64Cu-DOTATATE – a potential expansion of the Somatostatin Receptor PET Imaging for Neuroendocrine Cancer?


Edit 10 Jan 2019: RadioMedix and Curium Announce FDA Fast Track Designation For 64Cu-Dotatate.  Read more by clicking here.

Curium and RadioMedix Inc. announce an exclusive agreement to develop and commercialize 64Cu-Dotatate, an investigational positron emission tomography (PET) diagnostic agent for patients with Neuroendocrine Tumors (NETs). RadioMedix is currently engaged in Phase III clinical trials of the agent and expects to file a New Drug Application with the Food and Drug Administration in 2019. This partnership builds on the initial development work conducted by RadioMedix and will benefit from Curium’s regulatory, manufacturing, distribution, and commercial expertise. The radionuclide is not new, it’s been in use for some time, mainly in Denmark.

64Cu is a PET isotope that can be produced at a central location in quantities to meet the commercial needs of hospitals and imaging centers without the supply limitations of nuclear generator-based PET isotopes,” said Ebrahim Delpassand, MD, CEO of RadioMedix. “Once approved, 64Cu-Dotatate will be available to patients in medical centers with PET capability across the country. This will address the shortage or lack of availability of somatostatin analogue PET agents that we are currently experiencing in many parts of the U.S.”

Ga68 PET Shortages explained

This statement is in relation to the current shortage of Ga68 PET radionuclide. For those not aware, the Society of Nuclear Medicine and Molecular Imaging (SNMMI) has written a letter to the FDA about ongoing shortages of generators that produce gallium-68 (Ga-68), a radioisotope used regularly in medical imaging. The letter—available here.

The letter explains that Ga-68 is currently used to produce NETSPOT from Advanced Accelerator Applications (a Novartis company), which was approved in June 2016 to help treat neuroendocrine tumors (NETs) in adult and pediatric patients using PET. NETSPOT, however, is only approved using specific generators. And those generators are only approved for either 400 uses or one year, whichever comes first. This has led to shortages throughout the United States.

SNMMI notes some possible remedies for this shortage. For instance, “a temporary exemption to the 400-elution limit would have a major impact on NETSPOT capacity for patients,” according to the letter. In addition, using a wider variety of generators to produce NETSPOT or using cyclotron-produced gallium chloride are two other methods that could improve production in a relatively short amount of time. “Further discussion with the manufacturers is necessary,” the authors added.

Read more about Ga68 PET and its use in Neuroendocrine Cancer – click here. Worth also noting that RadioMedix is also involved in a number of NET related initiatives including:

1. Trials for a new type of PRRT called ‘Targeted Alpha-emitter Therapy (TAT) – I’ve written about this previously. Read my article here.
2. An exclusive distributor for the TM Isotopen Technologien München AG (ITM) PRRT product currently in trial. I wrote about this here.

How does 64Cu-Dotatate compare with Ga68 PET and Octreotide Scans?

To learn more about previous studies on 64Cu-Dotatate, here’s 2 articles published in the Journal of Nuclear Medicine which are a head to head comparison of 64Cu-Dotatate with Ga68 Dotatoc and with 111 Indium Octreotide (Octreoscan).

Head-to-Head Comparison of 64Cu-DOTATATE and 68Ga-DOTATOC PET/CT: A Prospective Study of 59 Patients with Neuroendocrine Tumors – http://jnm.snmjournals.org/content/58/3/451.full

PET/CT (left) and PET (right) scans of patient with intestinal NET and multiple metastases. More lesions are seen in intestinal region with 64Cu-DOTATATE than with 68Ga-DOTATOC.

Conclusion: 64Cu-DOTATATE has advantages over 68Ga-DOTATOC in the detection of lesions in NET patients. Although patient-based sensitivity was the same for 64Cu-DOTATATE and 68Ga-DOTATOC in this cohort, significantly more lesions were detected by 64Cu-DOTATATE. Furthermore, the shelf life of more than 24 h and the scanning window of at least 3 h make 64Cu-DOTATATE favorable and easy to use in the clinical setting.

64Cu-DOTATATE PET for Neuroendocrine Tumors: A Prospective Head-to-Head Comparison with 111In-DTPA-Octreotide in 112 Patients –http://jnm.snmjournals.org/content/56/6/847.full

Multiple small liver metastases (>10), peritoneal solitary tumor mass, and 3 lymph node metastases shown on 64Cu-DOTATATE PET/CT in patient with pancreatic NET. No foci were detected by 111In-DTPA-OC SPECT (Precedence scanner). All findings on PET were confirmed to be true-positive. (A) 111In-DTPA-OC planar images. (B) 64Cu-DOTATATE maximum-intensity-projection image with arrows pointing at liver and lymph node metastases. Insert is fused PET/CT of peritoneal solitary tumor mass. (C) Axial CT and SPECT of liver. (D) Axial CT and PET of liver revealing several small liver metastases.

Conclusion: With these results, we demonstrate that 64Cu-DOTATATE is far superior to 111In-DTPA-OC in diagnostic performance in NET patients. Therefore, we do not hesitate to recommend implementation of 64Cu-DOTATATE as a replacement for 111In-DTPA-OC.

Summary

The shortage of Ga68 PET radionuclide caused by limitations of the generators in use is unfortunate. Reading the SNMMI letter, I think progress can be made downstream. However, the introduction of a new scanning agent could be useful as long as the trials prove its safety and efficiently and is comparable to current tools. There is no news of any plans to extend this potential new radionuclide outside the US but I suspect that would change following an FDA approval.

If you can see it, you can detect it!

Thanks for reading

Ronny

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Lutetium Lu 177 dotatate (Lutathera®) – PRRT

prrt update

Short PRRT Primer

What is Peptide Receptor Radionuclide Therapy (PRRT)?

For those who are still not sure what it’s all about.  This is a non-surgical treatment which is normally administered intravenously.  It’s based on the use of somatostatin receptors to attract a ‘radiopeptide’.  The radiopeptide is a combination of a somatostatin analogue and a radioactive material. As we already know, somatostatin analogues (i.e. Lanreotide/Octreotide) are a NET cell targeting drug, so when combined radioactivity, it binds with the NET cells and delivers a high dose of targeted radiation to the cancer while preserving healthy tissue.  In general, patients tend to receive up to 4 sessions spaced apart by at least 2 months. 

PRRT will not work on all NETs and not everyone will suited to this treatment. In general, for this treatment to be more successful, you must have somatostatin receptors in your tumors. Success rates are not 100% – it should not be considered a cure or ‘magic bullet’. However, the results are said to be pretty good.  The NETTER-1 trial data which has led to formal approval in Europe, USA and other areas, can be found here.

LATEST ON EXPANDED NETTER-1 TRIAL DATA.  “Novartis has announced presentation of a new analysis of Lutathera (lutetium Lu 177 dotatate) NETTER-1 data at the 2018 European Society for Medical Oncology (ESMO) congress examining the impact of Lutathera treatment on patients with low, medium or high liver tumor burden. The data show that Lutathera treatment results in significant improvement in progression free survival (PFS) regardless of the extent of baseline liver tumor burden (LTB), elevated alkaline phosphatase (ALP) liver enzyme or presence of large (>30mm diameter) lesion in patients with progressive midgut neuroendocrine tumors (NETs) compared to octreotide LAR alone.”

THERANOSTICS

Understanding the terminology is half the battle in understanding the latest developments. I’ve included Ga-68 PET scans within this section (or in more general terms Somatostatin Receptor PET (SSTR PET)) as the term ‘Theranostics‘ is becoming a commonly used theme.  Theranostics is a joining of the words diagnostics and therapy.

LUTATHERA is the radionuclide ‘mix’ for use in Peptide Radio Therapy Treatment (PRRT).  You may also see this drug called ‘Lutetium’ or ‘Lu-177 dotatate’, or just ‘Lu-177’ on its own. Yttrium 90 (Y-90) is a  radionuclide also used in PRRT. 

NETSPOT (USA) or SOMAKIT TOC (Europe) is not PRRT but it is the commercial names for the radiopeptide used in Gallium 68 (Ga-68) PET diagnostic scans.

Together they form a ‘theranostic pair’. Theranostics is apt as together (NETSPOT / SOMAKIT TOC and Lutathera), both target NETs expressing the same somatostatin receptor, with Lutathera intended to kill tumor cells by emitting a different kind of low-energy, short-range radiation than that of the diagnostic version.

Moreover, thanks to the theranostic approach that nuclear medicine allows, Novartis/AAA’s NETSPOT/SomaKit TOC products will be able to determine when Lutathera is the appropriate treatment.

Read more about Theranostics by clicking here.

Hasn’t the therapy has been in use for some time?

Of course, this therapy has been in use in Europe and some other places for some time but to be honest, they have been on a limited scale and never formally approved by national drug agencies.  Despite its extensive use, the EU approval in 2017 was actually the very first approval of PRRT anywhere in the world. For example, in UK, it was used for some time for those in need but was removed from routine availability through a ‘slush fund’ formally known as the Cancer Drugs Fund – to cut a long story short, the funding source was cut off, although there are still ways of obtaining the treatment pending formal acceptance by the NHS (certain criteria apply).

In the meantime, I constantly see stories of patients travelling to Switzerland, Germany, Netherlands, Sweden, Great Britain and others; mostly at their own cost.   However, it does indicate one thing, there is a huge unmet need in that many patients do not have access to the best treatments in their own country. I see this daily through many private messages.

What about Grade 3 (High Grade) Neoplasms?  

The main treatment for Grade 3 is chemotherapy, particularly poorly differentiated.  PRRT tends to work better with efficient somatostatin receptors (i.e. somatostatin receptor-positive tumors).  The European approval wording only covers Grades 1 and 2. The US FDA approval indicates “somatostatin receptor-positive tumors”.  It’s also worth noting that with Grade 3, are more likely to exist in Grade 3 well differentiated NETs, particularly in the lower Ki-67 readings. However, there’s an interesting study from Australia which might be useful to read – check out the abstract here (note the full version is not available free).

Merkel Cell Carcinoma.  Although not indicated for this type of Neuroendocrine Neoplasm, there is evidence to suggest that this skin Neuroendocrine Carcinoma does express somatostatin receptors.  Read more here.

merkel cell prrt ga68 images
Case Rep Oncol 2019;12:98–103
Merkel Cell Carcinoma
https://doi.org/10.1159/000496335

What about Pheochromoctyoma/Paraganglioma?

There’s actually still a trial for Pheochromocytoma/Paraganglioma (Pheo/Para).  It is known that Pheo/Para can have somatostatin receptor tumors so a useful trial. The aim of the trial is to assess the safety and tolerability.  You can read about the trial here.

Where can I get PRRT?

global icon
Where can I get PRRT?

Regional Updates

The aim of this section is to update on a regional basis in order to inform an international community of followers and readers.

Background

I wanted a place to review what is happening globally given my following.  In many countries, however, I’m dependent on feedback from patients in those countries. Please note this is not intended to be a 100% complete breakdown on everything about PRRT or PRRT centres – it’s a summary.  It should be clear from below but please bear that in mind when reading.

This section of this article will cover each region, indicating where PRRT can be obtained (as far as I know). It is not designed to indicate whether this is through public or private facilities (this will depend to too many factors beyond the reach of this article). Please note this is not intended to be a 100% complete breakdown on every single PRRT centre – it’s a summary.  This actually should be clear from below but please bear that in mind when reading.

UNITED KINGDOM

On 29 August 2018. National Institute for Health Care Excellence (NICE) England has formally published that Lutetium (177Lu) oxodotreotide, within its marketing authorisation, is an option for treating unresectable or metastatic, progressive, well-differentiated (grade 1 or grade 2), somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumours (NETs) in adults.  CLICK HERE to read the approval.  Currently available in London and Liverpool.  The Christie Mancheter is advertising it on their website and there is anecdotal talk of Newcastle and Leicester going live soon. I await the rollout of PRRT – watch this space for a table listing. 

On 9 July 2018. The Scottish Medicines Consortium (NICE equivalent) has approved lutetium 177Lu (Lutathera) for patients in NHS Scotland. Good news for Scotland once their hospitals have the capability to deliver. Scottish patients would then not need to travel to England for the NHS Scotland funded treatment. Read more here.

It is funded in Wales and Northern Ireland but is currently administered in England with inter NHS budget transfers.

Canada

On 7th Feb 2019, Health Canada approved Lutathera™ (lutetium (177Lu) oxodotreotide) for the treatment of unresectable (not removable by surgery) or metastatic, well-differentiated, somatostatin receptor-positive (expressing the somatostatin receptor) gastroenteropancreatic neuroendocrine tumors (GEP-NETs) in adults with progressive disease.  The treatment was previously available on a trial basis. Read more here.

Site update to follow but the following trial locations may be up and running first:

Juravinski Hamilton,
LHSC London,
PMCC Toronto,
Sunnybrooke Toronto.


USA

PRRT was approved in USA on 26 Jan 2018. The approval is for the treatment of somatostatin receptor positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs), including foregut, midgut, and hindgut neuroendocrine tumors in adults. CLICK HERE.

The extended access program (trial) is no longer offered but these locations should be ahead of the game in terms of provision, notwithstanding insurance and provision of sufficient nuclear material.

In the meantime, known USA sites offering routine “live site” insurance based PRRT treatment are as follows – please note information has been gleaned from US patients due to no other consolidated source of this information being readily available. It’s possible some patients got mixed up between trial locations and live locations so let me know of any omissions or additions/corrections – thanks in advance.

DRAFT – NOT YET COMPLETE – (as at 24 Mar 2019)

STATE LOCATION Due in Service? CONTACT DETAILS
Arizona Banner Now Dr Boris Naraev
California UCSF Medical Center Mission Bay San Francisco Now tbc
California – Antioch Kaiser Permanente Antioch Medical Center Now tbc
California Cedars Sinai Medical Center LA now tbc
California Stanford Medical Center Now tbc
California Kaiser Permanente Los Angeles Medical Center Now tbc
California Hoag Hospital Newport Beach Now tbc
California UCLA Health Now tbc
California Kaiser Santa Clara Medical Center Now tbc
California City of Hope LA Now tbc
California San Diego Now tbc
Connecticut Yale New Haven Medical Center Now tbc
Colorado Rocky Mountain Cancer Center Denver Now Dr Eric Liu
Colorado University of Colorado UC Health Denver Now tbc
Florida Moffat Tampa Now Dr Strosberg
Florida University of Miami Now tbc
Florida Mayo Jacksonville Now tbc
Florida Winter Park, Florida Radiation Oncology Orlando Now David Diamond MD
Florida Orlando Health Now tbc
Georgia CCTA Newnan, Atlanta Now Dr. Phan
Hawaii Queen’s Medical Center Now Dr. Marc Coel
Illinois Rush University Chicago Now
Illinois Northwestern Chicago now tbc
Illinois The University of Chicago Medicine now Xavier M. Keutgen, MD
Illinois Loyola University Medical Center Maywood now tbc
Indiana Indiana University Health now tbc
Iowa University of Iowa now Dr T O’Dorisio
Kansas University of Kansas Medical Center Fairway now tbc
Kentucky University of Kentucky, Markey Cancer Center now tbc
Louisiana Ochsner now tbc
Maryland John Hopkins Baltimore now tbc
Massachusetts Dana Farber Boston Now tbc
Massachusetts Massachusetts General Hospital Now tbc
Michigan Ann Arbor Now tbc
Michigan Detroit – Karmanos Cancer Center Now tbc
Minnesota Mayo Rochester 26 Apr 2018 Dr. Thor Halfdanarson
Minnesota University of Minnesota Health Now tbc
Missouri Sara Canon Cancer Center Kansas City Now tbc
Missouri Siteman Cancer Center St. Louis/Barnes Jewish Hospital St. Louis Now tbc
Nebraska CHI Bergan Now Dr Samuel Mehr
Nebraska Nebraska Cancer Specialists Omaha Now Dr Samuel Mehr
New York Lenox Hill NYC Now tbc
New York Sloan Kettering Now tbc
New York Roswell Park Buffalo Now Dr Iyer
New York Mount Sinai Now tbc
New York NYU Langone Now tbc
North Carolina Dukes Durham Now tbc
Ohio The James, Columbus Now Dr Shah
Oregon Oregon Health & Science University (OHSU) Now tbc
Pennsylvania UPMC Pittsburgh Now tbc
Pennsylvania Fox Chase Philadelphia Now Dr Paul Engstrom
Rhode Island Rhode Island Hospital Providence Now Dr Paul Engstrom
Tennessee Vanderbilt Nashville Apr 2018 tbc
Texas MD Anderson Houston Summer 2018 tbc
Texas Excel Diagnostics Houston Now tbc
Texas CHI St Lukes Houston Now tbc
Utah Huntsman Cancer Institute, Salt Lake City 10 May tbc
Virginia Carilion Clinic Roanoke now tbc
Washington (State) Virginia Mason Seattle Now Dr. Hagen Kennecke
Washington (DC) VMedStar Georgetown University Hospital Now tbc
West Virginia VMU Cancer Institute Morgantown Now Shalu Pahuja, M.D
Wisconsin UW Health Madison, Carbone Cancer Center Now Noelle K. LoConte, MD Specialty: Medical Oncology Primary Location: UW Carbone Cancer Center (608) 265-1700 (800) 323-8942
 Wisconsin  Froedtert Milwaukee  Now  Dr Thomas

Europe 

The European Medicines Agency (EMA) “market authorisation” received a positive indication on 20th July followed by EC approval on 29 Sep 2017.   The positive indication reads “Lutathera is indicated for the treatment of unresectable or metastatic, progressive, well differentiated (G1 and G2), somatostatin receptor positive gastroenteropancreatic neuroendocrine tumours (GEP NETs) in adults”. Of Course, the decision to fund the drug will be with national approval organisations.  Whilst I’m sure there are many more, these well-known centres have been making PRRT available for some years (but please note there are others):

Netherlands – Rotterdam Treatment Centre – click here

Netherlands – the combined NET centres of the UMCU Utrecht and AVL Amsterdam have an ENET certification and they both do PRRT.

UMCU – Utrecht
https://www.umcutrecht.nl/nl/Ziekenhuis/Ziekte/PRRT-behandeling-bij-NET-kanker
(only available in dutch)

AVL – Amsterdam
https://www.avl.nl/behandelingen/peptide-receptor-radionuclide-therapie-prrt/
(only available in dutch)

Sweden – Department of Endocrine Oncology Uppsala University Hospital – click here

Switzerland – University Hospital Basel, Radiology & Nuclear Medicine Clinicclick here

Germany – Zentralklinik Bade Berkaclick here

Denmark – ‘Rigshospitalet’ since 2009. They have treated around 250 patients- and given 800 treatments.

Finland – Helsinki: Docrates Cancer Center

I’d be interested to hear from countries in Europe with their full list of centres or a link to it.

Australia

Australia seems to be ahead of the game or that is what I sense when I read output from there.  There’s a good section on the Australian effort – click here.

New Zealand

These guys have had to fight to get some progress on the provision of PRRT.  Currently New Zealanders have to go to Melbourne Australia for treatment – almost 50 New Zealanders with NETs are currently raising tens of thousands of dollars to pay for treatment in Australia because the life-prolonging treatment isn’t available locally. But this could change in 2018.  Unicorn Foundation New Zealand announced that Pharmac, the New Zealand government agency that decides which pharmaceuticals, have said that PRRT will be funded for patients with medium priority for the treatment of unresectable or metastatic, well-differentiated NETs (irrespective of primary site) that express somatostatin receptors.

Africa

South Africa:

Middle East, Asia and the Far East

Turkey – Istanbul, Dr.Levent Kabasakal.

IsraelHadassah Medical Center, Jerusalem – click to read

Lebanon – The American Hospital of Beirut – Dr Ali Shamseddine “We have started using Lu-177 here in Lebanon. So far, we have treated 3 patients, with good response. The operational cost is much less than in Europe”.  

Ali Shamseddine, MD, CHB Professor and Head of Division as04@aub.edu.lb

India – Mahatma Gandhi Cancer Hospital, Visakhapatnam. Recently started radionuclide therapy. Although only currently available privately, some patients have been sponsored by the companies that they work for. Point of contact is Dr. K. Raghava Kashyap. I’ve been assured by CNETS India that many locations have PRRT capability – contact them direct please.

TATA Memorial Hospital Mumbai (waiting time is long, but cost is low: $200) and there are private clinics in Pune (cost is $1500) and Bengaluru (cost is around $6000).  (Info from Russian patient group)

Malaysia

Sunway medical Centre

Beacon hospital

Pakistan – check out this article – click here

Singapore – Singapore General Hospital and National University Hospital.  

Philippines – St. Luke’s Medical Center, Global City, Taguig, Metro Manila.

South America

Chile – Instituto Oncológico Fundación Arturo López Pérez, Santiago

——————————————–

What’s next for NETs PRRT?

See this great summary from NET Research Foundation of what might be next plus basic facts about PRRT – click here

Thanks for reading

Ronny

I’m also active on Facebook. Like my page for even more news. I’m also building up this site here: Ronny Allan

Disclaimer

My Diagnosis and Treatment History

Most Popular Posts

Sign up for my twitter newsletter

Remember ….. in the war on Neuroendocrine Cancer, let’s not forget to win the battle for better quality of life!


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patients included

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Neuroendocrine Cancer – If you can see it, you can detect it!

octreo-vs-g68
Octreoscan vs Ga68 PET

Scanning is a key diagnostic support and surveillance tool for any cancer.  Even though you have elevated bloods or urine (….or not), a picture of your insides is really like a thousand words…. and each picture has a story behind it.  Scanning can be a game changer in the hunt for tumours and although scans do not normally confirm the cancer type and grade, they certainly help with that piece of detective work and are key in the staging of the cancer.

When I read stories of people in a difficult diagnosis, I always find myself saying ‘a scan might resolve this’ and I always suggest people should try to get one.  Even in the case of a story about late diagnosis or a misdiagnosis, I find myself thinking ‘if only they had done a scan earlier’.  Despite what you read on NET forums, a CT scan will be able to find some evidence of tumour activity in 90-95% of cases.  However, some are cunningly small or hiding and it can be like trying to find a needle in a haystack.

However, scans are not an exact science…..not yet!   Apart from human error, sometimes tumours are too small to see and/or there are issues with ‘pickup’ (i.e. with NETs, nuclear scans need efficient somatostatin receptors).  The differences between scan types are more quality (sensitivity) related as new technologies are introduced.

As for my own experience, I was very lucky.  I managed to get a referral to a specialist early on in my diagnosis phase. He looked at the referral notes and said “what are you doing this afternoon“. I replied “whatever you want me to do“.  He didn’t know I had cancer but his instincts led him to believe he needed to see inside my body, he wanted to scan me.  The scan results were pretty clear – I had a metastatic Cancer and further checks were now needed to ascertain exactly what it was. So I took my seat on the roller coaster.  Medicine is not an exact science (not yet anyway) but here’s something I believe is a very common occurrence in all cancers – If your doctors don’t suspect something, they won’t detect anything.

There’s frequent discussion about the best types of scans for different types of NETs and which is best for different parts of the anatomy.  There’s also different views on the subject (including in the medical community),  However, a few well known facts can be gleaned from authoritative NET sources:

Conventional Imaging

Computed Topography (CT)

CT scans are often the initial imaging study for a patient presenting with signs or symptoms suggestive of many cancers including NET. These studies are most useful for disease staging and surgical planning as they provide excellent anatomic detail of the tumors themselves and surrounding structures. Primary NETs (GI and lung NETs) and their metastases are generally hyperenhancing with IV contrast and are best seen in the arterial phase of a triple phase CT scan.

In primary NETs, the average sensitivity of a CT scan is 73%. CT scans have even better sensitivity in detecting NET metastases, as they demonstrate 80% sensitivity for liver metastases (but see MRI below) and 75% sensitivity for other metastases (non-liver). This modality is also useful when the primary tumor site is unknown. In one single-institution retrospective study, it was the most common study ordered to look for an unknown primary tumor site and was able to uncover the primary in 95% of cases.

Magnetic resonance imaging (MRI)

MRI is the best conventional study to detail liver metastases in NETs. It is not as useful as CT for the detection of primary small bowel lesions or their associated lymphadenopathy, but is good for the detection of primary pancreatic NETs. A study comparing MRI, CT and standard somatostatin receptor-based imaging (OctreoScan) reported 95.2% sensitivity for MRI, 78.5% sensitivity for CT and 49.3% sensitivity for the OctreoScan in detecting hepatic metastases. MRI also detected significantly more liver lesions than the other two modalities.

You may see something called Magnetic Resonance Cholangiopancreatography (MRCP).  Magnetic resonance cholangiopancreatography (MRCP) is a special type of magnetic resonance imaging (MRI) exam that produces detailed images of the hepatobiliary and pancreatic systems, including the liver, gallbladder, bile ducts, pancreas and pancreatic duct.

Ultrasound (US)

Liver_Metastases_Ultrasound

The primary role of conventional ultrasound in neuroendocrine disease is detection of liver metastases and estimation of total liver tumor burden. This technique has the advantages of near-universal availability, intraoperative utility, minimal expense and lack of radiation. Most examinations are performed without contrast, which limits their sensitivity (compared with CT and MRI).  I know in my own situation, US was used as a quick check following identification of multiple liver metastasis during a CT scan. I’ve also had US used to monitor distant lymph nodes in the neck area but always in conjunction with the most recent CT scan output.

Endoscopic Ultrasound (EUS)

EUS

With increased access to endoscopy, NETs in the stomach, duodenum, and rectum are increasingly incidentally detected on upper endoscopy and colonoscopy. Patients are frequently asymptomatic without any symptoms referable to the a NET (i.e. non-functional).  EUS has also been used to survey patients at increased risk of developing pancreatic NETs. For example, patients with multiple endocrine neoplasia (MEN).  They are also frequently used in conjunction with biopsies using fine needle aspiration (FNA) guided by EUS.

18FDG PET

18-Fluoro-Deoxy-Glucose PET (FDG PET) is used to detect malignancy for a variety of tumor types. Unfortunately, its utility has not been borne out in NETs, as the majority of NETs tend to be relatively metabolically inactive and fail to take up the tracer well. However, high-grade NETs are more likely to demonstrate avid uptake of 18FDG, giving these scans utility in identifying tumors likely to display more aggressive behavior.

18F-FDOPA PET

The use of Fluoro-18-L-Dihydroxyphenylalanine (18F-FDOPA) in PET was developed in the 80’s for the visualisation of the dopaminergic system in patients with degenerative disorders, such as Parkinson’s Disease and related disorders. The first publication on the use of 18F-FDOPA PET for brain imaging was in 1983, which was followed by many others on the use of 18F-FDOPA PET for the diagnosis of Parkinson’s disease. Years later, in 1999 the first publication on the use of 18F-FDOPA PET for imaging of neuroendocrine tumour appeared. The value of 18F-FDOPA PET has now been proven for the diagnosis and staging of many neuroendocrine tumours, brain tumours and congenital hyperinsulinaemia of infants.

18F-FDOPA is accurate for studying well differentiated tumours. However the difficult and expensive synthesis have limited its clinical employment. It currently can be successfully used for imaging tumours with variable to low expression of somatostatin receptors (SSTR) such as Medullary Thyroid Carcinoma, Neuroblastoma, Pheochromocytoma), and others that cannot be accurately studied with Somatostatin SSTR scans such as the OctreoScan (Somatostatin Receptor Scintigraphy (SRS)), which uses the ligand 111In-DPTA-D-Phe-1-octreotide or the newer 68Ga DOTA-peptides.

I-MIBG

Radioiodinated (123I) metaiodobenzylguanidine (MIBG) is an analog of norepinephrine that is used to image catecholamine-secreting NETs such as pheochromocytomas, paragangliomas and glomus tumors. It can also be used to look for Neuroblastoma in children. In patients with functional pheochromocytomas or paragangliomas, this modality has a sensitivity of 90% and positive predictive value of 100%. However, it has limited use in Gastrointestinal (GI) NETs, as this modality was positive in only 49.1% of patients. In the same cohort of patients, OctreoScan was positive in 91.2%. As an imaging tool, this study is best used to confirm a diagnosis of pheochromocytoma or paraganglioma and define the extent of metastatic disease in these tumors. (Note – the Ga68 PET is rising in prominence though). Its most practical use in GI NETs may be to determine whether patients with metastases may benefit from treatment with 131I-MIBG (a form of radiotherapy).

Somatostatin receptor-based imaging techniques

owl ga68
Graphic courtesy of Advanced Accelerator Applications

Somatostatin is an endogenous peptide that is secreted by neuroendocrine cells, activated immune cells and inflammatory cells. It affects its antiproliferative and antisecretory functions by binding to one of five types of somatostatin receptors (SSTR1- SSTR5). These are G-protein coupled receptors and are normally distributed in the brain, pituitary, pancreas, thyroid, spleen, kidney, gastrointestinal tract, vasculature, peripheral nervous system and on immune cells. Expression of SSTRs is highest on well-differentiated NETs. Somatostatin receptor type 2 is the most highly expressed subtype, followed by SSTRs 1 and 5, SSTR3 and SSTR4.

It must be noted that even the most modern scans are not an exact science.  Radionuclide scans are like conventional imaging, they can be subject to physiological uptake or false positives, i.e. they can indicate suspicious looking ‘glows’ which mimic tumours.  This article explains it better than I can – click here.

The ubiquity of SSTRs on NET cell surfaces makes them ideal targets for treatment (e.g. Somatostatin Analogues (Octreotide/Lanreotide) and PRRT), but also for imaging. There are two primary types of somatostatin receptor-based imaging available:

Octreoscan – In111 based

The most common (currently) is the OctreoScan or Somatostatin Receptor Scintigraphy (SRS), which uses the ligand 111In-DPTA-D-Phe-1-octreotide and binds primarily to SSTR2 and SSTR5. In its original form, it provided a planar, full body image. In modern practice, this image is fused with single photon emission computed tomography (SPECT) and CT. This takes advantage of the specificity of the OctreoScan and the anatomic detail provided by SPECT/CT, improving OctreoScan’s diagnostic accuracy. These improvements have been shown to alter the management in approximately 15% of cases, compared with just OctreoScan images. In primary tumors, the OctreoScan’s sensitivity ranges from 35 to 80%, with its performance for unknown primary tumors dipping beneath the lower end of that range (24%). Its ability to detect the primary is limited by the size but not SSTR2 expression, as tumors less than 2 cm are significantly more likely not to localize but do not have significantly different SSTR2 expression than their larger counterparts.

Octreoscan – Tc99m based

In one study, it was shown that sensitivity and negative predictive
values of Tc-99m-Octreotide scan is significantly higher than that of CT
and MRI. Using Tc-99m instead of In-111 had several advantages that
include better availability, cheaper and higher quality images. In
addition, to less radiation exposure to both patients and nuclear
medicine personnel.  In the absence of Ga68 PET, this could prove a reliable alternative.  Please note this scan is completed in a single day vs In111 Octreotide time of 2-3 days.

Ga68 PET (or SSTR PET in general)

The newest somatostatin receptor-based imaging modality, although it has been around for some time, particularly in Europe. The most common of these labeled analogs are 68Ga-DOTATOC, 68Ga-DOTANOC and 68Ga-DOTATATE. They may be known collectively as ‘SSTR-PET’.  Additionally, the DOTATATE version may often be referred to as NETSPOT in USA but technically that is just the commercial name for the radionuclide mix.

Read more about Ga68 PET scans by clicking here

These peptides are easier and cheaper to synthesize than standard octreotide-analog based ligands, boast single time point image acquisition compared to 2 or 3 days with Octreoscan. Its superior spatial resolution derives from the fact that it measures the radiation from two photons coincidentally. SPECT, in comparison, measures the gamma radiation emitted from one photon directly. This results in different limitations of detection – millimeters for 68Ga-PET compared with 1 cm or more for SPECT. There are a few choices of ligands with this type of imaging, but the differences lie primarily in their SSTR affinities – all of the ligands bind with great affinity to SSTR2 and SSTR5. 68Ga-DOTANOC also binds to SSTR3. Despite these differences, no single 68Ga ligand has stood out as the clear choice for use in NETs. As with standard somatostatin receptor-based imaging, these 68Ga-PET studies are fused with CT to improve anatomic localization.

Comparison studies between 68Ga-PET and standard imaging techniques (CT, OctreoScan) have universally demonstrated the superiority of 68Ga-PET in detection of NET primary tumors and metastases. Two early studies compared 68Ga-DOTATOC to standard somatostatin imaging (SRS)-SPECT and CT. Buchmann et al. reported that 68Ga-DOTATOC detected more than 279 NET lesions in 27 patients with histologically proven NETs, whereas SRS-SPECT detected only 157. The greatest number of lesions were detected in the liver. 68Ga-DOTATOC found more than 152 hepatic lesions, while SRS-SPECT found only 105, resulting in a 66% concordance rate between the two modalities. The concordance for abdominal lymph nodes was worse at 40.1%.  Cleary these advantages are going to impact on treatment plans, some needing to be altered.  In addition, 68Ga-DOTA PET imaging can be used to determine which patients might benefit from use of Somatostatin Analogues (Octreotide/Lanreotide) and PRRT – you can read more about this integrated and potentially personalised treatment in my article on ‘Theranostics‘ – click here.

It’s worth pointing out that SSTR PET is replacing previous types of radionuclide scans, mainly Octreoscan (Indium 111) and is not replacing conventional imaging (CI) such as CT and MRI etc.  Whilst SSTR-PET has demonstrated better sensitivity and specificity than CI and In-111, there are specific instances in which SSTR-PET is clearly preferred: at initial diagnosis, when selecting patients for PRRT, and for localization of unknown primaries. For patients in which the tumor is readily seen on CI, SSTR-PET is not needed for routine monitoring.  The Journal of Nuclear Medicine has just published “Appropriate Use Criteria for Somatostatin Receptor PET Imaging in Neuroendocrine Tumors” which gives guidance on it’s use – issued by the Society of Nuclear Medicine and Molecular Imaging (SNMMI).


Parathyroid Scan – Sestamibi

Sestamibi scanning is the preferred way in which to localize diseased parathyroid glands prior to an operation. This parathyroid scan was invented in the early 1990’s and now is widely available. Sestamibi is a small protein which is labeled with the radio-pharmaceutical technetium99 (Tc99m). This very mild and safe radioactive agent is injected into the veins of a patient with hyperparathyroidism (parathyroid disease) and is absorbed by the overactive parathyroid gland. Since normal parathyroid glands are inactive when there is high calcium in the bloodstream, they do not take up the radioactive particles. When a gamma camera is placed over the patient’s neck an accurate picture will show the overactive gland.  Only the overactive parathyroid gland shows up…a very accurate test.

The Sestsestamibiamibi scan will display the hyperactive gland which is causing hyperparathyroidism in about 90 percent (90% sensitivity) of all patients. If the Sestamibi does show the hyperactive gland it is almost always correct (98-100% specificity). It takes approximately two hours to perform the Sestamibi scan after it has been injected. Pictures of the neck and chest are usually taken immediately after the injection and again in 1.75 to 2.0 hours (shown above). Newer techniques allow for more complete two and three dimensional images to be obtained of a patient’s neck. This technique is called SPECT scanning (Single Proton Emission Computerized Tomography) but it is usually not necessary.

Taking the camera inside and directly to the Tumour

Of course there are other ways to “see it” via several types of Endoscopy procedures – taking the camera to the tumour.  Read my article about this by clicking here

A look to the future of PET Scans

explorer pet scan

Just imagine something which is 40 times better than current PET scan technology?  That’s what the scientists are working on now.  Here’s an example called “EXPLORER“.  Clearly there are more answers required in order to see if this is suitable for use with NETs (i.e. will it work with our radionuclide tracers etc) but it is very exciting and like something out of Star Trek.  A little bit of me is worried about ‘overdiagnosis’ so interpretation of something that detailed will be very important to avoid unnecessary worry. Read more here and there is a later update here.  Check out this cool video of the 3D images:

Summary

If you can see it, you can detect it.

Sources:

1. Imaging in neuroendocrine tumors: an update for the clinician, Maxwell, Howe.

2. Appropriate use Criteria for Somatostatin Receptor PET Imaging in Neuroendocrine Tumors.

3.  Useful video from NET Research Foundation about which scans to use for which job.  CLICK HERE to watch.

4.  Useful video summary from the NET Patient Foundation describing the different scans for NET Cancer and what to expect.  Worth a look.  CLICK HERE for the scan video

Sooner we can ALL get access to the latest radionuclide scans the better – this is currently an unmet need in many countries.

If you are any doubt about which type of scan is best for you and their availability, please consult your specialist.

 

Scanning is a key diagnostic and surveillance tool for any cancer.  Even though you have elevated bloods or urine (….or not), a picture of your insides is really like a thousand words…. and each picture has a story behind it.  Scanning can be a game changer in the hunt for tumours and although scans can’t (yet) confirm the cancer type and grade, they certainly help with that piece of detective work and are key in the staging of the cancer.

When I read stories of people in a difficult diagnosis, I always find myself saying ‘a scan might resolve this’ and I always suggest people should try to get one.  Even in the case of a story about late diagnosis or a misdiagnosis, I find myself thinking ‘if only they had done a scan earlier’.  Despite what you read on NET forums, a CT scan will normally find some evidence of most tumour activity.

However, scans are not an exact science…..not yet!   Apart from human error, sometimes tumours are too small to see and/or there are issues with ‘pickup’ (i.e. with NETs, nuclear scans need efficient somatostatin receptors).  However, technology is improving all the time and you can read about this in my blog Neuroendocrine Cancer – Exciting times Ahead.

As for my own experience, I was very lucky.  I managed to get a referral to a specialist early on in my diagnosis phase. He looked at the referral notes and said “what are you doing this afternoon”. I replied “whatever you want me to do”.  He wanted to scan me.  He didn’t know I had cancer but his instincts led him to believe he needed to see inside my body. The scan results were pretty clear – I had a metastatic Cancer and further checks were now needed to ascertain exactly what it was. So I took my seat on the rollercoaster.  Here’s something I always say I believe is so much better than the  impractical early diagnosis messages that seem to pervade our community:  If your doctors don’t suspect something, they won’t detect anything and I believe this is a very frequent outcome of many diagnoses for many cancers (not just NETs).

There’s frequent discussion about the best types of scans for different types of NETs and even for different parts of the anatomy.  This is correct and there’s also different views on the subject (including in the medical community),  However, a few well known facts that can be gleaned from authortative NET sources. I found this useful video summary from the NET Patient Foundation describing the different scans for NET Cancer and what to expect.  Worth a look.

Sooner we can all get access to the latest radionuclide scans the better!

CLICK HERE for the scan video

Thanks for reading

Ronny

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Remember ….. in the war on Neuroendocrine Cancer, let’s not forget to win the battle for better quality of life!

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