I have the privilege of caring for patients with a diagnosis of neuroendocrine tumors (NETs) as a part of what I do as a GI/NET medical oncologist. I had the great fortune of training at the University of Iowa in Iowa City, IA- a NET powerhouse, where I had the luxury of being exposed to a myriad of pathologies and get a rich experience of treating patients with a variety of NET diagnoses. I am equally fortunate that I got to start my career at a place like Winship Cancer Institute of Emory University in Atlanta, GA- another NET powerhouse where I get to see so many patients with NETs and participate in their care as their medical oncologist. If I had to list the most important lesson that I have learnt about NETs over the years is that “every patient is different” and “no two tumors are the same”. Every patient with a tumor that has the same grade and site of origin will have different experiences with their cancer- both in terms of symptoms/quality of life as well as how their cancer responds to NET-directed therap(ies). This is nothing but a reflection of the underlying heterogeneity in disease biology and speaks to our inability to use existing NET classification systems to parse out the intricate details that are such a crucial part of a tumor’s identity and clinical behavior. The current classification systems rely heavily on the tumor’s morphology, i.e., how the tumor looks like under the microscope (degree of differentiation and proliferation indices) and where it comes from (anatomical site of origin) to classify NETs. Therefore, we are only able to capture and present just a few pieces of this big puzzle.
There is a lot that we do not know about NETs. It can be very challenging for even those of us who treat these cancers regularly to get a good sense of the biology and make treatment recommendations. So one can only imagine how arduous and perplexing it may be for patients and their care partners to understand the diagnosis and navigate treatment decisions. To make this slightly easier for them, I have managed to develop a “NET spiel” that I give to all my patients when they see me for the first time (and then shorter versions at subsequent visits as necessary) to help lay out some of the key parameters that I and my colleagues like to take into consideration when making therapeutic recommendations. These also help patients understand their diagnosis better and appreciate the rationale for choosing one treatment over the other.
(Listed in no particular order).
Stage versus Grade: This is critical to understand. Unlike other solid cancers where the stage is typically the most important determinant of prognosis/therapeutic approach; I make sure my patients understand that the grade of their NET is more relevant to their overall care. The approach to treatment and outcomes in a patient with a pancreatic NET with liver metastases will be very different with a Ki67 of 1% versus 41%. Unfortunately the vast majority of patients that I see in my practice already have metastatic disease at diagnosis. However, taking time to explain the importance of grade over stage allays a lot of fear and anxiety that the “stage IV” label might bring with it. Even with a stage IV grade 3 diagnosis, the grade is just one of the things we consider when making therapeutic decisions. Many patients will still go on to have a favorable long-term outcome.
Somatostatin receptor expression: So much of what we do for treating NETs relies on the presence of somatostatin receptors. Typically, functional imaging in the form of somatostatin receptor PET (such as Ga68 DOTATATE or DOTATOC or Cu64 DOTATATE) are the most widely used and reliable modality for assessing somatostatin receptor expression. The two things I am looking for on the PET scan are: intensity of somatostatin receptor expression (by Krenning score or SUV) and homogeneity of somatostatin receptor expression. Although I typically don’t rely on a particular threshold of SUV but I tell my patients that as gestalt, the “brighter the better” mantra is pretty accurate. The use and clinical benefit of somatostatin analogs and somatostatin receptor-targeting radioligand therapies such as Lu177-DOTATATE as well as the newer alpha agents (Ac225 or Pb212 based) rely heavily on the expression of somatostatin receptors. This piece of information is therefore paramount to therapeutic decision making.
Site of origin: Although this is really something that I hope we could do away with in the future; where we currently stand- the site of origin is important. We have noted some key differences in biology and therapy-related outcomes based on the site of origin of NETs. For example, the combination chemotherapy capecitabine+temozolomide is an effective therapeutic option for pancreatic and also ?lung NETs but activity is limited in NETs of small bowel origin (particularly low and intermediate grade). We have also seen that outcomes and response rates with tyrosine kinase inhibitors are also relatively better in pancreatic NETs. Therefore, having knowledge about the anatomical site of origin is very helpful in clinical practice. It is important to know that in as many as 20-30% patients, the site of origin may remain unknown. The Bellizzi algorithm (or the Iowa algorithm) based on immunohistochemistry (IHC) staining is helpful (PMID: 31857137) to reliably ascertain the possible site of origin. However, implementation remains limited at centers outside of the University of Iowa mostly due to challenges with performing comprehensive IHC assessment.
Disease biology: The importance of disease biology in therapeutic decision making cannot be overstated. I often tell my patients- “We need the tumor to tell us what it may do if we don’t intervene, for us to know when and what to intervene with”. Assessment of the pace or tempo of disease progression on successive scans is a crude but very reliable test of biology which can inform therapeutic decisions (both with choice and sequencing of therapies). For example, I may recommend everolimus for a patient with a pre-treated low grade 2 SSTR+ small bowel NET progessing slowly but significantly over 15 months but go for Lu177-DOTATATE if that progression occured over 3-6 months. Implementing this test in practice for newly or recently diagnosed patients is going to become a challenge with the increasing use of therapies other than somatostatin analogs in the frontline setting; such as radioligand therapy [with NETTER-2 results and NETTER-3 now on the horizon].
Disease burden and pattern of spread: This is perhaps a continuation of the disease biology assessment. Assessment of how heavy the disease burden is and what the pattern of disease progression is are vital for therapeutic decision making. A patient with slow progression of liver metastases on successive radiographic imaging would make an ideal candidate for liver-directed therapies such as bland hepatic embolization or Y90-SIR spheres. However, in the presence of significant extra-hepatic metastatic disease progression, we may hesitate in using liver-directed therapies purely for disease control. Similarly, we may want to use Lu177-DOTATATE or CAPTEM upfront for a patient with advanced grade 2 pancreatic NET (Ki67 12%) with a very heavy liver disease burden (>75%) to achieve hepatic disease control. On the other hand, somatostatin analogs may be appropriate as frontline therapy if the same patient had a fairly low hepatic disease burden.
Functional syndrome: The presence of functional syndrome is a key consideration in therapeutic decision making among patients with advanced NETs. Approximately 30% patients with small bowel NETs may present with carcinoid syndrome resulting in symptoms such as flushing, diarrhea, bronchospasm, etc and long-term complications such as carcinoid heart disease. These symptoms obviously have a significant impact on the overall well-being and quality of life of patients. Among patients with NETs of other sites of origin such as pancreas or lung, functional syndromes are known but rare. While we have medications that assist with management of functional symptoms, often NET-directed therapies are necessary to achieve durable symptom control. What may classify as slow progression that is appropriate for continued surveillance without change in therapy in a patient with a non-functional NET may warrant intervention in a patient with a functional NET if there is concomitant worsening of associated treatment-refractory functional symptoms.
Co-morbidities: It is important to consider the overall health of the patient when making therapeutic recommendations. While this may be less relevant in the use of therapies such as somatostatin analogs, this is a key consideration in the selection of various other systemic therapies. For example, patients with poorly controlled diabetes mellitus may not be ideal candidates for everolimus and those with treatment-resistant hypertension may not be ideal candidates for cabozantinib. Partnering with the patient’s primary care provider to ensure that the underlying co-morbidities are well-managed and controlled prior to initiation of therapy has proven to be an effective strategy in my practice. Upfront and subsequent dose reductions to find a happy medium is necessary to safely use targeted therapies among patients at high risk of treatment-emergent adverse events.
Functional status and care preferences: I always like to remind myself that, “behind every diagnosis is a patient with unique aspirations and preferences”. What may be perfect for one patient may actually be the last therapy on the list for another patient purely because of the differences in what matters most to them. Assessing the overall well-being and functional status and understanding the long-term goals of care are all helpful strategies in making sure that each patient’s treatment plan is personalized to meet their expectations. It is also important to be cognizant that poor functional status portends poorer outcomes in NETs (like other cancers). Avoiding aggressive therapeutic interventions in vulnerable patient populations is necessary to ensure that the therapy does not become worse than the disease.
Overall, no decision in the care of patients with NETs can be made in isolation. Careful multi-disciplinary iteration and forging a strong partnership between physicians and patients as well as their care-partners is necessary to make sure that therapeutic decisions are as personalized as possible. Hope you enjoyed reading this.
Udhayvir S Grewal, MD
This is great! Dan Li, our founder Giovanna and I created NET VITALS, a fillable document to help patients “learn to speak NET” and prepare for their appointment with NET providers like yourself- https://www.ncf.net/netvitals