Neuroendocrine Cancer: Ga68 PET Scan – a game changer?

When I was offered my very first Ga68 PET/CT at a 6 monthly surveillance meeting in May 2018, I was both excited and apprehensive. Let me explain below why I had a mix of emotions.

I was diagnosed in 2010 with metastatic NETs clearly showing on CT scan, the staging was confirmed via an Octreotide Scan which in addition pointed out two further deposits above the diaphragm (one of which has since been dealt with). In addition to routine surveillance via CT scan, I had two further Octreotide Scans in 2011 and 2013 following 3 surgeries, these confirmed the surveillance CT findings of remnant disease. The third scan in 2013 highlighted an additional lesion in my thyroid (still under a watch and wait regime, biopsy inconclusive but read on….).

To date, my 6 monthly CT scans seem to have been adequate surveillance cover and all my tumour and hormone markers remain normal. I’m reasonably fit and well for a 62-year-old.

Then I ventured into the unknown

this is not actually my scan!

I wrote a comprehensive post about the Ga68 PET entitled “…. Into the unknown” – so named because that is how I felt at the time. It’s well-known that the Ga68 is a far superior nuclear scan to the elderly Octreotide type, showing much greater detail with the advantage of providing better predictions of PRRT success if required downstream. It has been a game changer for many and if you look below and inside my article, you will see statistics indicating just how it can ‘change the game’ in somatostatin receptor positive Neuroendocrine Cancer diagnostics and treatment.

The excitement of the Ga68 PET

I was going to get the latest ‘tech’ and thought it could be useful confirmation of what I already knew. I also felt lucky to get one, they are limited in UK and there has to be a clinical need to get access. I was excited because it might just rubber stamp the stability I’ve enjoyed for the past 5 or so years since my last surgery in 2012.

The apprehension of the Ga68 PET

I also felt apprehensive because of the ‘unknown’ factor with cancer, i.e. what is there lurking in my body that no-one knows about, and which might never harm me but this scan will light it up demanding attention. I was also apprehensive in case this more detailed scan found something potentially dangerous. As we know, NETs are mostly slow-growing but always sneaky. Of course, any new tumours found may not actually be new, they were just not seen until the Ga68 PET was able to uncover them.  How annoying!

Is the Ga68 PET Scan a game changer?

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.

  • Overall, change in management occurred in 44% (range, 16%-71%) of NET patients after SSTR PET/CT.
  • In 4 of 14 studies, SSTR PET/CT was performed after an 111In-Octreotide scan. In this subgroup, additional information by SSTR PET/CT led to a change in management in 39% (range, 16%-71%) of patients.
  • Seven of 14 studies differentiated between inter- and intramodality changes, with most changes being intermodality (77%); intramodality, (23%). (note: intermodality means changes within the same treatment, intramodality means change to another treatment).

In an older study, this slide from a NET Research Foundation conference shows some more interesting statistics:

wp-image-991783422jpg
This slide from a recent NET Research Foundation conference confirms the power of more detailed scanning

Was Ga68 PET a game changer for me?

Yes, I believe so.  I’m now in the ‘bone met club’ and although that single metastasis has probably been there for some time, it’s not a ‘label‘ I was keen to add to my portfolio. If I was to be 100% honest, I’m not totally convinced it’s a metastasis. The scan has brought more light onto my thyroid issue.  In fact it indicates even more potential issues above the diaphragm including what looks like a new sighting around my left pectoral lymph nodes.  The scan also lghts up a known issue in the left clavicle lymph nodes, first pointed out via Octreotide scan in 2010 and biopsy negative.

In addition to a nuclear scan update (routine surveillance), it also formed part of an investigation into progression of my retroperitoneal fibrosis (initially diagnosed 2010 but potential growth spotted on recent surveillance CT).  The Ga68 PET doesn’t make fibrosis light up (it’s not cancerous) but there are some hotspots in the area of the aorta close to the fibrosis, a potential source if the cause.  Surgery is on hold for now as my kidney function is fine following a renal MAG3 scan which reported no blockages. 

It would appear I’m no longer a boring stable patient

The Ga68 PET Scan confirmed:

Bone Metastases. Report indicates “intense focal uptake“. It always amazes me that people can be thankful for having an extra tumour.  I’m thankful I only have a single bone metastasis (right rib number 11). I had read so many stories of those who got their first Ga68 PET and came back with multiple bone metastases. I’ll accept one and add to my NET CV. I have no symptoms of this bone metastasis and it will now be monitored going forward. I’m annoyed that I don’t know how long it’s been there though!

Confirmation and better understanding of the following:

  1. Thyroid lesion There is some uptake showing. A 2014 Biopsy of this lesion was inconclusive and actual 2018 Ga68 PET report infers physiological uptake. I’m already diagnosed hypothyroidism, possibly connected.  (Edit – on ultrasound in Jan 2019, looks slightly smaller than previous check).
  2. Left Supraclavicular Fossa (SCF) Nodes lighting up “intense uptake“.  I’ve had an exploratory biopsy of the SCF nodes, 5 nodes removed negative. Nothing is ‘pathologically enlarged’ in this area. Monitored every 6 months on CT, annually on ultrasound.  I had 9 nodes removed from the left axillary in 2012, 5 tested positive for NETs and this area did not light up. This whole area on the left above the diaphragm continues to be controversial. My surgeon once said I had an unusual disposition of tumours.  (Edit: Nothing sinister or worryingly enlarged showing on Jan 2019 ultrasound – measuring 6mm).
  3. Report also highlights left subpectoral lymph nodes which is new.  The subpectoral area is very interesting as from my quick research, they are closer to the left axillary (armpit) nodes than they are to the SCF nodes. I’m hoping to get an ultrasound of these in January at my annual thyroid clinic (Edit: nothing sinister showing on ultrasound in Jan 2019).
  4. My known liver metastases lit up (remnant from liver surgery 2011) – not marked as intense though. The figure of 3 seems to figure highly throughout my surveillance scans although the PET report said “multiple” and predominately right-sided which fits.
  5. Retroperitoneal area. This has been a problem area for me since diagnosis and some lymph nodes are identified (intense word not used). This area has been highlighted on my 3 octreotide scans to date and was first highlighted in my diagnosis trigger scan due to fibrosis (desmoplasia) which was surrounding the aorta and inferior venous cava, some pretty important blood vessels. I wrote an article on the issue very recently – you can read by clicking here. So this scan confirms there are potentially active lymph nodes in this area, perhaps contributing to further growth of the fibrosis threatening important vessels – read below.

Retroperitoneal Fibrosis (Desmoplasia)

I have learned so much about desmoplasia since this issue arose that I now fully understand why I had to have radical surgery back in 2010 to try to remove as much of the fibrosis as possible from the aortic area. You can read more about this in my article.  Desmoplasia via fibrosis is still very much of an unknown and mystery condition in NETs.

I now know that my fibrosis is classed as clinically significant and according to the Uppsala study of over 800 patients inside my article, I’m in 5% of those affected in this way (2% if you calculate it using just the retroperitoneal area).

It appears this problem has come back with new fibrosis or growth of existing fibrosis threatening to impinge on blood vessels related to the kidneys and also my ureters (kidney to bladder urine flow). The Ga68 PET doesn’t make fibrosis light up (it’s not cancerous) but there are some hotspots in the area of the aorta close to the fibrosis.

I didn’t expect this particular problem to return – it was a bit of a shock. My hormone markers have been normal since 2011 and this just emphasises the importance of scans in surveillance. 

Conventional Imaging is still important though

There’s still quite a lot of hype surrounding the Ga68 PET scan and I get this.  However, it does not replace conventional imaging (CI) such as CT and MRI scans which still have their place in routine surveillance and also in diagnostics where they are normally at least the trigger for ‘something is wrong’. For the vast majority, a CT/MRI scan will find tumours and be able to measure reductions and progress in regular surveillance regimes. In fact, the retroperitoneal fibrosis has appeared on every CT scan since diagnosis but the changes were highlighted on my most recent standalone CT and it triggered the Ga68 PET (although my new Oncologist did say I was due a revised nuclear scan).  It’s not a ‘functional’ issue (although it is caused by functional tumours). In fact the fibrosis is not mentioned on the Ga68 PET because it is not lighting up – but the lymph nodes surrounding it are mentioned and they are under suspicious as being active.

Appropriate Use Criteria for Somatostatin Receptor PET Imaging in Neuroendocrine Tumors

There are actually recommended usages for the Ga68 PET scan here.  For example, it is not recommended for routine surveillance in place of CI.

Scans – ‘horses for courses’

Read a summary of all conventional scans and nuclear scans by clicking here.

Next Steps

I had a meeting with my Oncologist and Surgeon and a surgical plan is possible in the event of a problem. My surgeon explained it all in his wonderfully articulate and brilliant surgical mind. Fortunately it’s not really urgent but pre-emptive treatment may be required at some point as the consequences of kidney/bladder function are quite severe. Following some further checks, the anticipated surgery is on hold for now as my kidney function is fine following a renal MAG3 scan which reported no blockages.  I continue to have monthly renal blood tests and it was hinted another renal MAG3 could be done at the end of the year.

Summary

My game has changed, that’s for sure. I’m now entering a new phase and I’m waiting on details of my revised surveillance regime. However, at least my medical team and I now know what WE are dealing with and the risks vs benefits are currently being assessed. I’m heavily involved in that.

If you can see it, you can detect it. If you can detect it, you can monitor or treat it.

 

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).

What does it do?

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. Most machines have an inbuilt CT which forms part of 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.

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).

scans for nets
Octreoscan vs Ga68 PET

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.

This slide from a NET Research Foundation conference confirms the power of more detailed scanning

 

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

Lanreotide and Octreotide and timing 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).

*added by the author for completeness.

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 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.

20180605_141229

Door to the ‘hot room’

The Results of the Ga68 PET Scan – CLICK HERE

PRRT – The Sequel? – Clinical trial of Targeted Alpha-emitter Therapy (TAT) –  212 Pb-AR-RMX

Radioimmunotherapy

In 2018, RadioMedix Inc. and Areva (parent company Orano Med) initiated the Phase 1 trial for AlphaMedixTM in patients with somatostatin receptor (SSTR) positive Neuroendocrine Tumors (NETs) – an NIH supported trial.

AlphaMedixTM is composed of a somatostatin analogue radiolabeled with 212Pb, an isotope used for Targeted Alpha-emitter Therapy (TAT).  This open-label, dose escalation study’s objective is to determine safety, bio-distribution, and preliminary effectiveness of 212 Pb-AR-RMX in adult patients with differentiated (sic) NETs. “Targeted Alpha-emitter Therapy (TAT) is the wave of the future in nuclear oncology and has a tremendous potential to treat patients with NET and overcome some of the limitations of current Peptide Receptor Radionuclide Therapy (PRRT)” said Dr. Ebrahim S. Delpassand, Chairman and CEO of RadioMedix, sponsor of the trial. They further announced on 21 Feb 2018 that the first patients had undergone some treatment.

The funding for Phase 2 was granted by NIH on 22 Jan 2019.

What is Targeted Alpha-emitter Therapy?  Targeted Alpha Therapy is based on the coupling of alpha particle emitting radioisotopes to tumour selective carrier molecules, such as monoclonal antibodies or peptides. These molecules have the ability to selectively target tumour cells even if they are spread throughout the body. They recognize the targeted cancer cells through antigens that are expressed on the cell surface and can bind selectively to these cells, similar a key fitting into a lock. In targeted alpha therapy these carrier molecules serve as vehicles to transport the radioisotopes to the cancer cells. This is called the “magic bullet” approach. Radioisotopes that emit alpha particles seem particularly promising to selectively destroy cancer cells. Alpha particles have a high energy in the range of 5-9 MeV and at the same time a very short path length in human tissue below 0.1 mm, corresponding to less than 10 cell diameters. Consequently, the use of alpha emitters allows the specific targeting and killing of individual malignant cells, while minimizing the toxicity to surrounding healthy tissue. Extracted from EU Science Hub

According to the clinical trials document, this drug addresses an unmet need in the field of peptide receptor radionuclide therapy (PRRT) for NETs. Substitution of an alpha emitter (²¹²Pb) for the beta emitters currently being used (i.e., 177Lu or 90Y) will provide significantly higher Linear Energy Transfer (LET) and a shorter path length. Higher LET particles should cause more tumor cell death. Shorter path length should result in less collateral damage of the normal tissue and therefore less side effects for subjects receiving the drug.

What is the difference between PRRT and TAT?  From the scant ‘patient understandable‘ information currently available, it would appear that TAT has the potential to be more targeted and less toxic than PRRT – to me that seems like it would be able to target smaller tumors.  I also noted that TAT is sometimes described as a ‘radioimmuotherapy’ or ‘alpha immunotherpy’, indicating the mechanism of action is significantly different to that of conventional PRRT. It was also described as a ‘Trojan Horse’ which would seem to hint at its immunotherapy credentials.

I noted that TAT is also being studied for use in Prostate Cancer and Leukaemia.

Related articles:

Announcement of Phase 1 Clinical Trial – click here – results to follow.

Funding grant from NIH for Phase 2 – click here

Phase 1 Clinical Trial Document Phase 1 Study of AlphaMedix™ in Adult Subjects With SSTR (+) NET – click here – Phase 2 document to follow.

Areva Med Website – click here

RadioMedix Inc Website – click here

You may also enjoy my articles:

Lutetium Lu 177 dotatate (Lutathera®) – PRRT” – click here.
Expanding PRRT – Trial of 177Lu-Edotreotide (Solucin®) – COMPETE Trial” – click here.
Theranostics – a find and destroy mission” – click here
Ga68 PET Scans – into the unknown” – 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

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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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Theranostics for Neuroendocrine Cancer – A Find and Destroy Mission

 

theranostics
Courtesy of Pashtoon Kasi MD on Twitter https://twitter.com/pashtoonkasi/status/1078675398601396224

 

Theranostics is a joining of the words therapeutics and diagnostics. You may also see it conveyed as ‘Theragnostics’ and these terms are interchangeable.  The basic aim of theranotistics is to find and then destroy the ‘bad guys‘.  With Neuroendocrine Cancer, finding the tumours (the bad guys) can often be a challenge – they can be small and/or difficult to find – they are sometimes expert at camouflage.  Moreover, once found, they can then be difficult to treat (destroy), as they can often prove resistant to conventional cancer drugs and many are inoperable due to sheer quantity, spread and positioning.  When they are found and identified, it’s also really helpful to know from the intelligence gathered, how successful the destroy (therapeutic) part of the mission might be.

The nuclear scan uses the same nuclear material as the therapy, therefore if you cancer lights up on the nuclear scan, then the therapy will find its way to the cancer and hopefully work well. That is the beauty of theranostic pairing, i.e. the use of the same agent in the diagnostics – the ability to find, estimate likely success criteria and then hopefully destroy – or at least reduce the capability of the tumours and extend life.

A great example of an approved Theranostic Pair in Neuroendocrine Cancer, is the combination of the Somatostatin Receptor based Ga68  PET scan using NETSPOT or SomaKit TOC™ (US/Europe respectively) and Peptide Receptor Radiotherapy (PRRT) using Lutathera which both target NETs expressing the same somatostatin receptor, with PRRT intended to kill tumor cells by emitting a different kind of low-energy, short-range radiation than that of the diagnostic version. As mentioned above, the Ga68 PET scan can give a reasonably indication of therapeutic success using PRRT based on measurements taken during the scan (too complex for this article).

Theranostics – a step towards personalised medicine – graphic courtesy of Advanced Accelerator Applications.

THERANOSTICS – FIND

Octreoscan vs Ga68 PET

Ga68 PET 

Newer imaging agents targeting somatostatin receptors (SSTR) labelled with 68 Ga have been developed, namely, DOTATATE, DOTATOC and DOTANOC. They are collectively referred to as SSTR PET.

The full titles of the 3 types are:

68Ga-DOTA-Phe1-Tyr3-Octreotide (TOC),
68Ga-DOTA-NaI3-Octreotide (NOC),
68Ga-DOTA-Tyr3-Octreotate (TATE).

The main difference among these three tracers (DOTA-TOC, DOTA-NOC, and DOTA-TATE) is their variable affinity to SSTR subtypes. All of them can bind to SSTR2 and SSTR5, while only DOTA-NOC shows good affinity for SSTR3.

These agents have several benefits over In111-pentetreotide (Octreotide scan), including improved detection sensitivity, improved patient convenience due to the 2 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 PRRT. Eventually, all Octreotide scans should be replaced with SSTR PET.  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

Ga68 PET scans have been in many locations for some time. Current excitement is focused on USA locations with Ga68 PET (NETSPOT) only recently approved (DOTATATE). Other countries/scan centres may use one of the other types of imaging agent.

Read much more about this scan in my detailed article on Ga68 PET here.

So SSTR PETs above have the ability to find and estimate likely success criteria for therapy.  We are now in a position to move on to ‘THERApy’ – e.g.  Peptide Receptor Radiotherapy or PRRT.

THERANOSTICS – DESTROY

click on picture to watch video

Lutathera® (note the ‘THERA’ which makes up the brand name)

Definitions:

Europe Approval: LUTATHERA®(lutetium (177Lu) Oxodotreotide) is indicated for the treatment of unresectable or metastatic, progressive, well differentiated (G1 and G2), somatostatin receptor positive gastroenteropancreatic neuroendocrine tumours (GEPNETs) in adults.

USA Approval: LUTATHERA® (lutetium Lu 177 dotatate) is indicated for the treatment of somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs), including foregut, midgut and hindgut neuroendocrine tumors in adults.

For commercial purposes, the drug may be slightly different on a regional basis. For all intents and purposes it does the same job.

As an example of how the drug is administered, please watch this short video from the European site:

Video courtesy of Advanced Accelerator Applications

Please see the following post for a summary of PRRT activity worldwide.  Please note this linked article is not designed to contain a list of every single location or country available – please bear that in mind when you read it – CLICK HERE

I’m very grateful to the team at Advanced Accelerator Applications (a Novartis Company) for allowing me to use their site for graphics and videos.

In another ‘theranostic’ development, check out my article on the Satoreotide trial (Ops 201/202) from Ipsen (of Lanreotide fame) – click here to read – the trial is recruiting.

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

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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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PRRT and the NHS England Cancer Drugs Fund

cost cutting vs life cutting?
cost cutting vs life cutting?

As of 4 Nov 15, PRRT was delisted from the NHS England Cancer Drugs Fund. Appeals were made but were rejected, despite the glowing results from the NETTER-1 trial.  Although a replacement system is now in place, PRRT remains barred from routine NHS use.

Please see the following post for the very latest on PRRT worldwide – CLICK HERE

I was extremely disappointed to learn of the decision to remove PRRT (Lutetium or Yttrium) from the Cancer Drugs Fund (CDF) as reported by the NET Patient Foundation. You can read the detail of the decision here: CDF Statement.  PRRT has regularly been described by NET specialists and patients as the “magic bullet” due to its potential to shrink or kill tumours.

This is the second Neuroendocrine Cancer treatment to be withdrawn this year, after the earlier decision on Everolimus (Afinitor) in April . In fact, the recent cuts to the CDF were described in the media as a “massacre” as the list was reduced by two-thirds.  You can see the current CDF list by clicking here.

The timing of these cuts is extraordinary and when you look at the output from recent trial reports presented at the Europetwo-thirdsCongress (ECC) for both Neuroendocrine Cancer related drugs recently cut:

Everolimus

The RADIANT-4 trial said that Everolimus had a significant effect in non-functional NETs which are very difficult to treat.  This is particularly important for Lung NETs as no treatment currently exists.  The RADIANT-2 trial had already proven the efficacy of the drug for advanced carcinoid (in conjunction with Octreotide) and the RADIANT-3 trial proved good data for treatment with advanced functional pNETs.  Read the report here.

PRRT – 177Lu-DOTATATE

The ECC also reported a significant finding from the NETTER-1 trial.  Treatment with the novel peptide receptor radionuclide therapy (PRRT) Lutathera significantly increased progression-free survival (PFS) over Octreotide LAR (Sandostatin) in patients with advanced midgut NETs.  It shows a PFS that has never been shown before in this type of cancer adding that this was significant because these patients have a real unmet medical need.

Lutathera is a 177Lu-DOTATATE PRRT that targets somatostatin receptors, which are overexpressed in about 80% of NETs, to deliver cytotoxic radiation directly to the tumor – See more by clicking here.

To fully understand the background to the problem, you need to understand both PRRT and the Cancer Drugs Fund and a quick primer on both follows.

What is PRRT?

For those who are not entirely sure what PRRT is, here’s a quick primer from The Society of Nuclear Medicine and Molecular Imaging:

Peptide receptor radionuclide therapy (PRRT) is a molecular therapy (also called radioisotope therapy) used to treat a specific type of cancer called neuroendocrine carcinoma or NETs (neuroendocrine tumors). PRRT is also currently being investigated as a treatment for prostate and pancreatic tumors.

In PRRT, a cell-targeting protein (or peptide) called octreotide is combined with a small amount of radioactive material, or radionuclide, creating a special type of radiopharmaceutical called a radiopeptide. When injected into the patient’s bloodstream, this radiopeptide travels to and binds to neuroendocrine tumor cells, delivering a high dose of radiation to the cancer.

The cells in most neuroendocrine tumors have an abundance (called an overexpression) of a specific type of surface receptor—a protein that extends from the cell’s surface—that binds to a hormone in the body called somatostatin. Octreotide is a laboratory-made version of this hormone that binds to somatostatin receptors on neuroendocrine tumors. In PRRT, octreotide is combined with a therapeutic dose of the radionuclides. Yttrium 90 (Y-90) and Lutetium 177 (Lu-177) are the most commonly used radionuclides.  

What conditions are treated with PRRT?

PRRT may be used to treat NETs, including carcinoids, islet cell carcinoma of the pancreas, small cell carcinoma of the lung, pheochromocytoma (a rare tumor that forms in the adrenal glands), gastro-enteropancreatic (stomach, intestines and pancreas) neuroendocrine tumors, and rare thyroid cancers that are unresponsive to treatment with radioiodine.

PRRT is an option for patients:
• who have advanced and/or progressive neuroendocrine tumours
• who are not candidates for surgery
• whose symptoms do not respond to other medical therapies.

The main goals of PRRT are to provide symptom relief, to stop or slow tumor progression and to improve overall survival.

These video’s on Nuclear Medicine are by Professor Val Lewington – the UK’s most experienced person on PRRT.  I was at this presentation and she is absolutely amazing. It’s slightly dated but still very current.  This presentation also covers Octreotide and Gallium 68 scans under the heading of Nuclear Medicine – if you are still unsure about PRRT or Nuclear Medicine in general, these videos are definitely worth a watch.

The Role of Nuclear Medicine in NETs

Q&A Sessions

This is also a great source of information maintained by NET Patients in the USA.  Click here

What was the Cancer Drugs Fund?

The Cancer Drugs Fund was money the UK Government has set aside to pay for cancer drugs that haven’t been approved by the National Institute for Health and Care Excellence (NICE) and aren’t available within the NHS in England. This may be because the drugs haven’t been looked at yet. Or it may be because NICE have said that they don’t work well enough or are not cost-effective. This was introduced as a ‘political statement’ by the then Conservative/Liberal Democrat coalition government in 2010/11.  The aim of the fund is to make it easier for people to get as much treatment as possible.

The Cancer Drugs Fund was for people who live in England. The governments of Scotland, Wales and Northern Ireland decide on how they spend money on health and so far haven’t decided to have a similar programme.

Worth noting that on 1 April 2013, NHS England took on responsibility for the operational management of the Cancer Drugs Fund (CDF). The NHS spends approximately £1.3 billion annually on the provision of cancer drugs within routine commissioning. The CDF was established as an additional funding source to this.

There was a national list of drugs available through the fund – you may have heard this called the priority list. If you met the conditions for a drug that was on the list, you should have been able to have it on the NHS if you live in England. The Fund would also have considered applications on behalf of individual patients for other drugs that are not on the list.  However, under the new system, Individual funding requests (IFRs) relating to cancer drugs will no longer be considered via the CDF process.  All IFRs relating to cancer drugs will now be considered using NHS England’s single, national IFR system, which was updated in January 2016.

The new system came info force on 29 July 2016 and you can read more if you click this link

Summary

Although the decision is shocking to most, it was not totally unexpected as the Government and NHS have been hinting for sometime that the costs of the fund need to be reined in.  In any case if was only ever a temporary arrangement until a another model could be put into place.  There is a political element as the fund was set up by David Cameron with healthcare experts suggesting that it made no sense as a response to rising drug prices.  Moreover, by topping up the fund, the same experts claimed this was making the manufacturers the real beneficiaries of the fund as they have been able to sell their drugs to the NHS at prices that are unaffordable (and therefore unsustainable) for the NHS.

UK NET patients who have advanced and/or progressive neuroendocrine tumours which cannot be removed by surgery and whose symptoms do not respond to other medical therapies, still need help.

Ironically, the UK seems to be intent on cutting provision of the treatment (at least for NHS patients) as the US is trying very hard to formally introduce it.  This is a disgraceful situation and advanced Neuroendocrine Cancer patients and those who may need this treatment in the future are being terribly let down.

I will keep this blog ‘live’ in order to add information as things progress.

Thanks for reading

Ronny
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