1. Anthony, Lowell MD

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Last month, neuroendocrine tumors had an official "Awareness Day"-November 10, as Worldwide Neuroendocrine Tumor (NET) Cancer Awareness Day-marking significant advances in the management of these neoplasms, but they continue to fascinate physicians every day with symptoms and syndromes that range from being absent to florid.

NET Awareness Day... - Click to enlarge in new windowNET Awareness Day
Lowell Anthony, MD, ... - Click to enlarge in new windowLowell Anthony, MD, is Professor of Medicine at the University of Kentucky.

The astute diagnostician may recognize ectopic Cushing's Syndrome just by noting the rapidity of onset of the Cushingoid habitus. And while the minority of NETs are functional, many are symptomatic with the onset of vague and confusing symptoms that progress slowly in a crescendo fashion over time.


Clinical management has changed over the last two decades with the advent of the somatostatin analogs and tumor debulking procedures. While controlling hormonal excess symptoms has improved, controlling tumor growth is more challenging and is more likely to be life-limiting.


2 New FDA-Approved Agents

For the first time in 25 years the FDA approved not one, but two new agents for the management of progressive and unresectable pancreatic NETs. Two independent, global, blinded, and randomized clinical trials conducted in patients with metastatic and progressive disease demonstrated significant improvement in progression-free survival (PFS).


One trial evaluated the tyrosine kinase inhibitor sunitinib in 171 patients, and the other tested everolimus, an mTOR inhibitor, in 410 subjects. Both trials showed a doubling in the time to progression from approximately 4.6 to 5.5 months in the control arms to 11 months for everolimus and 11.4 months for sunitinib. The hazard ratios were 0.35 for everolimus and 0.42 for sunitinib, respectively.


The sunitinib trial was terminated early based on a recommendation from an independent Data Monitoring Committee and patients crossed-over to the active agent in a separate trial. The everolimus trial (Radiant-3) is the largest randomized trial ever conducted in pancreatic NET. As these trials were performed simultaneously, patients entered onto each trial had not received prior therapy with the opposing agent.


The improvement in PFS is accompanied by a two-three fold increase in drug-related adverse events when compared with placebo. While most of these side effects are Grades 1 or 2, Grades 3 and 4 events did occur.


For sunitinib, the most common severe events were neutropenia in 12% and hypertension in nearly 10% of subjects. Everolimus therapy was associated with stomatitis, diarrhea, hyperglycemia, and hematologic adverse events in three to seven percent. Quality-of-life measures with sunitinib therapy were not associated with any significant change. Side effects are generally easily managed with dose reduction or temporary cessation of therapy or both.


A current clinical conundrum is the selection of agents at the time of progressive pancreatic NET. As we practice evidence-based medicine, it is unknown whether the doubling of PFS remains in the third-line setting. We are left to choose which agent might be better tolerated as both agents will most likely be prescribed, sequentially.


Challenges of Testing New Agents in Rare Diseases

While these studies are criticized for not having demonstrated overall survival benefits, they show some of the limitations in testing new agents in rare diseases. Whether PFS is an adequate substitute for overall survival in NET remains debatable but is not likely to slow down new agent development though some NET trials are being planned where no cross-over is allowed.


The physician and patient community should react to this if regulatory requirements stall drug development.


Beyond Pancreatic NET

Even though the dominant advances in 2011 in NETs have occurred in pancreatic NET, progress continues in other primary sites. The process to validate peptide receptor radiotherapy (PRRT) will launch in 2012. A prospective randomized trial in midgut NETs will open early next year. Lu-177 octreotate will be compared with 40 mg octreotide LAR in progressive patients. It will be several years before the worth of PRRT, considered standard of care in Europe, is known.


Improving Detection and Staging

Improving detection and staging capabilities with PET technology is slowly evolving in the US. The assessment of Ga-68 DOTATOC is under way at several centers. This snail's pace of developing PET SMS analog technology reflects the slowness of FDG PET incorporation into oncologic practice.


Whereas the lack of intellectual rights protection slowed down FDG PET development, the lack of an industry sponsor is crippling SMS PET. Several centers such as Vanderbilt and the University of Iowa have assumed some of the costs and risks associated with new agent testing.



The most likely next new agent


FDA-approved for NET will be pasireotide, a multi-receptor targeted somatostatin analog. Registration of this second generation somatostatin analog is going forward for Cushing's Disease and acromegaly. The global randomized clinical trial for the control of octreotide-refractory flushing in midgut NET continues.


While NET disease mimics many other neoplasms, it has become evident that targeting only one pathway will be insufficient in controlling metastatic and unresectable disease. Current efforts are directed in identifying active combination therapies. Such approaches combine "targeted agents" such as erlotinib and everolimus or "non-targeted" approaches where temozolamide is compared with temozolamide plus capecitabine.


Progress is evident in a rare disease that perplexes many. Prospects for the future include the development of predictive and prognostic biomarkers. While early detection continues to elude us, it may be DNA microarray technology that offers the best clue to identifying the at risk population where screening could be more effective. The selection of therapy may also be improved with detecting mutations in certain signaling pathways.



Worldwide NET Cancer Awareness Day 2011 ushered in two new FDA-approved agents but leaves us with many more questions:


* Are treatments active in one NET disease active in others?


* Do all foregut NETs respond the same as pancreatic primaries? A subgroup analysis of the Radiant-2 data set suggests that that is the case; but then will insurance companies approve agents based on hypotheses?


* Are agents effective in the metastatic setting appropriate for the adjuvant one?



As questions remain, we will have to await more "awareness days" to acquire better insight into NET management. But this year we can at least see progress and what is on the horizon in a disease that has a history of having more papers published than actual cases. It appears now that with improved education, detection, and treatments, that is no longer the case.