Gallium 68 PET Scans – Into the Unknown

OPINION

Cancer is a growth industry …literally! More people are being diagnosed than ever before. Fortunately, more people are surviving than ever before. This is against a backdrop of better awareness, better screening in the big population cancers, and to a certain extent better diagnostic tools, all of which is leading to earlier diagnosis.

So how does this affect Neuroendocrine Cancer?

According to the latest SEER database figures for Neuroendocrine Cancer, one reason for the 7 fold increase in incidence rates since the 1970s is all of those things above including better diagnostics. This has led to a revised set of epidemiological information in many countries that have made the effort to accurately update their cancer registries and there are consistent reports of incidence rates way beyond the recognised rare thresholds. Another piece of good news is that the increase in NET incidence is also due to earlier diagnosis. To sum that up – NETs is also a growth industry.

Better diagnostics

Combined with more awareness and education (including the important pathologists), more NETs than ever are being found, and many found earlier. However, it’s not party time yet because there remains far too many misdiagnoses due to the low population of the disease and the difficulty in diagnosing it. I want to focus on scanning (thus the title of the article). Whilst there are really important factors involved in a diagnosis, such as tumor and hormone markers, and biopsies (tissue is the issue), a scan is very frequently what triggers many deeper investigations to unearth a NET, i.e. if you can see it, you can normally detect it (whatever the ‘it’ is). And I include the widespread availability and increasing advances in endoscopy/ultrasounds/cameras which have also been instrumental in picking up many Gastrointestinal NETs.

The Gallium 68 PET Scan

There’s a lot of excitement about the Gallium 68 PET Scan since it was approved by the US FDA. It’s not new though and has been in use in several countries for some time. It’s a ‘nuclear scan’ and can often form part of what is known as a ‘Theranostic Pair’ (i.e. in conjunction with a therapy – read more here).

Latest News on the Ga68 PET – 21st Aug 2019 

The US FDA has just approved a second radionuclide tracer for Ga68 PET.

NETSPOT which was approved some time ago, used the “DOTATATE” version but the latest approval is based on “DOTATOC”. I’m not sure why yet but the application has been in the pipeline for 2 years. I suspect it’s to increase availability. I checked several DOTATATE vs DOTATOC technical papers and it looks like they have similar effectiveness.

This radionuclide will be manufactured in the University of Iowa so it’s not a kit like NETSPOT or the European equivalent (SOMAKIT TOC – edotreotide). Details of how University of IOWA will price and market it (insurance companies etc), and then ship it etc, are not yet available.

New approval includes adult and pediatric patients.

“FDA approves new radioactive diagnostic agent indicated for use with positron emission tomography (PET) for localization of somatostatin receptor positive neuroendocrine tumors (NETs) in adult and pediatric patients”

. Read more by clicking here.

What does it do? How does it work?

It comprises two main components – a PET scanning machine, and the use of a diagnostic imaging agent which is injected into the person undergoing the scan. The agent is a somatostatin analogue labeled radionuclide (Gallium 68) and basically the PET will then be used to see where the peptide/radionuclide mix ‘loiters’ (i.e. where there are concentrations of somatostatin receptors (SSTR) normally indicating ‘focal intense abnormality‘ of the type that is regularly found with NETs.

Fusion of functional scans (e.g. PET) and anatomical scans (e.g. CT/MRI)

Most PET machines have an inbuilt CT (or much less frequently, a built in MRI) which forms part of the scan but normally only the Ga68 tracer will be given.  Your specialist is likely to show you the fused images of the PET and the CT as this provides both anatomical (CT) and functional (PET) view which is more efficient because the PET scan does not show ‘anatomical landmarks’.  When you get the written report summarising the scan results, you may find some of the observations are written in the context of what was saw on the fusion view, i.e. a correlation of both. Many measurements of tumours will have been taken from the CT rather than the Ga68 PET which is in effect a ‘glow’ and does not. Many people assume that the Ga68 sees everything – it doesn’t and it’s more likely to over-report (i.e. physiologic uptake – see pitfalls section below) – the CT remains a double check and is better at sizing tumours that can be seen.

The advantage of scan fusion is obvious and works both ways, i.e. subtle findings on a PET that might otherwise be disregarded or interpreted as physiologic variants, may lead to detection of a malignant process after being correlated with simultaneously acquired CT. Alternatively, equivocal CT findings, which could represent malignant tumor, reactive changes, or fibrosis, can be clarified with the help of the additional metabolic information provided by concurrent PET.

Accurate interpretation of Ga68 PET scans (and other NET related variants) requires a thorough knowledge of the normal physiologic distribution of the associated radionuclide tracer to avoid to ensure the patient gets the right therapy moreover not to get unnecessary therapy.

Imaging Agents. There are different agent variants, namely, DOTATATE, DOTATOC and DOTANOC. In USA, you may sometimes see this referred as NETSPOT which is more of a commercial label for the agent (NETSPOT is a DOTATATE). Ga68 PET or SSTR PET are common descriptors for the entire process regardless of the compound. Clearly the scan works best for those with ‘somatostatin receptor positive’ tumours.

These newer agents have several benefits over the elderly In111-pentetreotide (Octreotide scan), including improved detection sensitivity, improved patient convenience due to the 2-3 hour length of the study (compared to 2 or 3 days with Octreoscan), decreased radiation dose, decreased biliary excretion due to earlier imaging after radiotracer administration, and the ability to quantify uptake. The quantification of the uptake can help decide whether a patient is suitable for radionuclide therapy such as PRRT. Eventually, all Octreotide scans should be replaced with SSTR PET but it will take some time (and money).

To confirm the advantages of SSTR PET over Octreotide scans, a study comprising 1,561 patients reported a change in tumour management occurred in over a third of patients after SSTR PET/CT even when performed after an Octreotide scan. Worth pointing out that SSTR PET is replacing the ageing Octreotide scan and not conventional imaging (CI). You can see the recommended scenarios for use of SSTR PET in this article published by the Journal of Nuclear Medicine. The slide below is interesting, although it was a small study. However, you can see the treatment changes as a result of a Ga68 PET are quite striking.

Appropriate Use Criteria for Somatostatin Receptor PET Imaging in Neuroendocrine Tumors

I see many people complaining because the cannot get access to a Ga68 PET which is available through their healthcare system or local hospital. Many of these issues are insurance based.  Worth pointing out that there are actually recommended usages for the Ga68 PET scan here.  For example, it is not recommended for routine surveillance in place of Conventional Imaging (CI).

Any pitfalls with Ga68 PET Scan?

When you look at the study data above, it looks like an excellent addition to the diagnostic and surveillance toolkit for NETs. However, one of the challenges with modern scanning equipment and techniques is the ability to correctly interpret the results – in my opinion, this is almost as important as the efficiency of the machines and radionuclides. This requirement has been acknowledged in many articles and I particularly like this technical paper from a very experienced nuclear medicine physician Professor Michael Hofman from the Centre for Cancer Imaging at the Peter MacCallum Cancer in Melbourne. I had a chat with Professor Hofman who added that this is a very sensitive scan, so often picks up “new” disease, which isn’t really new, just never identifiable on standard imaging. However, there’s an excellent section on pitfalls in interpretation and I’m quoting an abstract below.

“Although GaTate PET/CT is a highly sensitive and specific technique for NETs, the attending physician or radiologist must be aware of various physiologic and other pathologic processes in which cellular expression of SSTR can result in interpretative error. Most of these processes demonstrate low-intensity and/or nonfocal uptake, in contrast with the focal intense abnormality encountered in NETs. Causes of interpretative pitfalls include prominent pancreatic uncinate process activity, inflammation, osteoblastic activity (degenerative bone disease, fracture, vertebral hemangioma), splenunculi or splenosis, and benign meningioma.”

“The highest-intensity physiologic uptake of GaTate is seen in the spleen, followed by the adrenal glands, kidneys, and pituitary gland”

It follows that failure to interpret nuclear scans alongside the patient’s clinical history can sometimes result in two big issues for patients:

1. Unnecessary worry when ‘something’ shows up which is actually a false positive.

2. Something which leads to irreversible treatment when it is was not required.

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“. You can update yourself here. The issue of interpretation will be even more difficult when the new generation of scans appear. There’s an excellent article from Cancer Research UK talking about the modern phenomenon called ‘overdiagnosis’ – read here

Short extract of interpretative pitfalls in this table:

Lanreotide/Octreotide and timing of the scan?

From the same technical document referred above, here’s an extract (updated to include Lanreotide). “Uptake at physiologic and pathologic sites may change in patients who undergo concomitant short- or long-acting somatostatin analog therapy, which competes with the radiotracer for bioavailability. We generally discontinue short-acting octreotide for 12–24 hours and perform imaging in the week before the next dose of long-acting Octreotide/*Lanreotide, which is typically administered monthly“.  It’s actually the same text as found in the manufacturer’s drug leaflet (click here). More evidence behind the reason for this restriction is found here (please refer to the comments on Ga68 PET – the article also covers the issue of PRRT which is very interesting as a separate subject to the scan timings).  There are no other restrictions on standard therapy for NETs.

*added by the author for completeness.

Dietary Restrictions and Preparation

There appears to be conflicting guidance issues by centres. However, other than drinking plenty of water there are no dietary restrictions or preparations for this scan, this appears common in the world’s most experienced PET centres. The main reason is that Ga68 is known to almost exclusively target somatostatin receptor 2A which is not affected by diet.  This is confirmed in the manufacturer’s drug leaflet (click here).

Radiation safety after the scan

A frequently asked question is how safe am I after the scan.  According to Royal Free London, one of the most experienced centres in the world, “the amount of radiation that you will receive from the scan is equivalent to seven years of background radiation. If you have any concerns about radiation you can ask to talk to a physicist or a doctor in the nuclear medicine department.  There are no side-effects associated with the scan and once you finish your test you may resume normal activities, although we advise you not to spend prolonged time in close contact (<1m distance) with pregnant women or small children for six hours following your scan”.  Read more of the Royal Free advice by clicking here.  Please note this advice may differ from hospital to hospital and from country to country.  Always check with your own specialist or PET Centre.

Having my first Ga68 PET Scan after 8 years of  living with NETs?

When I was offered my very first Ga68 PET/CT at my recent 6 monthly surveillance meeting, I was both excited and apprehensive. I was diagnosed in 2010 and my staging was confirmed via an Octreotide Scan pointing out two further deposits (one of which has since been dealt with). I’ve had two further Octreotide Scans in 2011 and 2013 following 3 surgeries. The third octreotide scan in 2013 highlighted my thyroid lesion – still under a watch and wait regime. So far, my 6 monthly CT scans seemed to be adequate surveillance cover and my markers remain normal.

I’m apprehensive because of the ‘unknown’ factor with cancer – what is there lurking in my body that no-one knows about and which might never harm me.

I’m excited because it might just confirm that there is nothing new to worry about.

However, I’m both excited (morbidly) and apprehensive because the scan might find something potentially dangerous. As we know, NETs are mostly slow growing but always sneaky. That said, at least I will know and my medical team will know and be able to assess the risk and decide on a course of action.

Doing the Scan

On 5th June 2018, I attended a very experienced Ga68 PET establishment called Guys Cancer Centre in London.  I arrived and was immediately taken under the wing of the nuclear medicine guys who asked me fairly in depth questions about my clinical background.  They then inserted a cannula ready for the injection of the radiolabelled tracer.  I was then installed in the ‘hot room’ where they injected the radionuclide tracer through the cannula and then I had to remain in the hot room for 1 hour to let the tracer circulate.  After 1 hour, I was taken to the PET scanner and it took around 30-35 minutes. Following that I was allowed to leave for home.  It was an extremely easy experience and a significant improvement on doing the 3 day Octreotide scan.

The Results of the Ga68 PET Scan – CLICK HERE