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 indicate even more potential issues above the diaphragm including what looks like a new sighting around my left pectoral.  The can 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.   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 nodesI’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 for 8 years 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. There are actually recommended usages for the Ga68 PET scan here.  For example, it is not recommended for routine surveillance in place of CI.

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.

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

Next Steps

I’ve since has meetings with my Oncologist and Surgeon and a treatment plan is underway. 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.

177Lu-DOTA-EB-TATE – Long-lasting radionuclide therapy for advanced neuroendocrine tumors proves effective

For your information only. In the News.

Since PRRT was formally approved last year in USA and Europe (and other places), it’s triggered a whole mini-industry in PRRT variants or enhancements. An interesting study from China, a country starting to become very active in the NET world. I guess they have been active for some time given that I’ve seen their NET experts presenting at the last 2 years of ENETS in Barcelona.  In this particular study, there is linkages to the Laboratory of Molecular Imaging and Nanomedicine, NIBIB/NIH, Bethesda, Maryland in USA.

This is news of a first-in-human study presented at the 2018 Annual Meeting of the Society of Nuclear Medicine and Molecular Imaging (SNMMI) which demonstrated the benefits and safety of a new, long-lasting type of radionuclide therapy (PRRT) for patients with advanced, metastatic neuroendocrine tumors (NETs) – 177Lu-DOTA-EB-TATE. 

How is this different from the current PRRT standard – Lutathera?

“Lu-DOTA-EB-TATE is a “three-in-one” therapeutic compound, with an octreotate peptide to find the tumor, an ‘Evans blue motif’, which uses endogenous albumin as a reversible carrier to effectively extend the half-life in the blood and substantially increase targeted accumulation and retention within the tumor, and a therapeutic radionuclide to kill the tumor cells, to finally provide effective treatment of NETs,”  …….. explains Shawn(Xiaoyuan) Chen, PhD, senior investigator, of National Institute of Biomedical Imaging and Bioengineering at the National Institutes of Health , Bethesda, Maryland.

Lutathera-177 (177Lu)-DOTATATE (trade name Lutathera), a peptide receptor radionuclide tharapy (PRRT) with radiolabeled somatostatin analogues (peptides), was recently approved by the USA FDA and the EMA for the treatment of somatostatin receptor positive NETs. It is the therapeutic part of a nuclear medicine theranostic pairing. Gallium-68 (68Ga)-DOTATATE is the diagnostic agent used in  PET/CT scans that first locates and marks the lesions for follow-up with targeted PRRT delivery directly to the tumor cells which express high levels of somatostatin receptors (SSTRs). Because the PRRT binds to receptors expressed by the tumor cells, healthy cells are unharmed. However, the peptide quickly clears from the blood through the kidneys limiting the accumulation of radioactivity within tumors and making additional treatment cycles necessary to provide the therapeutic dose.

177Lu-DOTA-EB-TATE.  This first-in-human, first-in-class, Phase I trial (ID: NCT03308682) investigated the safety and dosimetry of a novel long-lasting radiolabeled somatostatin analogue that adds an albumin-binding Evans blue (EB, an azo dye) derivative to 177Lu-DOTATATE. Albumin, the most abundant plasma protein in human blood, is a natural transport protein and has a long circulatory half-life.  This is an open-label, non-controlled, non-randomized study.

For the study, conducted in collaboration with researchers at the U.S. National Institute of Biomedical Imaging and Bioengineering, 8 patients (6 men and 2 women ranging in age from 27 to 61 years old) with advanced metastatic neuroendocrine tumors were recruited from Peking Union Medical College Hospital and the Chinese Academy of Medical Sciences in Beijing, China.

Each patient underwent whole-body 68Ga-DOTATATE PET/CT. Five of the patients then accepted intravenous injection with a single dose of 0.35-0.70 GBq of 177Lu-DOTA-EB-TATE within one week, and were monitored at 2, 24, 72, 120 and 168 hours after 177Lu-DOTA-EB-TATE administration with serial whole-body planar and single photon emission computed tomography (SPECT)/CT images acquired. The other 3 patients accepted a dose of 0.28-0.41 GBq of 177Lu-DOTATATE and were monitored at 1, 3, 4, 24 and 72 hours with the same imaging procedures. Complete physical examinations, including vital signs, blood count, biochemistry, and immunology analyses were performed immediately before and 1, 3, and 7 days, as well as 3 months, after treatment.

Administration of 177Lu-DOTA-EB-TATE was well tolerated, with no adverse symptoms reported throughout the procedure and follow-up. The total effective dose equivalent and effective dose were 0.2048 ± 0.1605 and 0.0804 ± 0.0500 mSv/MBq for 177Lu-DOTA-EB-TATE and 0.1735 ± 0.0722 and 0.0693 ± 0.0317 mSv/MBq for 177Lu-DOTATATE. The liver, kidneys, bone marrow and total body received slightly higher doses (mGy/MBq) with 177Lu-DOTA-EB-TATE than with 177Lu-DOTATATE, while the spleen received lower doses with 177Lu-DOTA-EB-TATE. Blood clearance of 177Lu-DOTA-EB-TATE was also slower. Most importantly, 177Lu-DOTA-EB-TATE lasted in the tumors more than 4 times longer than 177Lu-DOTATATE.

Jingjing Zhang and Zhaohui Zhu of Peking Union Medical College Hospital point out, “By introducing an albumin binding moiety, this long-lasting radiolabeled somatostatin analogue has remarkably enhanced uptake and retention in SSTR-positive tumors, which is important to increase the therapeutic efficacy in patients. With proper selection of patients with advanced metastatic neuroendocrine tumors, 177Lu-DOTA-EB-TATE has great potential to be a highly effective treatment, while providing a safe dose with less frequency of administration than is possible with 177Lu-DOTATATE.”

FIGURE: SPECT/CT of a 45-year-old male patient with advanced NETs and multiple liver metastases – persistently retained in the tumors after 168 hours

Scans were done at 2, 24, 72, 120 and 168 hours after the administration of 177Lu-DOTA-EB-TATE. The radiopharmaceutical cleared from the blood pool over time and persistently retained in the tumors (arrows). Credit: J Zhang et al., Peking Union Medical College Hospital, Beijing, China; X Chen et al., Laboratory of Molecular Imaging and Nanomedicine, NIBIB/NIH, Bethesda, MD

Sources:

Abstract 118: “Safety, Pharmacokinetics and Dosimetry of a Long-lasting Radiolabeled Somatostatin Analogue 177Lu-DOTA-EB-TATE in Patients with Advanced Metastatic Neuroendocrine Tumors: A Phase 1 First-in-human Study,” Jingjing Zhang, MD,PhD, Yuejuan Cheng, MD,Hao Wang, MD, Jie Zang, PhD, Fang Li, MD, Chunmei Bai, MD, and Zhaohui Zhu, MD, Peking Union Medical College Hospital; Gang Niu, MD, Orit Jacobson, PhD4, and Xiaoyuan Chen, PhD, U.S. National Institutes of Health, Bethesda, MD. SNMMI’s 65th Annual Meeting, June 23-26, Philadelphia.  Link to SNMMI Abstract

Other articles in this series:

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!

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).

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

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

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!

 

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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Neuroendocrine Cancer: Somatostatin Receptors

ct compare to g68 pet
CT and G68 PET fused showing somatostatin receptor pick up

Don’t understand Somatostatin Receptors?  Join the club!  I got my head around the term ‘Somatostatin’ and ‘Somatostatin Analogues’ some time ago but the term ‘Somatostatin Receptor’ (SSTR) is still a bit of a mystery and it’s come to the top of my list of things to study.  SSTRs do come up in conversation quite often and I’m fed up of nodding sagely hoping it will eventually become clear! On analysis it looks like a technical subject – and therefore a challenge 🙂

I’ve taken a logical approach working from ‘Somatostatin’ to ‘Somatostatin Analogue’ before commencing on the ‘receptor’ bit.  It is intentionally brief and (hopefully) simplistic!

Somatostatin

It’s important to understand this hormone and then why your ‘butt dart’ is generically called a ‘Somatostatin Analogue’.

Some Neuroendocrine Tumours secrete hormones and peptides that cause distinct clinical syndromes, including amongst others, carcinoid syndrome.  Somatostatin is a naturally occurring hormone and a known inhibitor of some of these NET related hormones and peptides that can be over secreted and cause syndromes. For example, somatostatin from the hypothalamus inhibits the pituitary gland’s secretion of growth hormone (GH) and Thyroid Stimulating Hormone (TSH). In addition, somatostatin is produced in the pancreas and inhibits the secretion of other pancreatic hormones such as insulin and glucagon.  However, the naturally produced Somatostatin does not have the lifespan to have any effect on Neuroendocrine Tumours which are over secreting these hormones and peptides. ……. cue manufactured versions that can!

Somatostatin Analogue (SSA)

These are manufactured versions of Somatostatin known as Somatostatin Analogues.  These are designed to have a lasting effect to inhibit for much longer and therefore reduce the symptoms caused by the over secretion (i.e. the syndrome).  Examples of Somatostatin Analogue include Octreotide (Sandostatin), Lanreotide (Somatuline) and Pasireotide (Signifor).

So how do Somatostatin Analogues actually work? 

For the inhibition to work effectively, there needs to be a route into the over secreting tumours, normally via short or long acting injections or even intravenously. On the tumour cells, there are currently 5 known sub-types of ‘Somatostatin Receptors’  (SSTR) which are ‘expressed’ by most NETs.   These are known as SSTR1 through to SSTR5.  The naturally occurring hormone Somatostatin attempts to bind with all 5 but as above, it lacks the lifespan to make any impact to inhibit sufficiently in cases of overecretion. However, SSAs can overcome this with the longer lifespan.  They can successfully in most cases bind with these receptors to inhibit the hormones and peptides causing the problems, particularly SSTR2 with modest affinity to SSTR5. Clearly it’s therefore advantageous to target SSTR2.

Somatostatin Receptors

The subtypes expressed by NETs are variable and the efficiency of different SSAs in binding to each SSTR subtype also varies. For example the table below lists the variability of Somatostatin Receptor efficiency in different types of NET.  Interesting to note that non-functional NETs might not have efficient SSTRs but SSAs will still try to bind to them albeit it might not work or have a lesser effect.

Somatostatin receptors are found in high numbers on the surface of NET’s. Most receptors are in the inactive state (based on something called the phosphorylation status). Traditionally, agents such as dotatate have only bound to activated receptors on the surface.  Scientists are looking at ways to bind to inactive receptors to increase therapy success (for example see clinical trial OPS 201)

Table 1 – Somatostatin receptor subtypes in neuroendocrine tumours (mRNA) (See Copyright)

Tumour SSTR1 (%) SSTR2 (%) SSTR3 (%) SSTR4 (%) SSTR5 (%)
Gastrinoma 79a 93 36 61 93
Insulinoma 76 81 38 58 57
Non-functioning pancreatic tumour 58 88 42 48 50
Gastro-intestinal NET 76 80 43 68 77

This table above clearly shows the variability of SSTRs when binding with different types of NETs.  It follows that manufacturers of SSAs will be using this data in the formulation of their drugs.  If you now look at the table below, you can see how efficiently the 3 well-known SSAs inhibit NETs on each SSTR.

Compound SSTR1 SSTR2 SSTR3 SSTR4 SSTR5
RECEPTOR SUBTYPE AFFINITY (IC50, nM)
Octreotide 1140 0.56 34 7030 7
Lanreotide 2330 0.75 107 2100 5.2
Pasireotide 9.3 1 1.5 >100 0.16

View it in a separate window

You can see from the data why Octreotide and Lanreotide target SSTR2 and to a lesser extent SSTR5 but Pasireotide (Signifor or SOM-230) is interesting as it appears to have affinity for SSTRs 1-3 and 5, probably why it has been approved for Cushing’s Disease (ATCH producing).  However, to date, there has not been enough evidence showing that Pasireotide has a progression-free survival benefit over the other 2 therapies. It is also associated with hyperglycemia. You may find this video interesting as the doctor is suggesting it could be used by NET patients in certain scenarios.

What about SSA labelled diagnostics?

The same principles apply.  For example, an Octreotide Scan (actually known as ‘Somatostatin Receptor’ Scintigraphy (SRS)) works by taking pictures using a gamma camera which is designed to see radiation from a ‘tracer’.  The tracer in question is a radio labelled with an Octreotide variant (such as pentetreotide) which will bind to somatostatin receptors on the surface of the tumour cells  In the simplest of terms, this shows up where NETs are.  The same principles apply to Ga 68 PET scans which are more advanced and more sensitive than SRS.

What about SSA labelled therapies?

With (say) Peptide Receptor Radiotherapy (PRRT), there is a similar binding mechanism going on.  In PRRT, Octreotide or a variant, is combined with a therapeutic dose of the radionuclides, e.g. Yttrium 90 (Y-90) and Lutetium 177 (Lu-177).  It binds with the SSTRs on the tumour cells and the therapeutic dose attacks the tumour having been brought there by the binding effect.  Simple isn’t it?

Do Somatostatin Receptors work for everyone?

Unfortunately not.  Some people have more sensitive receptors than others and the figure of 80% appears to be the most common statistic indicating one-fifth of all NET patients may not be able to respond correctly to SSA treatment or get the right results from Octreoscans/Ga 68 PET and/or PRRT.  However, that needs to be taken into context and probably applies to midgut NETs measured against SSTR2 – the tables above tend to confirm this figure.  During my research, I did read that higher than normal doses of SSAs may have some effect on those with less sensitive SSTRs.  Also, SSAs seem to work much better with well-differentiated tumours.

How do I know if my Somatostatin Receptors work?

When I was completing my NET checks after diagnosis, my Oncologist declared I was “Octreotide avid” shortly after my Octreoscan was compared with my CT.  I’m guessing that is a simple and crude test and how most people find out they have working receptors.  I also suspect that if your syndrome symptoms are abated somewhat by SSA injections, then you there is a good chance your SSTRs are working normally.  I also suspect those who show clear signs of tumour on CT but not on Octreoscan or Ga 68 PET, could have a receptor issue.

The advent of modern PET scanning (e.g. Ga68) has meant more accurate methods of working out if someone has the right receptors for PRRT through analysis of something known as standardized uptake values (SUV).

A more modern approach is to use a ‘Theranostic Pair” where the same radiolabelled tracer is used with the advantage that the diagnostic element can predict suitability for the therapy component  – read more here

lutathera owl - Copy


Somatostatin Receptor Research – Interest Point

I was please to see a piece of research ongoing to look at the issues with lack of somatostatin receptors.  The research is looking at novel imaging agents for NETs which do not have working receptors.  Read more here.

Summary

I hope this gives you a very basic outline of why Somatostatin Receptors are important to support the diagnosis and treatment of NETs.

My article “If you can see it, you can detect it” is almost 100% accurate but having working receptors really helps with nuclear scans.

Preclinical and clinical studies have indicated that somatostatin receptor (SSTR)expressing tumors demonstrate higher uptake of radiolabeled SSTR antagonists than of the currently approved SSTR agonist versions. See clinical trial OPS 201 for an example of the next generation of somatostatin receptor based theranostics where the use of a somatostatin antagonists.

thanks for reading

Somatostatin Analogues and delivery methods in the pipeline

As most of you will be aware, there are currently two main types of Somatostatin Analogues (SSA) in use for the treatment of mainstream Neuroendocrine Tumours (NETs) – Octreotide and Lanreotide. You can click on the links for information on both of these well-known NET treatments. This post will focus on the not so well known and anything in the pipeline including different delivery systems.

This is my live blog post covering new developments in the area of new Somatostatin Analogues and new delivery systems. 

Abstract

As most of you will be aware, there are currently two main types of Somatostatin Analogues (SSA) in use for the treatment of mainstream Neuroendocrine Tumours (NETs) – Octreotide and Lanreotide.  You can click on the links for information on both of these well-known NET treatments.  This post will focus on the not so well known and anything in the pipeline including different delivery systems.

Those who have read the Octreotide/ Lanreotide patient leaflets will know those SSAs are also used in the treatment of a condition known as Acromegaly. You can see why the drug is used for both as they control the release of excess secretions of various substances, a problem that has an effect on both conditions. In the case of Acromegaly, the condition is typically caused by pituitary tumours that oversecrete the growth hormone leading to elevated levels of IGF-1. Like NETs, Octreotide/Lanreotide is currently the mainstay non-surgical treatment for this condition. For those not aware of Acromegaly there is a nice infographic explaining it here.   

Delivery methods discussed in this post include: a smaller, faster and easier Octreotide injection, an Octreotide capsule, an Octreotide nasal spray.  Other somatostatin analogues includes Pasireotide which has already been approved for Cushing’s Syndrome and Acromegaly (core NET possibilities have been investigated) and a new kid in the pipeline called Veldreotide for Acromegaly but potential additional applications in Cushing’s syndrome and neuroendocrine tumors. Finally for those with an interest in Cushings, a drug currently in phase 3 trials called RECORLEV™ (Levoketoconazole) which is not actually a somatostatin analogue, rather it’s a cortisol synthesis inhibitor.

It’s important to understand that NETs and other conditions including Cushings and Acromegaly, very often share the same hormone inhibiting drugs, thus why any development for these type of drugs is of interest to all physicians and patients in the associated conditions.

It’s also useful to understand that many of these drugs/delivery mechanisms are driven by availability of funding and are subject to the vagaries of the market. One entry on the previous version of this article has been removed as the company manufacturing it went into administration (Solid Dose Injections).

Somatostatin Analogues – New Delivery Methods in the Pipeline

New delivery system for Octreotide LAR – “Q-Octreotide” (MDT201)

757z468_1-SG02126-(1)
MTD201 (Q-Octreotide)

Updated 20 Dec 2018.

An unnamed ‘pharma giant’ has signed a deal with Midatech Pharma Plc that will see it evaluate the latter’s Q-Sphera drug delivery platform.  Only a guess from me, but I suspect it’s either Novartis or Ipsen.

Midatech’s Q-Sphera™ is an advanced microencapsulation and polymer-depot sustained release (SR) drug delivery platform produced using a novel and disruptive printing based process, with numerous and distinct advantages over conventional reactor based technologies. From a manufacturing perspective Q-Sphera™ is a precise, scalable, efficient, and environmentally friendly microparticle platform. From a clinical perspective Q-Sphera™ ensures monodispersed microparticles that release active drug compounds into the body in a superior linear tightly controlled and predictable manner over an extended period of time from 1 – 6 months.  An injection lasting 6 months sounds very exciting but I have no more detail on the feasibility or likelihood of such a change in frequency with Octreotide or Lanreotide but the press release does mention the possibility, i.e. “Q-Sphera allows drug compounds to be released into the body in a “highly controlled manner” over a prolonged period of time; potentially from a few days to up to six months.”

What’s the main differences?

The current trials are based on the use of Sandostatin LAR (Octreotide) using the Q-Sphera delivery system (previously known as Q-Octreotide). The key aspects of usability are reconstitution and needle size but there is also an inference that less frequent injections could be possible.

Apparently, the delivery method (see picture) is smaller, faster, easier with the possibility of less frequent injections. More to follow when known but in the meantime, please see a useful Video about Q-Octreotide. Apologies for the use of the out of date term ‘carcinoid‘.

New Octreotide Delivery Method – Chiasma Capsule

mycappsa
Octreotide Capsules? Graphic from http://www.chiasmapharma.com/

Updated 14 Dec 2017. Acromegaly appears to be in the lead in terms of new delivery methods.  A pharma company called Chiasma is working on an oral version of Octreotide for this condition and they are currently at Phase 3 trials.   You can check out the technology here.

Clearly, we want drugs to be safe and the announcement is another reminder of why drugs take so long to be approved.  Chiasma’s investigational oral octreotide uses their proprietary TPE® (Transient Permeability Enhancer) technology to facilitate gastrointestinal absorption of the unmodified drug into the bloodstream safely (i.e. it keeps the drug safe until it reaches its destination).  Hopefully, the new trial can convince the FDA to finally approve.  The trial is currently only Acromegaly based and details are here.

This is potentially an exciting development given that both conditions use the same drugs (Octreotide and Lanreotide injections) so there is always the hope that NETs might be next in line if the capsule version is finally approved.  However, still very early days as the company does not anticipate the release of top line date from the Phase 3 trial until 2020. 

Intranasal administration of Octreotide Acetate 

intravail
Nasal Spray Octreotide?

Updated 14 May 2017.  Dauntless Pharmaceuticals, Inc., a privately held biopharmaceutical company focused on the development of specialty therapeutics, announced the outcome of a Phase 1 clinical study to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of DP1038, a novel formulation of octreotide acetate for intranasal administration, compared to subcutaneous Sandostatin® (octreotide acetate) injection in healthy volunteers.  DP1038 (octreotide acetate for intranasal administration) is being developed via the 505(b)(2) regulatory pathway for the treatment of acromegaly and neuroendocrine tumors.  DP1038 leverages patented technology for enhanced intranasal absorption developed by Aegis Therapeutics, LLC, a drug delivery and drug formulation company that has successfully licensed its technology to leading pharmaceutical and biopharmaceutical companies whose partners have multiple late stage clinical programs under development. The drug will most likely use an administration system patented by Aegis called Intravail® Aegis Therapeutics LLC announced last year that it has been awarded U.S. Patent No. 9,446,134 providing non-invasive metered nasal spray delivery of Octreotide (click here to view the announcement). The enabling Aegis Intravail formulation technology is broadly applicable to a wide range of small molecule and biotherapeutic drugs to increase non-invasive bioavailability by the oral, nasal, buccal, and sublingual routes and to speed attainment of therapeutic drug levels in cases where a non-invasive (i.e., non-injectable) form of the drug is unavailable or where speed of onset is important.  A description of Intravail delivery systems can be found by clicking here.

About the Phase 1 Trial
The Phase 1 trial was designed to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of DP1038, a novel formulation of octreotide acetate for intranasal administration, compared to subcutaneous Sandostatin® (octreotide acetate) Injection in healthy volunteers. In Part 1 of the study, each of 12 subjects received three doses of DP1038 plus 100 micrograms of subcutaneous octreotide acetate in a randomized 4 x 4 Latin square design. DP1038 was well tolerated across all doses and demonstrated a consistent, dose-proportional pharmacokinetic profile with significant nasal bioavailability. In Part 2 of the study, a single dose of DP1038, which was selected to exhibit a similar pharmacokinetic profile to subcutaneous octreotide acetate, was evaluated in 20 subjects in a cross-over design to compare the pharmacodynamic effect to 100 micrograms of subcutaneous octreotide acetate. Subjects were given a GHRH-arginine challenge, a standard test to stimulate growth hormone release, followed by administration of DP1038 or subcutaneous octreotide acetate. DP1038 showed comparable growth hormone suppression to the subcutaneous reference product. The news announcing the output from the Phase 1 clinical trial can be found by clicking here. Clearly, this is very early days and the product would need to go through the normal drug approval and acceptance routes etc.  However, a Phase 1 trial using patients is very exciting.

New Somatostatin Analogues in the Pipeline

New Somatostatin AnaloguePasireotide

signiforlar-22

Updated 14 Dec 2017.  Not really new but I wanted to include it because it’s not very well-known. Pasireotide is also known as Signifor and SOM230.  This drug is already in the pipeline but only for Acromegaly and Cushing’s Syndrome.  I found it interesting that is able to function as a multireceptor-targeted SSA by binding with high affinity to 4 of the 5 somatostatin receptors (sstrs 1, 2, 3 and 5), with the highest affinity for sstr5, resulting in inhibition of adrenocorticotropic hormone (ACTH) secretion (Octreotide only binds to sstrs 2, 3 and 5). In fact, Signifor represents the first specific treatment for ACTH-secreting pituitary adenomas.  Moreover, it is the first approved medical treatment for Cushing’s disease.  If you’ve read my blog on NET Syndromes, you will see the connection – both involve pituitary tumours and this drug is designed to cater for scenarios where surgery has not solved the problem or is not an option. Interestingly Novartis describes it as a second generation SSA, inferring that Octreotide is first generation.  It comes in short and long acting (LAR) forms with a similar delivery system to Octreotide. It is a US FDA approved orphan drug and is also approved for use in the EU.  Novartis has also submitted additional regulatory applications for Signifor LAR worldwide.   You can read more by clicking here

However, there have been studies in its use for advanced NETs where Octreotide is not working or has not sufficiently controlled the effects of the syndrome.  You can read a full text article about the study results by clicking here (you will recognise some of the authors including Edward M Wolin, Christos Toumpanakis, John Ramage, Kjell Öberg).  My interpretation of the trial conclusion is that there does not appear to be any significant advantages of Pasireotide over Octreotide.  The attachment also confirmed studies are ongoing including a potential combination treatment of Pasireotide and Everolimus (Afinitor).  There does not appear to be a study comparing it to Lanreotide.

Jonathan R. Strosberg, MD, associate professor at H. Lee Moffitt Cancer Center, discussed pasireotide as a potential treatment for patients with neuroendocrine tumors (NETs). He said “Pasireotide is a somatostatin analog similar to octreotide (Sandostatin) and lanreotide (Somatuline). However, pasireotide targets 4 out of the 5 somatostatin receptor subtypes, which may provide it with an advantage over the other 3 agents. Thus far, there has not been enough evidence showing that pasireotide has a progression-free survival benefit over the other 2 therapies. It is also associated with hyperglycemia. Pasireotide may be an appropriate choice for patients in later lines of therapy. In the future, he envisions that patients could be selected for therapy based on their somatostatin receptor profile.”

New Somatostatin Analogue  – Veldoreotide (COR-005)

Updated 14 Dec 2017. There is another new drug in the pipeline currently known as Veldoreotide or COR-005 (although I can see the term ‘Somatoprim’ used on other searches). COR-005 is an investigational SSA in phase 2 development for treatment of patients with Acromegaly. Although the page on the manufacturer’s website does not mention NETs, an announcement of its progress has just been made at the Endocrine Society’s annual conference for 2016. The announcement states that the drug has “potential additional applications in Cushing’s syndrome and neuroendocrine tumors”.  COR-005 targets somatostatin receptors 2, 4 and 5. Read about the drug here.

COR-005 has received orphan drug designation (only for Acromegaly) in the US and EU. There is not enough data to understand how this might benefit NETs and what the differences would be.  Hopefully, an update will be available later which will result in an update to this post.

For those interested in Cushing’s Syndrome, (hypercortisolism or high levels of cortisol), the same manufacturer working on Veldoreotide is also working on a new drug in Phase 3 trials known as RECORLEV™ (Levoketoconazole). Not actually a somatostatin analogue, rather it’s a cortisol synthesis inhibitor

Summary

This information is provided for information only.  There is no intent to indicate at this point that these new drugs will eventually be approved for NETs.  However, it’s another indication that people are working on new treatments which might end up being available at some stage.

The pipeline for new treatments and methods of delivery continues to grow!

Thanks for reading

Ronny

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Lanreotide – it’s calling the shots!

Lanreotide calling the shots

UPDATE:

Please note a new syringe for Lanreotide will be available in June 2019. Further information will be communicated to healthcare professionals in advance of this, to enable them to inform their patients, whom have been prescribed Lanreotide. In addition, the patient information leaflet included in the packet will have clear instructions for use. There will be a prominent yellow box located on the outer carton of the medicine, alerting healthcare professionals and patients that a new syringe is contained inside. Please note that the medicine is still the same and the formulation and storage conditions have not changed.

new lanreotide
Diagram of new injection system for Lanreotide

When I was discharged from hospital following major surgery in Nov 2010, I knew I would shortly be commencing long-term monthly ‘somatostatin analogue’ treatment and had assumed Octreotide (Sandostatin LAR) would be the drug of choice. However, my Oncologist prescribed Lanreotide (known in the UK as Somatuline Autogel and elsewhere as Somatuline Depot).  Technically this is a hormone therapy (it’s not chemo).

Somatostatin Analogues (Octreotide/Lanreotide) are mainstay treatments for many Neuroendocrine Cancer patients and their introduction is a very significant factor in the improvement of both prognostic outcomes and quality of life.  Both drugs are designed to control Carcinoid Syndrome (but can be used selectively in other NET syndromes) and both have anti-tumour effects.  Check out my Lanreotide vs Octreotide comparison blog.

butt dart with words

Although I didn’t relish the thought of any injection in the ‘rear end’ every 28 days for the rest of my life, I admit to being slightly relieved with his choice.  I had been reading about patient experiences with the alternative, mainly the needle length and the occasional problems mixing the drug prior to injection.  Although Lanreotide has a similar gauge (thickness), the needle is a good bit shorter and is deep subcutaneous rather than Octreotide LAR’s intramuscular (IM) route. No mixing is required as Lanreotide comes prefilled.

If you’re interested in the science, please be aware that a somatostatin analogue is a synthetic (manufactured) version of a naturally occurring hormone which inhibits the peptides and amines that can be dangerously hypersecreted by certain neuroendocrine tumours.

Following an Octreotide Scan, various areas lit up confirming the output from previous CT scans.  It also confirmed new ‘hotspots’ for further investigation.  This specialist scan confirmed I probably had working receptors to receive something known as a Somatostatin Analogue to help with combatting the effects of Carcinoid Syndrome (please note that not having working receptors does not mean there is no benefit of receiving somatostatin analogues). I was therefore prescribed daily Octreotide (self-injecting) whilst I was waiting for my first major ‘debulking’ surgery, This treatment did eventually lessen the main effect of the carcinoid syndrome, facial flushing.  It wasn’t until after my first surgery that the facial flushing was dramatically reduced.  I commenced Lanreotide on 9 Dec 2010 and I haven’t had a facial flush since. It’s worth adding that my Chromogranin A (CgA) blood test (correlated to tumour mass) did not return to normal until after a liver resection 3 months later.  My 5HIAA urine test results (mainly correlated to serotonin levels) returned to normal prior to liver surgery in Apr 2011 indicating the Lanreotide was doing its job! Somatostatin Analogue side effects are to be expected and most people seem to have different and/or greater or lesser effects than others. The daily Octreotide did not bother me too much other than some discolouring of the stomach at the injection sites (i.e. black and blue!) ….I’m more observant nowadays, so it’s possible I may not have recorded this experience properly.

If you read the UK patient leaflet which comes with each injection, you can see a list of potential side effects as long as your arm.  Neuroendocrine Cancer comes with many signs, syndromes, symptoms and suspicions, so I always advise caution and some analysis when assigning reasons for problems encountered.  For North America, the equivalent instructions can be found here (Somatuline Depot). I don’t know precisely why (……. I do have my suspicions), but I’m always very sceptical about the criteria used to compile the list of side effects for any medicine. In my own mind, I’m fairly certain that people have existing symptoms or new symptoms as a result of coincidental treatment that are erroneously labelled under drugs during trials.

You can also self-inject Lanreotide but I’m not ready for that yet!  If you do self inject, please note it the site is “the upper outer part of your thigh”.  Check out the Ipsen leaflet here.

I think the injection site is very important and getting this wrong will worsen the side effects. For the Healthcare Professional or trained family member administration, the site should be the superior external quadrant but not of the whole ‘butt’, it means of the left or right buttock that is being used on an alternative basis.  If nurses think the whole ‘butt’, they might be tempted to stick it quite close to the ‘intergluteal cleft’ – not advisable!

Although the patient leaflets are very clear on how to administer the drug, once the location is established, I always discuss the following with the Nurse before I receive the ‘dart’:

1.  The injection should have been removed from the fridge at least 30 minutes before treatment. However, please the product can be put back in the fridge in the original packaging for later use, provided it has been stored for no longer than 24 hours at below 40 deg C (104 deg F) and the number of ‘temperature excursions’ does not exceed three. If you are taking the drug somewhere to be administered or were waiting on a home visit, this might with scheduling issues.

2.  Don’t pinch the skin, stretch it.

3.  Put the needle in fast at 90 degrees, inject the drug slow – 20 seconds is recommended. As the drug is viscous, in any case, there is normally some resistance to a fast release.

4. Do not rub or massage the area after as this action can interfere with the formulation of the drug.  This is clearly stated on the drug information leaflet.

My experience with side effects.  People have different experiences with side effects and just because a particular side effect is mentioned, does not mean to say that everyone will be troubled – many patients experience little or none.  For me, over 7 years, I think I can attribute the following to Lanreotide:

  • itching but only on the legs below the knees centred on the ankles – and nearly always the right leg.  Occasionally, the injection site will itch but only for a day or two.  I have a tub of emollient cream (almond oil) on standby which seems to calm it down.  Note …… a little bit of me thinks there could be a connection with vitamin/mineral deficiency and perhaps a coincidental occurrence and this problem seems much less of an issue over 7 years later. EDIT- could have been Hypothyroidism – click here.
  • minor pain at the injection site but this only lasts for an hour or two and I believe this to be associated with the administration of the injection, i.e. if the injection is done properly, I don’t really have this problem except for a second or two as it enters.  Once, I had pain for 10 days.  In my own experience, the best and least painful injections are those done by trained personnel who are confident.
  • small lumps form at the injection site which is alternating superior external quadrant of the each buttock. You may occasionally hear these being called ‘granulomas‘ or ‘injection site granulomas’. The issue of ‘injection site granulomas’ seems to figure in both Lanreotide and Octreotide. Gluteal injection site granulomas are a very common finding on CT and plain radiographs. They occur as a result of subcutaneous (i.e. intra-lipomatous) rather than intramuscular injection of drugs, which cause localised fat necrosis, scar formation and dystrophic calcification. But no-one seems to know why they occur with somatostatin analogues. I find that they are more conspicuous if the injection is done slightly too high which was my initial experience and they took months to fade.  I opted to stand up for the first two injections and I attribute this decision for a slightly too high injection site.  I now lie down which is actually recommended for the smaller and thinner patient. Although the lumps have reduced in size, I have not seen a new lump for some time indicating location might have been the cause. They sometimes show up on scans.  This is not a new problem and has been highlighted for the last 10 years in academic papers.  This particular paper is useful and the conclusion confirms this is not something that should worry patients too much. Read more here
  • fatigue normally within 24-48 hours of the injection but this is not consistent. Not even sure it can be classed as proper fatigue but it’s a ‘you need to sit down and fall asleep‘ feeling! When this occurs, it normally only lasts for 1 day before the normal energy levels return.  Again, like the itching, this appears to be less of an issue today.
  • malabsorption. although the side effects of gastro-intestinal (GI) surgery and gallbladder removal can cause malabsorption issues leading to steatorrhea (basically the inability to digest fat properly); somatostatin analogues can cause or exacerbate existing steatorrhea, as they inhibit the production of digestive/pancreatic enzymes which aid fat digestion.  Most months, I notice a marked but short-term increase in this problem normally within 48-72 hours of the injection.
  • elevated blood glucose.  This is a new issue in 2018 but has been brewing for a year or two. The patient information leaflet for Lanreotide (and for Octreotide) clearly states that this is a potential side effect and also asks those who are already diabetic, to consult their doctor about monitoring doses of diabetic medicine.  I’m working with my doctors to keep my blood glucose down to avoid becoming diabetic.  Please read this article covering the connections between NETs and Diabetes

Watch a useful injection demonstration video here (for administration by a healthcare professional or family member) (click here)

A few years ago, there was some ‘talk’ that somatostatin analogues were also able to stunt or reverse the growth of certain neuroendocrine tumours.  Has this been the case for me?  Possibly.  I’ve had regular CT scans every 3-6 months and since two bouts of major surgery in 2010/2011, I’ve also had 3 x Octreoscans over the same period.  I did once spend a day analysing 5 years of scan results looking for variations in size and concluded that there was a stable trend and potentially a fading of one or two of my largest liver tumours. I was reminded these two types of scans were not really precise enough to detect small millimetre increases or decreases and as there were other factors at play, there was little commitment to make this declaration.  However, I did note in the summary of the CLARINET study, Lanreotide was associated with prolonged progression-free survival among patients with advanced, grade 1 or 2 (Ki-67 <10%) enteropancreatic, somatostatin receptor–positive neuroendocrine tumours with prior stable disease, irrespective of the hepatic tumour volume.  In terms of its anti-proliferative effects, an interim report from the CLARINET extension study suggested longer-term Lanreotide treatment is well tolerated with ‘anti-tumour’ effects in patients with progressive disease.  The final CLARINET open label extension study report additionally provided evidence for long-term PFS benefits of Lanreotide Autogel 120 mg in patients with indolent pancreatic and intestinal NETs.

There’s currently a trial ongoing in relation to Lanreotide and Lung NETs – read by clicking here.

I have my ups and downs and I do feel quite well most of the time.  Most people tell me I look quite well too – lucky they can’t see my insides!  Over the last 7 years, I’ve made some fairly significant adjustments to cope with my condition and maintain a reasonable quality of life – my monthly injection of Lanreotide is no doubt playing a big part.

Finally, please spend 5 minutes watching this fascinating video from Ipsen.  It explains in easy terms how Lanreotide works.  It also has a useful summary of the side effects at the end.  Click here to watch the video.

I’ve just been enrolled onto a new service called HomeZone whereby the injection is now administered at my home via an Ipsen provided and funded nurse.  Read here to see if you can also take advantage of this service.

THE SOMATULINE ‘RESERVOIR’ FORMING IN THE DEEP SUBCUTANEOUS TISSUE

In July 2018, I received my 100th injection of Somatuline Autogel (Lanreotide).  I was very grateful to still be here so I thought it was worth a celebratory cake – injection themed!

Cake with Needle

CAKE PHOTO1 WITH NURSE2

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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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