As it’s Testicular Cancer Awareness Month, I thought I’d share a personal story with you. This is something regarding my own diagnosis and something as yet unpublished. I don’t tend to share some very personal stuff but this is on the boundary of that rule and there are some important messages to be teased out. For those who follow my blog in detail, you will remember the post entitled “Neuroendocrine Cancer – Signs, Suspicions, Symptoms, Syndromes, Side-Effects, Secondary Illnesses, Comorbidities, and Coincidences”. As you can see from the title, I got hooked on a bunch of synonyms (small s) that represent the difficulty in sorting out what can be attributed to Neuroendocrine Tumours (NETs) and what might be something else. You’ll note they all begin with the letter ‘S’ except ‘Comorbidities’ and ‘Coincidences’. These 2 were actually retrospective add-ons to the blog title and there is a potential overlap between both.
Life is full of coincidences and I’m certain this is also the case with issues NET patients have from time to time. There is a high possibility that some things which were going to happen health-wise before NETs came along, will most likely still happen and it can often seem like the NETs have some causal effect. As my friend Dr Eric Liu says ‘Even NET patients get regular illnesses’.
I also suspect the same thing can happen pre-diagnosis and if you’re unlucky, during the diagnostic phase. This sort of event has the potential to confuse an already confusing diagnosis! So here’s a story about my ‘COINCIDENCE’ which eventually turned out to be a ‘COMORBIDITY’.
At the beginning of 2010 (remembering my diagnosis was July that year), I did what all men should regularly do – I checked my ‘chaps’ for lumps. Sometime in January, I got the feeling my left ‘chap’ was bigger than the right and I monitored that for a few days. Eventually, it was patently obvious there was an abnormality. I immediately went to my GP and he diagnosed a hydrocele. Apparently these are quite common with men. He was able to quickly work this out by shining a torch through the offending gonad area and as the light came out the other side, this was confirmation it was excess fluid. He said it might go away on its own but explained there were medical procedures to correct it including fine needle aspiration (not normally a permanent fix) or surgical repair (the most permanent fix). I left it for a few weeks and as time passed, the size of my left ‘chap’ increased. It became really uncomfortable and painful so I asked to be referred to a specialist. Bear in mind at this point, I still didn’t know I had Neuroendocrine Tumours burrowing away inside me for years.
Fast forward 1 month, the hydrocele is not yet sorted and I’m speaking to a specialist having been referred for a low hemoglobin score (the trigger for my NET diagnosis). At this point, I’m convinced there is a connection and amongst the plethora of tests and checks, the specialist also carried out a fine needle aspiration of my left ‘chap’ (I can hear the male audience wincing). The fluid was sent off for testing and subsequently returned negative. My left ‘chap’ was now back to normal (every cloud…..). By the way, the hydrocele returned around 2 months later. I eventually got the date for my hydrocele surgical procedure (hydrocelectomy) but decided to postpone it to sort out another little matter …… Cancer!
I eventually got it repaired in Sep 2011 after 14 months of NET treatment and had no issues since. Now…… I can almost hear the cogs turning …… the testes are an endocrine organ etc. I’ve been through this too and I was still suspicious for a year after diagnosis. However, I’ve been categorically told there is no connection and there is nothing showing on ultrasound, CT scan or Octreoscan. 4.5 years later, I’m happy there was no connection 🙂
However, I did my duty, I checked my chaps, found an issue and fortunately it was nothing too serious. Crap timing though!
I’ve mentioned ‘luck’ a few times in the past month following some more ‘cancerversary’ milestones – these tend to make me reflect on my experience. Even though I was metastatic at diagnosis, I think of myself as lucky on the basis that my tumours were found by ‘chance’, or to be more accurate, found following an innocuous set of circumstances. Click here to hear me talk about my diagnosis.
As we know, Neuroendocrine Cancer can sometimes be very difficult to discover and diagnose. However, sometimes with a bit of luck or a chance event, it can be intercepted and can then often lead to a much better outlook for the person concerned. But sometimes there is also a cost and I don’t just mean financial (although that is also a very real problem). Despite me thinking I had been lucky, the ‘little suckers’ had burrowed their way into many places and I now deal with those consequences following significant treatment to get rid of as many as possible.
With my blogging and advocate activity, I get to hear other people’s stories, some of which have tweaked my emotions from ‘man style leaky eyes’ to wide-eyed surprise and astonishment, but very occasionally with smiles. I had one such exchange with Mary who subsequently agreed to let me use her story which immediately caught my eye because it not only triggered a wide range of emotions, but made me reflect on the cost aspect I described above.
Mary’s is a lung NET patient and her tumour was caught early. Although it was a totally chance discovery, it was in really unfortunate circumstances. Her brother Dan was fighting leukaemia and needed a life saving stem cell transplant. During the checks for her suitability as a donor, the lung NET was discovered. Clearly a very worrying time for Mary as she had gone to the hospital to try to save her brother’s life and ended up being admitted with her own cancer diagnosis and was therefore unable to take any part in the donation. I cannot begin to imagine how that felt for the whole family. Fortunately Mary’s sister was also found suitable and was able to donate, Their brother later had a successful transplant but unfortunately his cancer recurred and he passed away a short while later.
That’s an amazing albeit sad story but it invokes a wide range of emotions. It’s also a very inspiring story about a family coming together in time of crisis. Mary went to hospital that day to try to save Dan’s life and despite her own diagnosis, she still felt guilty that she was unable to fulfil that task. However, before his passing, Dan let it be known that he must have gotten sick to save her life. That’s a heart-warming thought – RIP Dan.
I’m very thankful to Mary who agreed to let me publish her story here. It was actually featured a couple of years ago in their local newspaper – you can read it here – <Click here>
I’d love to hear from others who had a lucky or chance tumour find.
The majority of Neuroendocrine Tumours (NETs) are slow-growing (well differentiated). However, many tumours can be silent (non-functioning) for some years before they start to ‘function’ and inform you of their presence. Even then, it may take some time to work out the real cause as thesymptoms can mimic regular ailments. Moreover, in most cases, the appearance of a functional tumour normally indicates the disease has metastasized and could now be incurable. Some tumours will grow and metastasize without syndromes, i.e. they are non-functional. These may become functional at some point in the future.
However, with most slow-growing NETs, this does not mean terminalas there are various treatment options even at Stage IV. In fact, NETs are one example wheresurgery at the metastatic stage can often provide prognostic advantages denied in other more aggressive types of cancer at the same stage. However, it’s true to say that many NET patients regardless of tumour type or grade and stageof tumour, need to live with quality of life (QoL) challenges.
I sense a change of thinking about people living longer with cancer and the reasons are fairly obvious. Due to better diagnostics and treatment (including for NETs), more people are now living with their cancer; and as a species were are actually living longer. Add the two together and you can see why the big charity organisations are now saying that one in two people will develop cancer at some point in their lives. Ergo – as we live longer we are more likely to come into contact with cancer on the basis that age is a big factor whether someone gets it or not. Now that sounds pessimistic but this needs to be put into context. For example, in UK today, more than one in three (35%) of those people who die having had a cancer diagnosis will now die from other causes. This is up from one in five (21%) 20 years ago. By 2020 this will improve further to almost four in 10 people (38%). This means the number of people who get cancer but die from another cause has doubled over the past 20 years. According to Macmillan Cancer, the cancer story is changing. What was once feared as a death sentence is now an illness that many people survive. A small bit of research indicates this type of thinking is becoming more apparent in other countries too. As survival rates increase, so too will the number of people living with the legacy of cancer and its treatment.
Although more people are living with cancer rather than dying from it, quality of life must be a factor going forward. Any quality of life campaign fits nicely into the existing challenges faced by many Neuroendocrine Cancer patients who need support well beyond their diagnosis and treatment and for some time.
I consider these campaigns additional help in fighting our corner. And of course we need help because for many NET patients there will be no remission, there will be no cure. Cancer patients need more support after a cancer diagnosis. NET patients are effectively already in this position and have been for some time. We have been at the forefront of a group of people living with cancer and needing close support and surveillance. For example:
Late diagnosis. People will be dealing from the effects of late diagnosis which has resulted in metastatic disease – and some people will have been fighting misdiagnosed illnesses for years. That takes its toll.
Consequences of Surgery. People will have had surgery which in many cases is life changing – various bits of the gut (gastrointestinal tract) are now missing, lungs are now missing – many other locationswill have been excised or partly excised. These bits of our anatomy were there for a reason and QoL takes a hit when they are chopped out. Many patients succumb to gastrointestinal malabsorption.
Inoperable Tumours and Syndromes. People will be dealing with remnant and/or inoperable tumours which may or may not be producing an associated NET syndrome (some of the symptoms can be rather debilitating in the worst cases)
Consequences of Non-surgical Treatment. Additionally, people will be dealing with the side effects of multi-modal non surgical treatments, such as somatostatin analogue hormone therapy (Octreotide/Lanreotide), chemotherapy, biological therapy (mTOR inhibitors) (i.e. Everolimus (Afinitor)), biological therapy (protein kinase inhibitors (i.e. Sunitinib (Sutent)), radionuclide therapy (i.e. PRRT). Whilst it’s great there are a wide range of therapies, they all come with side effects.
Secondary Illnesses and Comorbidities. Some people will have gained secondary illnesses in part due to the original cancer or treatment – i.e. somatostatin analogue hormone therapy can have a side effect of increasing blood sugar to diabetic levels and reduce thyroid function. There are many other examples.
Finances. NET Cancer can be an expensive cancer to treat and this is exacerbated by the length of time the treatment lasts. Whilst people have access to free public services or private insurance, many people will end up out-of-pocket due to their cancer. Over time, this adds up.
Emotional Aspects. Many NET patients are kept under surveillance for the remainder of their lives. With that comes the constant worrythat the cancer progresses, tumours get bigger, new tumours show up, treatments are denied (i.e. PRRT in the UK). It’s no surprise that anxiety and depression can affect many patients in these situations. To some extent, there can be a knock-on effect to close family members and carers/caregivers where applicable.
Living with Neuroendocrine Cancer is not easy – it takes guts (both metaphorically and literally).
From day 1 of my diagnosis, I knew my liver was going to need some attention but I had always known that total removal of all tumours would not be possible. This critical organ did in fact produce the biopsy confirming Neuroendocrine Cancer. The early scans indicated multiple liver lesions and an Octreotide scan reported several quite avid isotope activity.
However, as you can see from my clinical history, they first stabilised my syndrome via daily Octreotide so my tumours were subdued ready for major surgery ’round 1′ which took place Nov 2010 – I wrote about this as Part 1 and Part 2 stories. As we are talking about my liver, it’s worth noting that a bland Liver Embolization was carried out prior to ’round 1′ as there was an option to look at the liver whilst I was ‘open’. However, after 9 hours sorting out my other areas, there was insufficient time.
My surgeon (Mr Neil Pearce) promised me a hard year so after 4 months ‘rest’, I was brought back in for major liver surgery (round 2) which took place on 12 Apr 2011. The ‘luck’ word has to be mentioned again because my local NET MDT was led by Mr Pearce who just happened to be one of UK’s top GI surgeons and one of the pioneers of Laparoscopic surgery – that is what I was to receive. In the end, I had a right hepatectomy and a metastasectomy which was calculated to be approximately 66% of my liver removed. Thank goodness it grows back!
The operation went well lasting 6 hours although it could have been shorter. Mr Pearce unfortunately had to spend a quarter of this time picking through ‘dense right sided abdominal adhesions’ caused by ’round 1′. My liver metastasis was described as significant on inspection and around 90% of the tumours were removed during this procedure leaving around half a dozen sub-centimetre deposits. Interestingly he said my pattern of disease was more conspicious on intra-abdominal ultrasound than it had been on previous scans. You can see from the post picture, the type of instruments used in laparoscopic surgery and the fact that they pump air into the abdomen to give sufficient space to operate.
I recovered quickly after only 5 days in hospital and was back at work in 3 weeks. My Chromogranin A finally returned to normal readings recognising the reduction in tumour bulk. My 5HIAA was already back in normal after ’round 1′ and subsequent commencement of Lanreotide. For those who have not had a liver laparoscopic procedure, the healing time is much quicker and you only have limited scarring. I had 3 ‘stab wounds’ (that’s my name for the marks!) across the area of my liver and then a 3 inch scar at the base of my abdomen which was used to remove the ‘bits’ of resected liver.
A follow-up chemo-embolization or TACE (Trans Arterial Chemo embolization) was scheduled a few weeks after the liver surgery which was looking to target the remnant liver tumours. However, this had to be aborted following some routing issues caused by ’round 1′ surgery.
I still have some residual (but stable) disease on my liver but there has been no progression in these 6 years. It’s no secret that debulking or cyto-reductive surgery can be of benefit even to those with advanced or metastatic well differentiated Neuroendocrine disease. I remain thankful for the care and attention I received in the months after my diagnosis.
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.
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 andLanreotide. 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
Crinetics Pharmaceuticals Initiates Phase 1 Study of CRN01941 for the Treatment of Neuroendocrine Tumors
Updated 21 May 2019. Click here to read about this exciting development.
New delivery system for Octreotide LAR – “Q-Octreotide” (MDT201)
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
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
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 studyto 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 Analogue – Pasireotide
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
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!