small bowel NETs as a participating site,(13) which led to FDA approval in January 2018. There was a large influx of patients who had been waiting for PRRT approval. Along with Joe and Yusuf from endocrinology and nuclear medicine, a dedicated PRRT tumor board was set up in 2018 to discuss patients who may be appropriate for this therapy. This ongoing tumor board also evaluates patients for current ongoing clinical trials with alpha particle emitting theranostic agents open at University of Iowa, such as ACTION-1 (NCT05477576) and the ²¹²Pb VMT alpha PRRT trial (NCT06148636). We also reported our experience with repeat PRRT and noted a shorter progression-free survival following the second PRRT course, similar to studies published from Europe.(82)

A key role for a medical oncologist in a NET clinic is to understand the biology of the cancer to help direct therapy. Most treatment decisions in this cancer are made based on the grade and differentiation of the tumor. This is often ascertained at the time of diagnosis and in some patients may be many years prior to their first visit to a NET Center. The recognition and addition of grade 3 well differentiated NET in the WHO 2017 classification also raises the question of the role of conventional therapies like surgical cytoreduction in this group. The NET team at Iowa performed a single institution retrospective review of surgery in grade 3 NETs and NECs.(83) We noted that the median overall survival for resected G3 NETs and NECs exceeded historical non-surgical series, making an argument for careful patient selection for such therapies. It is also being increasingly recognized that grade is not a constant, especially in a subset of patients where a higher-grade tumor can evolve from a previously indolent behaving NET. Thus, repeating a biopsy to reassess the grade of the tumor based on a more aggressive clinical course is a key insight that medical oncology can provide to help direct therapy.

As patients with poorly differentiated NECs are often metastatic at diagnosis with a poor prognosis, the role of conventional NET therapies like surgery, PRRT or embolization is limited in this aggressive subset. Thus, in our NET clinic, they are primarily managed by medical oncology. Beyond first line platinum-based chemotherapy, options with demonstrated efficacy are limited in this subgroup. Thus, many patients are enrolled in clinical trials. The use of immunotherapy in high grade NECs is also evolving with some studies showing its efficacy in this space. In the era of precision oncology, next generation sequencing of tumor DNA, especially in high grade NETs and NECs may also pave the way for novel therapeutics.

With the availability of more than one therapeutic option comes the issue of sequencing those therapies and finding the optimal treatment for the individual patient. The appropriate sequence of therapy in NETs remains unclear. Most of the studies addressing the optimal therapeutic sequence in this cancer are retrospective in nature and suffer from inherent selection bias. We evaluated our patient cohort that had received upfront surgical cytoreduction and then PRRT. The progression-free survival benefit of PRRT was noted to be similar both if given upfront as first therapy at progression or as a later line of therapy.(84) There is no prospective clinical trial yet that suggests a particular sequence of therapy is preferential and associated with an improved overall survival. In the absence of compelling evidence for a particular sequence, the medical oncologist plays a key role in facilitating a balanced discussion weighing the pros and cons of all available therapeutic modalities. As many patients with metastatic NET may be asymptomatic from their cancer itself, it is pertinent for the team and especially the medical oncologist to consider the burden of any proposed therapy on the patient’s quality of life and involve the patient in treatment decisions. While there are no established guidelines on the optimal timing of referral to palliative care service in cancer, early integration of palliative care should be considered on an individualized basis in patients with neuroendocrine tumors despite their more indolent nature. When available therapeutic options have been exhausted or the patient is no longer a candidate for NET-directed therapies, the medical oncologist along with palliative care and hospice team is also a key part of the transition towards end of life in these patients.

Advances in the Pathologic Classification of NETs

Andrew Bellizzi, MD (Andrew) joined the Pathology faculty at the University of Iowa in 2011, focused on gastrointestinal and specifically neuroendocrine pathology, where he has significantly advanced the use of immunohistochemistry (IHC) as a diagnostic and research tool. This section will describe his clinical and research efforts relatd to the NET Clinic, key advances in the diagnosis and classification of NETs since 2010, and some Iowa-developed practices for grading, assigning site of origin, and distinguishing NET G3 from NEC (reviewed in(85)).

Andrew’s initial collaboration with Tom and Jim involved his optimization of a pancreatic polypeptide IHC.(86) He then optimized an existing Iowa research IHC for somatostatin receptor 2 (SSTR2) expression using a newly available monoclonal antibody (clone UMB-1,(87)) and incorporated it into the regular laboratory workflow. Iowa Pathology has been performing this SSTR2 IHC assay on all neuroendocrine neoplasms (NENs) since 2014. Although SSTR functional imaging remains the gold standard to determine SSTR expression, knowing that a tumor was SSTR2 negative altered the interpretation of a negative SSTR PET scan. Prior to the widespread availablility of SSTR PET, Tom appreciated having the SSTR2 IHC result available for his patients’ initial visit, because of its therapeutic and prognostic value.

Andrew raised the bar for NET pathology diagnosis and reporting by rigorously incorporating the 2010 NET TNM classification in the 7^th Edition of the American Joint Committee on Cancer (AJCC) Staging Manual(88) and the updated NET classification in the 4^th Edition of the World Health Organization (WHO) Classification of Tumours of the Digestive System (the ‘GI Blue Book’).(89) He collaboratively developed a NET TNM synoptic report (i.e., cancer reporting template) and launched a subspecialized GI Pathology sign-out so that all GEP-NET surgical pathology specimens were signed out by subspecialists. Reporting was fully integrated into the Epic electronic medical record (EMR) using the Beaker AP pathology information system. The GI Pathology group at Iowa has grown and Andrew started a GI Pathology Fellowship in 2017 (two of his former fellows self-identify as “NET Pathologists”).

In the 2010 WHO GEP-NET Classification, NETs were stratified based on mitotic counting and Ki-67 IHC into G1 or G2 tumors. Tumors with a mitotic count >20 per 10 HPF and/or a Ki-67 proliferation index >20% were considered “NEC (neuroendocrine carcinoma) G3.” However, with the widespread adoption of Ki-67 staining, a subset of tumors with well-differentiated histology, mitotic counts and/or Ki-67 proliferation indices in the G3 range, (90) and a prognosis intermediate between NET G2 and NEC, was recognized. Andrew’s team reported these for years as “neuroendocrine neoplasm, morphologically well-differentiated but with a proliferation index in the G3 range.” These tumors are now considered NET G3, a diagnostic category that was initially introduced in the 2017 WHO Endocrine Blue Book(91) and more widely applied in the 2019 WHO GI Blue Book.(92) Andrew participated as a co-author on the chapter on NETs of the small intestine and ampulla for the 2019 Blue Book.

Historically, NETs were not subject to the AJCC TNM Classification, as it was well established that the biology of NETs was distinct and outcomes generally more favorable (especially in the setting of metastatic disease) than for non-neuroendocrine carcinomas. By 2010 there was sufficient epidemiologic data to construct TNM Classifications for GEP-NETs, which were published in the 7^th edition of the AJCC Cancer Staging Manual.(88) and subsequent editions have seen refinements of the NET TNM classifications. Tom was a member of the NET Expert Panel for the 8^th edition, and Andrew was a member for the 9^th edition (2024).

Elucidation of the molecular genetic landscape of NENs has provided tools to inform diagnosis, prognosis, and therapy, and Andrew has validated multiple IHCs based on these genetic discoveries. For example, the biallelic inactivation of TP53 and RB1 is a molecular genetic hallmark of small cell lung cancer,(93) and prompted Andrew to validate an Rb IHC test and to incorporate p53 and Rb IHC into algorithms to distinguish NET G3 from NEC.(94) GEP-NECs tend to combine alterations of one or both of these genes with those typical of non-neuroendocrine carcinomas arising at those sites (e.g., APC, BRAF, FBXW7).(95) In another example, Andrew validated an IHC test for Merkel cell polyomavirus large T antigen (96) because these NECs are driven by a polyomavirus or UV-light and, unlike other NECs, are highly responsive to checkpoint inhibitor therapy. (97)

Pancreatic NETs have been shown to demonstrate a high rate of inactivation of MEN1 (40% biallelic), DAXX (20–25%), and ATRX (10–15%), as well as molecular alterations leading to activation of the mTOR pathway (15%).(98) DAXX and ATRX inactivation are associated with alternative lengthening of telomeres (ALT), and loss of DAXX and/or ATRX, by IHC, and/or ALT-positivity, by fluorescence in situ hybridization, are associated with a metastatic phenotype in pancreatic NETs. These analyses are now starting to inform clinical decision making in patients with small tumors (≤2 cm).(99) Andrew validated an ATRX IHC in 2016, and simultaneously began testing all pancreatic NETs. He is currently validating DAXX IHC and is developing a chromogenic in situ hybridization assay for ALT.

Midgut and lung NETs demonstrate a lower mutation frequency than pancreatic NETs. Midgut NETs are characterized by recurrent inactivation of CDKN1B (p27) in 5–10% of tumors. These tumors also demonstrate frequent loss of chromosomes 11 and 18 and gains of chromosomes 4, 5, 19, and 20.(100–102) The most frequently mutated gene in lung NETs is MEN1 (10%), while other frequently mutated genes include EIF1AX (9%) and ARID1A (6–7%).(103) Andrew is validating an MEN1 assay and has validated one for ARID1A (which has also demonstrated utility in distinguishing amongst some endometrial carcinomas).

Next-generation sequencing (NGS) molecular assays are increasingly deployed to identify therapeutic targets. Andrew participated in the NANETS clinical guideline on high-grade GEP and Gynecological NENs which recommended that NGS and DNA mismatch repair (MMR) testing be routinely performed in NECs to identify disease-agnostic therapeutic targets, including NTRK fusions and high-level microsatellite deficiency (MSI-H)/MMR deficiency.(103) Although the Iowa group routinely uses IHC to assist in the distinction of NET G3 from NEC, Andrew has advocated for NGS testing in NET G3, both to potentially inform treatment and as an adjunct diagnostic tool.

Dhall et al demonstrated that a Ki-67 proliferation index >2% in either the primary or the metastatic site in ileal NETs was the only significant predictor of progression-free survival on multivariate analysis.(104) Based on these compelling results Andrew’s group began simultaneously testing primary, regional, and distant disease and validated these findings in 2017.(105) In 2020 the use of a whole slide scanner and analysis software in the digital image analysis for Ki-67 was optimized, validated, and implemented at Iowa.(106) This method replaced the tedious manual-counting of camera-captured Ki-67 images and inaccurate “eyeball estimates”.

Twenty percent of NETs may present as metastasis of occult origin and IHC is useful for site of origin assignment. Based on observations that polyclonal PAX8 antibodies identified pancreatic origin in NETs,(107) whereas CDX2 and TTF-1 expression supported midgut and lung NET origins, Andrew published an extensive review on the use of IHC to assign NET site of origin in NETs and NECs. (108) The algorithm he proposed and validated in a study with Jim and Tom in 2014 (Figure 2)(109), forms the basis of the clinical protocol used at Iowa today for extablishing tissue of origin. As most NETs of occult origin arise from the midgut or pancreas, the algorithm starts with CDX2 (midgut) and islet 1 and PAX6 (pancreas). The biggest developments in NET site of origin assignment in the last 10 years have been the identification of OTP as a superior marker of lung orign (2.5-times more sensitive than TTF-1) and SATB2 as a marker of rectal origin (especially important since rectal NETs often express the “pancreatic” markers, islet 1 and PAX6).(110, 111)

Figure 2:

Iowa Well-Differentiated Neuroendocrine Tumor Classifier

Up to 5% of NETs are G3 and their distinction from NECs is prognostically and therapeutically important. This distinction can be challenging based on morphology alone. Andrew developed an IHC algorithm based on the molecular genetics of NEC and his experience with two G-protein coupled receptors. The identification of “mutant-pattern” p53 staining and/or loss of Rb expression supports a diagnosis of NEC, while “wild-type pattern” p53 staining and intact Rb expression are typical of NET G3.(112) Strong SSTR2 expression favors a diagnosis of NET, though up to one-third of NECs are SSTR2-positive (sometimes very strongly so). Strong CXCR4 expression favors a diagnosis of NEC over NET G3 and is seen in about 80% of NECs; GEP-NETs, including NET G3s, show little-to-no staining. At Tom’s suggestion, Andrew developed an IHC test for CXCR4 (a promising biotheranostic target in NEC), based on the UMB-2 monoclonal antibody.(113) This test has been routinely run on all NECs since 2017 (in addition to its use in the distinction of NET G3 vs NEC).

Important Components of a Multidisciplinary NET Team: Pursuit of ENETS Certification of Excellence Designation

Recognizing the increasing incidence of NETs with multiple potential lines of therapy, but without a change in survival over the prior 30 years, a multi-national panel of experts recommended the establishment of multi-disciplinary “centers of excellence”(COE) in order to more effectively diagnose and manage patients with these rare malignancies.(114) ENETS established rigorous criteria for such centers and initiated their COE program with 6 pilot centers in 2009. It has grown to 67 centers by 2024, mainly in Europe. Long before applying for ENETS COE status, Tom modeled the Iowa NET Clinic after the early ENETS “Centers of Excellence” model criteria (Table 1).

Table 1.

Iowa NET Clinic Goals

1. ≥50 GEP NET patients/month* 2. ≥3 NET experts, each with ≥ 5 years’ experience 3. Multi-disciplinary support (e.g., cardiology, surgery, GI) 4. Radiology (MR, CT, Nuclear) and interventional specialists 5. Pathological expertise, evaluation by guidelines 6. Multi-disciplinary tumor board for all new patients 7. Therapy options: surgery, biologicals, chemotherapy, radiation, theranostics 8. Documented long term follow-up 9. Patient advocacy (nutritional, QOL programs, palliative care) 10. Translational research

^*subsequently changed to ≥80 new GEP and ≥20 new lung NETs per year.

When ENETS began to consider centers outside of Europe for COE designation, the University of Iowa, led by Sue and Tom, organized a successful application and joined Jerusalem and Melbourne as the inaugural non-European centers in 2018, followed by Sydney in 2019. Sue was the initial director followed by Joe. The University of Iowa has maintained its ENETS COE status since 2018 (Figure 3).

Figure 3:

Receipt of ENETS COE. Left to right: Eva Tiensuu Jansen (ENETS Vice Chair), James Howe, Joseph Dillon, Dermot O’Toole (ENETS Chair)

A principal reason for the ENETS COE program is to enhance patient care and outcomes. Many institutions in the USA have a breadth of expertise in management of patients with NET. However, how does a patient who is dealing with a new diagnosis or has come to doubt that they are on the right therapeutic path, find quality care with an ability to employ a full range of therapeutic options? These patients may seek care at a prestigious cancer center (e.g., Memorial Sloan Kettering Cancer Center, the Mayo Clinic, MD Anderson Cancer Center), which has all the components needed for excellent NET patient care. For patients unable or unwilling to go to those institutions, are there other options to find excellent care for their NETs? Currently, this crucial patient need is partially satisfied by the NET patient care organizations (e.g., Neuroendocrine Cancer Awareness Network, Carcinoid Cancer Foundation) that advise patients about NET experts in their vicinity. However, there are significant differences between a physician with NET expertise and a coordinated, multidisciplinary NET Center. The University of Iowa NET Center, originally under the leadership of Tom and Sue, continues to believe that our patients deserve to have confidence that they are receiving care in a place with the required coordinated expertise to optimally assist them. In the absence of a formal US-based NET Center accreditation body, the Iowa NET program adopted the clearly described standards of the ENETS COE framework.

The fundamental aspects of the NET COE are not unusual for any clinic seeking to achieve high quality patient care. However, moving from informal adoption of standards through development of a formalized and coordinated program, with a responsibility to review data annually and pass a rigorous outside audit, is a challenge requiring a level of institutional support, time commitment from clinic leadership, and cost. The fundamental requirements for certification by ENETS include: a sufficiently large clinic throughput (≥80 new patients with GEP NETs and ≥20 new patients with lung NETs), documented and formalized ‘contracts’ or relationships with a range of key providers, clear standards of practice (SOP) for all specialties involved in NET patient care, multiple personnel who are clearly experts in NET patient care, a formally documented multidisciplinary discussion about every new patient who is seen in the NET clinic, and a demonstrated commitment to NET research. Beyond the core clinician group, there are specifically identified individuals in Nuclear Medicine, Interventional Radiology, Gastroenterology, Cardiology, Cardiac Surgery, Thoracic Surgery, Radiology, and Pathology, who are true NET experts or have a high volume NET practice and a formal commitment to supporting the NET Clinic. This clinical effort is intertwined with related basic, clinical or epidemiological research.

All of these fundamentals for certification are open to scrutiny during the audit process and in-person review. Annual data submitted to the auditing group include the following patient data: numbers and diagnoses of new and return clinic patient, numbers discussed in Tumor Board, numbers of surgical procedures and types of operations performed with surgical morbidity and mortality, numbers and morbidity of interventional radiology procedures and PRRT, numbers of patients receiving specific tumor directed therapies and chemotherapies with mortality and morbidity information, and numbers of GEP NET pathology specimens assessed (and the same for lung NETs, if certified). Also reviewed are publication records, and patient satisfaction surveys. These data are audited annually by a centralized professional audit company and a formal report is issued. An on-site audit takes place every 5 years at least. The exhaustive on-site audit involves one audit company professional and one senior European NET expert. They attend a Tumor Board, listen to presentations from all NET Clinic senior staff, interview senior staff of the center, interview associated staff (Cardiology, Gastroenterology, Pathology, Interventional Radiology, Nuclear Medicine), review the clinic space and randomly review a sample of charts for adherence to ENETS guidelines and consistency with submitted data.

Institutional support is required for the annual audit fees and the larger cost of the 5 yearly in-person audits. The in-person audit cost is significantly higher for non-European than European sites because of the extra travel and time required of the auditors. Preparation of both the annual reviews and especially the in-person audit requires a large time commitment by clinic and administrative staff, which requires institutional support. While the availability of EMR has allowed for straightforward data mining, the deficiencies of the clinical EMR, when used for the purposes of generating accurate patient data on specific therapies, morbidity and mortality, etc., become evident. The data recovered from any text word search require time-consuming data cleanup for these audits. The data frequently require cross referencing review of Tumor Board lists and even New Patient lists for the primary NET clinicians to ensure completeness.

It is clear that administering a program like this is a huge undertaking for a professional organization. Perhaps because of this burden, ENETS has recently narrowed the scope of their program by not accrediting any more non-European centers over the next 3–5 years. They are also working with the ERN-EURCAN, a European Union-funded agency focused on rare cancers (including NETs), to develop a unique NET accreditation and certification program in Europe. ENETS plans to “support non-European NET societies to establish and maintain their own national audit programs”.Thus, we in North America cannot rely on the ENETS COE structure to develop a broader program here (although we can benefit from their experience and their development of criteria for excellence).

Setting up a COE program in the USA has been discussed but has not been initiated, either by NANETS or by patient organizations. There are precedents for centers of excellence programs organized by patient care groups. One such example is the VHL Alliance designations of Comprehensive Clinical Care Center or Clinical Care Center program. Another example of a COE program developed by a patient advocacy group is the PheoPara Alliance (PPA) Center of Excellence program. In 2020, the PPA undertook the demanding task of setting up a COE program to benefit patients with pheochromocytoma or paraganglioma (these NETs are not covered in the ENETS COE program). The University of Iowa received the designation of Clinical Center of Excellence (CCE) in 2021 recognizing high-quality, multi-disciplinary adult and pediatric care and facilitation of pheochromocytoma/paraganglioma-related research. Additionally, there is a designation of Clinical and Research Center of Excellence (CRCE), which recognizes centers that provide all the qualities of CCE but also have a related comprehensive research program.

The process for achieving the PPA COE designation involved submission of documentation supporting our multidisciplinary and coordinated expertise in the field for initial review by members of the Medical Advisory Board and subsequent video presentation and interview with 2 eminent experts in the field, a patient representative, and PPA administrative staff. There are now 11 Clinical Centers and 4 Clinical and Research Centers in the USA and Europe.

As with the ENETS COE, there are many centers in the USA and elsewhere which have the expertise to achieve the COE distinction for care of patients with pheochromocytoma paraganglioma, but have not applied. Some of these are “brand name” medical centers where patients are likely to get excellent care for most malignancies, but patients are otherwise unclear about where they can find true multidisciplinary expertise for their disease. The PPA program is younger and smaller in scope than the ENETS COE and will need further development to keep the designations meaningful for patients, as expertise in any center changes over time. Annual central review of individual COE clinic data and intermittent re-audits are not yet fully developed. It is unclear how the program is funded since there are as yet no fees for application and thus it is may become significantly burdensome for the PPA to administer.

It is evident that these programs have significant challenges, both for the COEs and the adjudicating body. They are expensive and time-consuming for the organization to run. To maintain validity there must be a high level of scrutiny at sufficient frequency to be able to downgrade programs that have lost the expertise needed to maintain them. Without adequate support and regular quality control reviews, the designation of COE loses its qualitative and quantitative impact on patient care. However, when appropriately executed the COE programs fulfill a critical need that patients with rare diseases will benefit from.

Based on our experience at Iowa, the goal of developing a COE for patients with NETs starts with one or more passionate, committed, persistent individuals and a long term goal of achieving a set of standards (such as those put forward by ENETS, see Table 1). There was no specific interest in NETs at Iowa prior to Tom and Sue’s arrival here in 1999 and it took almost 20 years to achieve the first in the nation SPORE in NET research and ENETS COE designation. Tom and Sue strategically recruited faculty over time, changing the trajectory of many professional lives. Tom and Sue benefitted from some administrative support, but this generally came after they had demonstrated their commitment and progress.

The integrated multidisciplinary care model initiated by Tom at the Iowa NET Clinic was developed to be consistent with the ENETS COE model. In our current practice at Iowa, 3 principal clinicians (Jim, Joe and Chandrikha), each with a deep understanding of NETs and with some complementary expertise, work together in one clinic space allowing efficient patient review by 1, 2, or 3 physicians and informal consultation with other key providers for patients who are only seeing 1 or 2 physicians in clinic. Working in one clinic space is an important component of the integrated clinic concept (but did require administrative support). Importantly, besides direct interaction of clinicians in one clinic space there is also direct interaction of the critical Clinic Nurses assigned consistently to the three senior clinicians. Additionally, all visit scheduling for the three clinicians is handled by a small group of onsite schedulers who are used to dealing with the specific testing, imaging and scheduling patterns for the clinic. Every patient with diagnosed NET attending the clinic is invited to join the NET patient Registry, which facilitates recruitment of these patients to research trials and review of medical histories for research purposes. It is important that the core physician group be a vocal presence at relevant tumor boards in GI and Lung (and Endocrinology or Otolaryngology for pheochromocytoma paraganglioma) and seek opportunities to give talks in other relevant divisions and departments. This enhances a centralization of referral to designated physicians. The core physician group must also become well known by the major patient groups through lectures, appearances at conferences and social media presence. Involvement with NANETS also raises the profile of the center when appropriately publicized.

The Iowa SPORE Grant: Melding clinical practice with research

Under the leadership of Sue, the Iowa NET team decided to apply for an NIH/NCI SPORE grant in 2012. Several years of extensive planning, brainstorming, recruiting basic scientists, and writing ultimately led to Iowa being awarded the first ever NET-focused SPORE in 2015 (Figure 4). This was a remarkable feat for a rare cancer type like NETs, as most other SPOREs in the nation (~55 funded per year) address more common types of cancers.

Figure 4:

The Iowa SPORE. Projects for first 5 years, extension, and proposed renewal. At right, picture of University of Iowa Hospitals and SPORE announcement.

SPOREs are large, programmatic federal grants that support bi-directional translational research to improve the detection, prevention, and/or treatment of human cancers. The grant mechanism provides a substantial maximum budget of $1.4M in direct costs per year. That high level of funding enables each SPORE to have multiple research projects (often 3 per grant, each equivalent to a small R01 grant) as well as 3 to 4 cores (e.g., Clinical, Biospecimens, and Biostatistics and Bioinformatics) that facilitate the proposed investigations in the projects. The SPORE also funds small projects within a developmental research program (DRP) and career enhancement program (CEP) to support novel, potentially high risk/high reward research ideas and/or bring new researchers into the field. DRP and CEP awardees may come from any institution and often help to establish new scientific and clinical relationships. A SPORE award emphasizes collaboration between basic and clinical scientists, and requires that each project and core be co-led by such a team. Each SPORE project must include meaningful human endpoints (e.g., biomarker discovery or validation, a clinical trial, or population study). The intent is that every project will have a clear clinical impact by the end of the funding period. Each SPORE team meets regularly with internal and external advisory boards comprised of scientific and clinical leaders in the field, and patient advocates. We were grateful that Dr. Vinik served as one of our external advisors.

The Iowa NET SPORE has sought to address innovative, critical translational questions in NET pathobiology and treatment. This has been accomplished through a dynamic investigative team of basic, clinical, and population science researchers at the University of Iowa and collaborating institutions. Projects in the original SPORE grant addressed: 1) optimization of theranostic peptide design for improved NET treatment, 2) delineation of biomarkers and druggable pathways that drive pancreatic NET progression, 3) genomic identification of new diagnostic and therapeutic targets in SBNETs and PNETs, and 4) testing a novel radionuclide combination paired with imaging to maximize therapeutic efficacy in patients with SBNETs. The researchers came from wide-ranging disciplines including pediatrics, internal medicine, surgery, radiology, pharmacology, pathology, radiation oncology, epidemiology, biostatistics, chemistry, and biomedical engineering. As the team worked toward renewing the SPORE in 2020 and obtained extended NCI support, 3 new projects evolved that focused on innovative PRRT trials in lung NENs and SBNETs as well as markers underlying NET metastasis. Currently, the team is seeking continued SPORE funding with a new, multi-institutional application co-led by founding NET SPORE members (Jim, Yusuf, and Dawn Quelle, PhD).

NET SPORE investigators, including DRP and CEP awardees as well as those leading the primary projects listed in Figure 4, have been remarkably productive. They have conducted numerous new clinical trials, led changes in NET guidelines and clinical practice, developed new models of the disease to support NET research worldwide, defined novel biomarkers and targets for therapy, published hundreds of papers, secured millions of dollars in new grant support, and directed national and international NET society meetings. Most importantly, discoveries from the Iowa NET SPORE studies have advanced our understanding of NETs and improved their clinical management.

Concluding Thoughts

This manuscript has summarized the history, philosophy, and many of the achievements of the Iowa multidisciplinary NET Clinic. The clinic was created from the unique perspectives of Tom and Sue, and their interest in patients with NETs. Tom O’Dorisio and Aaron Vinik were gifted endocrinologists who lived through and significantly contributed to the golden era of hormone discovery and development of assays allowing their quantification in patient samples. These advancements led to clinically useful methods for diagnosing endocrine disorders and identifying cancers in symptomatic patients. Tom established a specialty clinic at OSU, but had a dream to create a multidisciplinary NET clinic when he came to Iowa. His enthusiasm and perseverance, coupled with Sue’s scientific accomplishments and knack for getting INDs for promising therapies, led to the early success of building the clinic. They attracted people from multiple specialties to join them in their passion project, all of whom have become known as authorities in their fields. The academic productivity and inter-connectedness of these clinicians and faculty in the basic science disciplines paved the way for the successful application for a SPORE grant, which allowed the research to flourish. The clinical activity and productivity eventually led to successful application as an ENETS COE, and excellence in patient care and research continues at Iowa. Although Aaron and Tom have sadly passed on, their memories burn strongly within us and are an inspiration to deliver the most expert and cutting-edge care to our patients with NETs, as we know they always did.

Figure 1:

Selected members of the Iowa SPORE and NET Clinic team. First row (left to right): David Bushnell, Melissa Fath, PhD, M. Sue O’Dorisio, MD, PhD, Thomas O’Dorisio, MD, Dawn Quelle, PhD, Charles Lynch, MD. Middle row: Andrew Bellizzi, MD, Yusuf Menda, MD, James Howe, MD, Terry Braun, PhD. Top row: Joseph Dillon, MD, Dijie Liu, PhD, Chandrikha Chandresekharan, MD, George Weiner, MD.

Teaching Points:

• Learn how a multi-disciplinary cancer clinic was developed

• Understand the importance of multiple specialties to deliver cutting-edge care

• Review the perspectives of multiple specialties in the diagnosis and treatment of neuroendocrine tumors

Clinical Points:

In this manuscript, we discuss the history, accomplishments, and philosophy of clinical care delivered at the University of Iowa Neuroendocrine Tumor Clinic. Our clinic was founded by the Endocrinologist Dr. Thomas O’Dorisio in 1999, where he brought together experts in surgery, nuclear medicine, medical oncology, gastroenterology, pathology, endocrinology, interventional radiology, and basic scientists. Tom O’Dorisio was a close friend and colleague of Aaron Vinik, and both shared a passion for managing patients with neuroendocrine tumors. The story of the Iowa NET Clinic is a wonderful example of how a remarkable multi-disciplinary clinic was built, culminating in the only European Neuroendocrine Tumor Society designated center of excellence in North America, and the awarding of the only SPORE grant ever for Neuroendocrine tumors.