Neuroendocrine Tumors: Less known, often misunderstood and rapidly growing

Cancer is a great equalizer; it does not differentiate between rich or poor, young or old. The history of cancer is as ancient as the origins of humans and continues to be an enigma in the 21st century. Much has been uncovered about the etiology of various cancers, and tremendous advances in both diagnostics and therapeutics have been made. Indeed, cancer patients today live longer, with a better quality of life and the horizon looks even more, promising. However, one “supposedly” rare neoplastic condition called neuroendocrine tumor (NET) is often ceded to obscurity by academia, the pharmaceutical industry, health care policymakers and media. It may surprise many readers that celebrities including Steve Jobs and Aretha Franklin were diagnosed with the neuroendocrine tumor and yet there had been no public awareness about this condition.

Neuroendocrine neoplasms are a spectrum of pathologies that originate in neuroendocrine cells and can affect almost any part of the body. The biology of the disease comes in various flavors from low-grade NETs (also known as carcinoids) to high-grade neuroendocrine carcinomas. While a patient with low-grade tumor can survive many years, the high-grade counterpart is extremely aggressive and has a dismal outcome.

The United States (U.S.) is among the countries with a robust epidemiological database of cancer statistics. Surveillance, Epidemiology and End Result (SEER) is the premier cancer registry and regularly updates cancer statistics in 18 states. While comforting to know that the incidence of common cancers like breast, colon and lung cancer have plateaued over past few decades, the NET incidence has skyrocketed almost seven times in the same period. In a seminal paper published in the Journal of American Medical Association in 2017, Desari et al reported that the incidence of NETs had risen from 1 in 100,000 population (the 1970s) to 6.98 in 100,000 (2012)¹ . In 2018, we reviewed the Kentucky Cancer Registry database and found results in concordance with SEER; the incidence of NETs was close to 10 per 100,000 in Kentucky².

Due to the indolent nature of the disease, its prevalence poses an imminent health care crisis. It may come as a surprise to many that gastrointestinal NETs are now the second most prevalent gastrointestinal neoplasm after colon cancer (Figure 1). It is estimated that there are over 170,000 NET patients in the U.S. alone¹. With the majority of NETs being a chronic disease, the prevalence will continue to grow, adding significantly to our health care expenditure. The average yearly healthcare cost of managing a metastatic NET patient in the U.S. can exceed $30,000³. With the growing incidence and prevalence of this condition, the healthcare system will be challenged with exorbitant costs.

Figure 1: Prevalence of various solid tumors in the US per the most recent SEER data (2016).

While we as a society have heavily invested in the fight against cancer, it is sobering that NET is indolent but ultimately lethal. As with most rare cancers, NETS receives limited, focused attention. There have been few FDA approved therapies for progressive metastatic NETs in the last decade. Sunitinib and everolimus were FDA approved for pancreatic NET in 2011, followed by lanreotide’s approval as a front-line agent in 2014 for gastroenteropancreatic neuroendocrine tumors (GEPNETs), and most recently lutetium 177 dotatate was FDA approved in 2018 for progressive GEPNETs. It is important to highlight that most of the above-mentioned FDA approvals are limited to GEPNET’s; however, 30% of NETs are non GEPNETs. Hence, the treatment options are not only limited but also cater to a subset of NETs. Moreover, most FDA approved agents except for lutetium 177 dotatate have not shown overall survival (OS) benefit. Data on lutetium 177 is maturing but is expected to confirm OS benefit.

To date, there are no validated patient derived xenograft (PDX) models available to study NETs. Most preclinical drug development relies on few NET cell lines (BON, QGP-1, NCI H727). Those in vitro and in vivo models were originally designed 20 years back. Without robust preclinical models, future drug development and our understanding of underlying pathophysiology will be challenged. The root cause of this sluggish preclinical development is limited research funding, very tight pay lines, and poor awareness among our scientific community about this rapidly growing problem.

NET patients are unfortunately often misdiagnosed before the cause of their symptoms are finally diagnosed, recognised, and managed appropriately. It is not uncommon for a NET patient to experience a delay in the diagnosis by many years. This is in part due to significant lack of public and even physician awareness about NETs. Chronic diarrhea, flushing, fatigue, among other carcinoid syndrome symptoms, often results in loss of work, income and significantly impacts quality of life. While therapeutic drug development is slow, advancement in supportive symptom care management is even more sluggish. To date we have only two FDA approved agents for carcinoid syndrome diarrhea, somatostatin analogs and telotristat ethyl.

We are often asked, “Why is NET incidence growing at such a rapid pace? Are we getting better at detecting it or is the changing environment responsible?” The truth is, we do not know. It is reasonable to attribute some hike in incidence to better diagnostics with increased colonoscopies, endoscopies and CT scans; however, we are highly skeptical that is the sole reason. The seven-fold increase in incidence is noteworthy, and if the current trend continues, we will be obligated to look into environmental factors that might be contributing to this increase.

Researchers have formed effective collegiums like North American Neuroendocrine Tumor Society (NANETS) and European Neuroendocrine Tumor Society (ENETS) to develop management guidelines and to spread awareness. Walking shoulder to shoulder with medical fraternity, NET patient community and support groups like the NET Research Foundation, Carcinoid Cancer Foundation and Neuroendocrine Cancer Awareness Network (NCAN) work tirelessly to raise awareness, provide support to patients and caregivers and increase funding for NET research. These efforts alleviate patient anxiety and channel pent-up frustration into momentum against neuroendocrine tumors. Despite the obstacles, there is reason to be optimistic that persistent efforts and advocacy for NET patients will one day gather enough critical mass to reach goals for better therapeutics, as well as effective screening and preventative measures.

Cancer researchers, the pharmaceutical industry, mass media and health care policymakers must acknowledge this growing need and allot resources and expertise to constrain it. It has to be a group effort. President John F. Kennedy inspired the nation when he said, “We choose to go to the moon in this decade and do the other things, not because they are easy, but because they are hard, because that goal will serve to organize and measure the best of our energies and skills, because that challenge is one that we are willing to accept, one we are unwilling to postpone, and one which we intend to win, and the others, too.” Curing NETs seems herculean, but, just like putting man on the moon, finding a cure for NETs is a challenge that must be accepted and won.