Lenvatinib has just completed a Phase 2 trial in Gastrointestinal (GI) and Pancreatic Neuroendocrine Tumours. The trial was sponsored by Grupo Espanol de Tumores Neuroendocrinos (Spanish NET scientific organisation) and the manufacturers. A European venture with sites in Austria, Italy, Spain, UK. Headline: The responses are better than Everolimus (Afinitor) and Sunitinib (Sutent).
What is Lenvatinib?
It is a type of targeted therapy known as a multikinase inhibitor. The brand name is ‘LENVIMA‘. These work by inhibiting multiple intracellular and cell surface kinases, some of which are implicated in tumour growth and metastatic progression of cancer, thus decreasing tumour growth and replication. A range of receptor kinases are involved in these processes, including vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), stem cell factor (c-KIT), Flt3, fibroblast growth factor receptor (FGFR), which can be hyperactivated during tumour formation and progression. Tumour growth may be prevented by inhibiting the action of these hyperactivated receptor kinases, and as tumour progression usually involves the action of multiple kinases rather than just one, it is logical to target multiple kinases.
The Lenvantinib mechanism of action is similar to targeted therapy drugs already in use (or in trial) for Neuroendocrine Tumours:
Sunitinib (Sutent) – a targeted therapy receptor protein-tyrosine kinase inhibitor. It inhibits the actions of vascular endothelial growth factor (VEGF) and is an angiogenesis inhibitor (i.e. the development of blood vessels to supply the tumour with nutrients, which they need to grow). It is a mutlikinase in inhibitor.
Everolimus (Afinitor) – a targeted therapy kinase inhibitor that inhibits mammalian target of rapamycin (mTor) kinase, an enzyme required for cell growth and survival. By blocking this enzyme, the medication prevents cell division and, in turn, tumor growth. The medication can also interrupt angiogenesis.
Cabozantinib, an oral potent inhibitor of vascular endothelial growth factor receptor 2, MET, and AXL, and currently on trial for Neuroendocrine Cancer. Click here.
Multikinase inhibitors such as Lenvatinib, may be used to treat advanced kidney cancer as well as other specific types of cancer (in my research I also noted that in addition to kidney cancer, the drug is already approved for liver and thyroid cancers). Worth also noting that the 3 examples of targeted therapy above are not just in use/in trial for Neuroendocrine Cancer, they are also in use/in trial for others including Renal (Kidney) Cancer, Breast Cancer. Often more than one single kinase inhibitor can be given as a combo treatment, perhaps in sequence, to tackle multi kinases.
Anything special about Lenvatinib for Neuroendocrine Cancer?
Recent reports from oncology conferences indicate that Lenvatinib showed significant antitumor activity and a favourable toxicity profile in progressive advanced NETs. This is the highest reported ORR with a targeted agent, confirmed by central radiology assessment in pancreatic NETs and Gastrointestinal (GI) NETs with promising progression free survival (PFS) in a pre-treated population; further evaluation is warranted.
Adverse events were mild to moderate in 90% of patients, the most frequent being fatigue, diarrhea and hypertension.
Lenvatinib showed the highest reported overall response rate (ORR) by central radiology assessment with a targeted agent in advanced NETs:
pNETs: 40.4% (95% CI 27.3-54.9),
GI NETs: 18.5% (95% CI 9.7-31.9.
Worth noting that Everolimus and Sunitinib were approved with ORRs much less than these figures.
Given the responses in comparison to other approved targeted agents, a phase 3 trial should be anticipated. Studies are “currently ongoing” and “further evaluation warranted”. I will keep this article live to provide updates.
New Trial using Lenvatinib and Everolimus in Treating Patients With Advanced, Unresectable Neuroendocrine Tumors
Under ClinicalTrials.gov Identifier: NCT03950609, there is a trial being setup at MD Anderson in Texas USA. Use of a combo of Lenvatinib along with Everolimus (Afinitor) in treating patients with advanced, unresectable Neuroendocrine Tumors (the word ‘Carcinoid’ is used in the trial documentation).
Reference material used in the compilation of this article:
1. Annals of Oncology – Efficacy of Lenvatinib in patients with advanced pancreatic (panNETs) and gastrointestinal (giNETs) grade 1/2 (G1/G2) neuroendocrine tumors: Results of the international phase II TALENT trial (GETNE 1509) 23 Oct 2018 – click here.
2. ESMO Congress 2018 – Efficacy of Lenvatinib in patients with advanced pancreatic (panNETs) and gastrointestinal (giNETs) grade 1/2 (G1/G2) neuroendocrine tumors – click here
3. Prime Oncology Slide Show – click here (useful)
4. Clinical Trials Document NCT02678780 – click here
6. Clinical Trials Document NCT03950609 for the trial of combo treatment Lenvatinib and Everolimus. Click here. As at 15 May 2019, the trial was not recruiting but see document for contact details, quite often these documents can be behind in updating. Trial start date recorded as 30 June 2019.
My chest infection is now settled, as too is the excitement and apprehension behind my first ever Ga68 PET – the outcome of that is still a work in progress. Earlier this year, my thyroid ‘lesion’ on watch and wait was given a ‘damping down’ with the prescription of a thyroid hormone supplement but I await a re-ignition of that small bush fire downstream.
Bubbling behind the scenes and clamoring for attention is the spiking of my blood glucose test results and I was very recently declared ‘at risk’ for diabetes One of my followers entitled a post in my group with “The hits keep coming” in reference to encountering yet another problem in the journey with Neuroendocrine Cancer. I now know how she feels, this issue is a bit of a ‘left fielder’. However, having analysed the situation and spoken to several doctors, I can now put pen to paper.
Neuroendocrine Cancer is not a household name (…… I’m working on that) but diabetes certainly is. The World Health Organisation reports that the number of adults living with diabetes has almost quadrupled since 1980 to 422 million adults. In USA, estimates from CDC stated around 10 million people diagnosed with diabetes with a further 84 million in pre-diabetes state (at risk). In UK around 3.7 million people have diabetes with about 4 times that amount ‘at risk’. It’s a growth industry (…….. but so is NETs – in the last 40 years, the incidence of NETs is rising at a faster rate than diabetes, a disease which some writers have described as an epidemic).
With those numbers, it follows that many NET patients will be diabetic before diagnosis, some will succumb to diabetes whether they have NETs or not, and some may have an increased risk of succumbing due to their treatment. Some may even be pushed into diabetes as a direct result of their NET type or treatment. It’s important to understand diabetes in order to understand why certain types of NET and certain treatments could have an involvement.
For understanding of this article, it’s worth noting the pancreas has two main functions: an exocrine function that helps in digestion and an endocrine function that regulates blood sugar. I have talked about the exocrine function in relationship to Neuroendocrine Cancer at length – check out this article on Pancreatic Enzyme Replacement Therapy. In this article, I now want to cover the issues with the endocrine function and blood sugar. First a short primer on diabetes – it is necessarily brief for the purposes of this article.
TypeS OF DIABETES
Type 1 and Type 2 Diabetes are fairly well-known. There’s actually more than two types, but these are the most common. Type 2 is the most prevalent with around 90% of diabetes cases. When you’ve got Type 1 diabetes, you can’t make any insulin at all. If you’ve got Type 2 diabetes, the insulin you make either can’t work effectively, or you can’t produce enough of it. Additional types may come up in the subsequent discussion.
What is the problem?
What all types of diabetes have in common is that they cause people to have too much glucose (sugar) in their blood. But we all need some glucose. It’s what gives us our energy. We get glucose when our bodies break down the carbohydrates that we eat or drink. And that glucose is released into our blood. We also need a hormone called insulin. It’s made by our pancreas, and it’s insulin that allows the glucose in our blood to enter our cells and fuel our bodies.
If you don’t have diabetes, your pancreas senses when glucose has entered your bloodstream and releases the right amount of insulin, so the glucose can get into your cells. But if you have diabetes, this system doesn’t work properly. Diabetes is associated by being overweight but there isn’t a 100% correlation with that. However, when an individual becomes overweight, there is an increase in free fatty acids in the blood stream which may contribute to reduced insulin sensitivity in the tissues, leading to increased glucose levels in blood.
Symptoms and diagnosis of Diabetes
Different people develop different symptoms. In diabetes, because glucose can’t get into your cells, it begins to build up in your blood. And too much glucose in your blood causes a lot of different problems. To begin with it leads to diabetes symptoms, like having to wee a lot (particularly at night), being incredibly thirsty, and feeling very tired. You may also lose weight, get infections like thrush or suffer from blurred vision and slow healing wounds.
I see these symptoms mentioned very frequently and normally people are trying to associate them with NETs and/or the treatment for NETs.
Diabetes diagnosis is normally triggered diagnosed based on blood tests such as fasting Blood Glucose (snapshot) and/or Glycated Hemoglobin (A1C) or HbA1C.
Over a long period of time, high glucose levels in your blood can seriously damage your heart, your eyes, your feet and your kidneys. These are known as the complications of diabetes.
But with the right treatment and care, people can live a healthy life. And there’s much less risk that someone will experience these complications.
What are the direct connections with Diabetes and NETs?
It’s not surprising that diabetes is mostly associated with Neuroendocrine Tumors of the Pancreas but there are other areas of risk for other types of NETs including to those who are existing diabetics – see below.
The main types of surgery for Neuroendocrine Tumors of the Pancreas are Distal Pancreatectomy (tail), Sub-total pancreatectomy (central/tail), Classic Whipple (pancreaticoduodenectomy – head and/or neck of pancreas), Total pancreatectomy (remove the entire pancreas) or an Enucleation (scooping out the tumour with having to remove too much surrounding tissue). From the PERT article link above (exocrine function), you can see why some people need this treatment to offset issues of reduced production of pancreatic enzymes. The same issue can develop with a reduced endocrine function leading to the development of diabetes.
The different types of functional pancreatic NETs often called syndromes in their own right due to their secretory role. One might think that Insulinomas are connected to diabetes issues but this hormonal syndrome is actually associated with low blood sugar (hypoglycemia), although low blood sugar can turn out to be a complication of diabetes treatment.
A NET syndrome known as Glucagonoma (a type of functional pancreatic NET) is associated with high blood glucose levels. About 5-10% of pancreatic neuroendocrine tumors are Glucagonomas, tumors that produce an inappropriate abundance of the hormone glucagon. Glucagon balances the effects of insulin by regulating the amount of sugar in your blood. If you have too much glucagon, your cells don’t store sugar and instead sugar stays in your bloodstream. Glucagonoma therefore leads to diabetes-like symptoms (amongst other symptoms). In fact Glucagonoma is sometimes called the 4D syndrome – consists of diabetes, dermatitis, deep venous thrombosis (DVT), and depression.
Another functional pancreatic NET known as Somatostatinoma is prone to developing insulin resistance. Somatostatinomas produce excessive amounts of somatostatin which interferes with the insulin/glucagon function and could therefore lead to diabetes.
Diabetes caused by cancer or cancer treatment
Worth noting that this type of diabetes is sometimes known as ‘Pancreatogenic diabetes’ and this is actually classified by the American Diabetes Association and by the World Health Organization as type 3c diabetes mellitus (T3cDM) and refers to diabetes due to impairment in pancreatic endocrine function due to acute cancer and cancer treatment (and several other conditions). The texts tend to point to cancers (and other conditions) of the pancreas rather than system wide. Prevalence data on T3cDM are scarce because of insufficient research in this area and challenges with accurate diabetes classification in clinical practice. (Authors note: Slightly confusing as many text say that type 3 diabetes is proposed for insulin resistance in the brain (diabetes associated with Alzheimer’s disease). There’s another term for a complete removal of the entire pancreas – Pancreoprivic Diabetes
Other treatment risks
Somatostatin Analogues (e.g. Octreotide and Lanreotide) are common drugs used to control NET Syndromes and are also said to have an anti-tumor effect. They are known to inhibit several hormones including glucagon and insulin and consequently may interfere with blood glucose levels. The leaflets for both drugs clearly state this side effect with a warning that diabetics who have been prescribed the drug, should inform their doctors so that dosages can be adjusted if necessary. The side effects lists also indicates high and low blood glucose symptoms indicating it can cause both low and high blood glucose (hypoglycemia and hyperglycemia). For those who are pre-diabetic or close to pre-diabetic status, there is a possibility that the drug may push blood tests into diabetic ranges. Afinitor (Everolimus). The patient information for Afinitor (Everolimus) clearly states “Increased blood sugar and fat (cholesterol and triglycerides) levels in blood: Your health care provider should do blood tests to check your fasting blood sugar, cholesterol and triglyceride levels in the blood before you start treatment with AFINITOR and during treatment with AFINITOR” Sutent (Sunitinib). The patient information for Sutent (Sinitinib) clearly states that low blood sugar (hypoglycemia) is a potential side effect. It also advises that low blood sugar with SUTENT may be worse in patients who have diabetes and take anti-diabetic medicines. Your healthcare provider should check your blood sugar levels regularly during treatment with SUTENT and may need to adjust the dose of your anti-diabetic medicines.
In rare cases, certain NETs may produce too much Adrenocorticotropic hormone (ACTH), a substance that causes the adrenal glands to make too much cortisol and other hormones. This is often associated with Cushing’s syndrome. Cortisol increases our blood pressure and blood glucose levels with can lead to diabetes as a result of untreated Cushing’s syndrome.
I think it’s sensible for all NET patients, particularly those with involvement as per above and who are showing the signs of hypoglycemia and hyperglycemia, to be checked regularly for blood glucose and if necessary HbA1c. Many patient information leaflets for the common NET treatments also indicate this is necessary. Always tell your prescribing doctors if you are a diabetic or about any history of low or high blood glucose before treatment for NETs.
My brush with Diabetes (as at Jan 2019)
My blood glucose levels started to climb slightly in 2016 but HbA1c remained normal. However, an HbA1c test in early 2018 put me into pre-diabetic range (44 mmoL/moL). I explained some of the above article to my GP who is corresponding with a diabetes expert at secondary care – the expert suggested that I need to be monitored carefully as weight loss is not necessarily the best response. I have kept my NET team up to date.
At the time of updating, two separate and sequential HbA1c tests (3 month interval) came back normal at 36 mmoL/moL. I’m pragmatic enough to know that I do not need to lose weight as one of the aims of reducing my blood glucose and HbA1c levels (something emphasised by the above mentioned diabetes specialist).
I even got on my bike to do a little bit more exercise just in case!
At this point, I cannot yet say if this is the beginning of progressive Type II diabetes or if my medication is causing these spikes in my blood glucose and HbA1c. Judging by 2 x normal HbA1c, looks like the somatostatin analogue (Lanreotide in my case) may caused a spike to a pre-diabetes score. I will keep you posted.
Summary – if you are noticing these symptoms, get your blood sugar checked (with acknowledgement to Dr Pantalone from Cleveland Clinic)
1. You’re making more trips to the bathroom
Having to go to the bathroom more than normal, particularly at night, is a sign that your blood sugar might be out of whack.
Dr. Pantalone says one of his patients came in for a diagnosis after a family member noticed that he was using the bathroom during each commercial break when they watched TV.
2. You’re getting frequent urinary or yeast infections
When your blood sugar is high and your kidneys can’t filter it well enough, sugar ends up in the urine. More sugar in a warm, moist environment can cause urinary tract and yeast infections, especially in women.
3. You’re losing weight without trying
If you have diabetes, your body isn’t able to use glucose (sugar) as effectively for its energy. Instead, your body will start burning fat stores, and you may experience unexpected weight loss.
4. Your vision is getting worse
High sugar levels can distort the lenses in your eyes, worsening your vision. Changes in your eyeglass prescription or vision are sometimes a sign of diabetes.
5. You’re feeling fatigued or exhausted
Several underlying causes of fatigue may relate to diabetes/high sugar levels, including dehydration (from frequent urination, which can disrupt sleep) and kidney damage.
This feeling of exhaustion is often persistent and can interfere with your daily activities, says Dr Pantalone.
6. You’re noticing skin discoloration
Something that Dr. Pantalone often sees in patients before a diabetes diagnosis is dark skin in the neck folds and over the knuckles. Insulin resistance can cause this condition, known as acanthosis nigricans.
I’ve posted extensively about Oncolytic virus trials, focused on the ongoing Neuroendocrine Cancer trial in Uppsala Sweden. I wanted to incorporate this information into a single article ready for future news, whilst at the same time updating you on further developments in the field of Oncolytic Viruses for Neuroendocrine Cancer. The excitement of the Uppsala work has dampened in recent years, not helped by the fact that one of the first patients unfortunately died. In the absence of any news, I suspect there has been no real progress and/or the funding has run out.
What exactly are Oncolytic Viruses?
Oncolytic Viruses infects and breaks down cancer cells but not normal cells. Oncolytic viruses can occur naturally or can be made in the laboratory by changing other viruses. Certain oncolytic viruses are being studied in the treatment of cancer. Some scientists say they are another type of immunotherapy whilst others say it’s too early to classify as such. The good news is that Neuroendocrine Cancer seems to figure in this work with two of these viruses apparently working on mice to date. Listed below are two active projects involving NETs, one directly and one indirectly.
I’ll briefly describe what’s happening and then you can link to my Facebook article if you need more background.
The trial is called AdVince after Vince Hamilton who funded it. Unfortunately he died before he saw any output but his forward thinking and benevolence lives on and might hopefully help NET patients in the longer term. It’s quite a small trial and is being conducted in Uppsala University Sweden, a famous European NET Centre of Excellence and where many people from across the world attend to take advantage of PRRT availability and experience and is home to famous NET specialist Kjell Öberg, MD, PhD, a professor of endocrine oncology.
A Swedish man (Jan-Erik Jannsson) was the first to get the virus to their cancer (NETs) using a genetically modified virus.
Unfortunately, I was given the news from a source close to the trial that Jan died last year of pneumonia. I have no evidence to suggest his death is in anyway connected to the trial but I’m told he was an ill man prior to the trial commencing. I have therefore dedicated this post to him. RIP Jan.
The initial data presented by the trial indicated that AdVince can be safely evaluated in a phase I/IIa clinical trial for patients with liver-dominant NET. The last I heard from the trial is that they are trying to recruit a further 12 patients to Phase IIa (the trial document allows for up to 36).
Read more background on my Facebook post here: Click here
The trial document on Clinical Trials Website: Click here
This is an oncolytic viral therapy currently in phase III and phase Ib/II clinical trials for use against primary liver (Hepatocellular Carcinoma) and Colorectal cancers, respectively. Pexa-Vec is a weakened (or attenuated) virus that is based on a vaccine used in the eradication of smallpox. The modified virus is injected directly into the cancer tumour, to grow inside these rapidly growing cancer cells and hopefully kill them.
According to the Colorectal Clinical Trial, the aim of the study is to evaluate whether the anti-tumor immunity induced by Pexa-Vec oncolytic viral therapy can be enhanced by immune checkpoint inhibition i.e. they are testing it in conjunction with Immunotherapy drugs (in the case of Colorectal, Durvalumab, and a combination of Durvalumab and Tremelimumab).
The Hepatocellular Carcinoma trial (Phocus) is at Phase III where the sponsors are evaluating Pexa-Vec to determine if it can slow the progression of advanced liver cancer and improve quality of life. I can other trials appearing such as this one for Colorectal Cancer and this one for any solid tumour type.
The work is a collaboration forged between University of California San Francisco (UCSF) vascular researcher Donald McDonald, MD, PhD, and researchers at San Francisco-based biotech SillaJen Biotherapeutics Inc. (formerly Jennerex Biotherapeutics, Inc.), a subsidiary of SillaJen, Inc., headquartered in Korea.
So what’s the Neuroendocrine Connection with Pexa-Vec?
As part of the research, McDonald’s lab injected it intravenously into mice genetically modified to develop pancreatic neuroendocrine cancer. They found that the virus failed to infect healthy organs or make the animals ill, but succeeded in infecting blood vessels within tumors. These initial infections caused the vessels to leak and expose the tumor cells to the virus. In these experiments, the virus managed to infect and destroy only a small proportion of tumor cells directly, the researchers found, but within five days of the initial infection, the rest of the tumor began to be killed by a powerful immune reaction. Live human trials have commenced in 2018 and the “patient 1” is a pancreatic NET patient. Read more here. Interestingly they added Keytruda (an immunotherapy) to the mix. It’s only been four months since ‘Patient 1’ (Tamara) began the trial, but a mid-treatment CT scan was said to be “promising”. I will keep this article live and bring you updates as I receive them.
Clearly it’s still early days in the Oncolytic Virus field with minimum breakthrough in terms of success on humans. In terms of the Neuroendocrine connection, it is exciting that two programmes are showing results (albeit in mice). We wait to hear from Uppsala on how the human test of AdVince is coming along. My agents are scanning the internet every day looking for any comment.
If you want to learn more about Oncolytic Viruses in general – there’s a great summary here.
There’s a lot of inaccurate and out of date information out there. Some is just a lack of understanding, often with a combination of patient forum myth spreading. Some can only be described as propaganda.
Myth 1: All Neuroendocrine Tumours are benign
Not true. By any scientific definition, the word ‘tumour’ means ‘an abnormal mass of tissue that results when cells divide more than they should or do not die when they should. Tumours may be benign (not cancerous), or malignant (cancerous)’. Sure, some NETs will be benign. However, The World Health Organisation (WHO) 2010 classification for digestive system is based on the concept that all NETs have malignant potential, and has therefore abandoned the division into benign and malignant NETs and tumours of uncertain malignant potential. This has been reinforced in the 2017 update to include clarification for other endocrine organ types of NET including Pheochromocytoma. Read more here. The word ‘Carcinoid’ is inextricably linked with this issue – read here why we need to stop using the term to help fight the benign myth.
Myth 2: Neuroendocrine Tumours is a terminal condition
Not true. By any definition of the word terminal in a medical diagnostic context, most NET patients have a good prognostic outlook, even those with metastatic and incurable variants of the disease. Read more here.
Myth 3: Carcinoid is another word for Neuroendocrine Tumours
Not true. Carcinoid is a very old term and was phased out years ago. Carcinoid is not mentioned in the latest WHO Classification schemes for Neuroendocrine Neoplasms (a term covering Neuroendocrine Tumours and Neuroendocrine Carcinoma). Unfortunately, the problem is exacerbated by organisations and individuals who still use the word. Also, those who use the following terms:
“Carcinoid and Neuroendocrine”,
“Neuroendocrine and Carcinoid”,
“Carcinoid NETs” or “CNET”
These are all contextually incorrect and misleading terms (not to mention the bad grammar). ENETS, NANETS and NCCN publications are gradually phasing the word out except in relation to Carcinoid Syndrome (and even then there could be easy solutions for this). Read more here and here.
Myth 4: All NET patients get ‘carcinoid syndrome’
Not true. Firstly, many NET cancers are non-functional; and secondly, carcinoid syndrome is only one of a number of “NET Syndromes” associated with the various types of NET. However, the issue is further confused by those who use the word ‘Carcinoid‘ to incorrectly refer to all NETs and use Carcinoid Syndrome to refer to all NET Syndromes. Read more here.
Not true. Steve Jobs had a Neuroendocrine Tumour of the Pancreas. Ditto for a few other famous names. Read more here.
Myth 7: I’m not getting chemotherapy, I must be doing OK?
Not true. For some cancers or some sub-types of cancers, although it remains an option, chemotherapy is not particularly effective, e.g. some types of Neuroendocrine Cancer (NETs). In general, well differentiated NETs do not normally show a high degree of sensitivity to chemotherapy, although some primary locations fare better than others. However, many of the treatments for NET Cancer are somewhat harsh, have long-term consequences, and have no visible effects. NET patients are often said to “look well” but that doesn’t mean they are not struggling behind the scenes or under the surface. Read more here. P.S. Afinitor (Everolimus), Sutent (Sunitinib) are not chemo – Read more here.
Myth 8: All diarrhea is caused by carcinoid syndrome
Not true. It could be one of the other syndromes or tumor types or a side effect of your treatment. Check out this post.
Myth 9: Neuroendocrine Tumours is a ‘good cancer’
Not true. Simply, no cancer is good. Some are statistically worse than others in prognostic terms, that’s true…… but living with NETs is very often not a walk in the park. However, no one cancer is better to get than any other – they’re all bad. Read more here.
Myth 10: Every NET Patient was misdiagnosed for years
Not true. Many NET Patients are correctly diagnosed early on in their investigation and in a reasonable time. This myth is perpetuated because of two things: firstly, on forums, the ratio of long-term misdiagnosis is high creating a false perception; and secondly, the method of capturing patient surveys is not extensive enough – again creating a false perception. In fact, the latest and largest database analysis from US indicates earlier diagnosis is improving, with more and more NETs being picked up at an early stage. Read more here.
Myth 11: Somatostatin Analogues are a type of Chemotherapy
Not true. Somatostatin Analogues (e.g. Octreotide and Lanreotide) are not chemotherapy, they are hormone inhibiting drugs. They are more biotherapy. As the drugs latch onto somatostatin receptors, they are more targeted than systemic. For the record, Everolimus (Afinitor) and Sunitinib (Sutent) are not chemotherapy either. Read more here.
Myth 12: Stuart Scott (ESPN) and Audrey Hepburn had Neuroendocrine Cancer.
Not true. This is a common misunderstanding within the community. They both had Pseudomyxoma Peritonei (PMP). Read more about PMP here.
Myth 13: I’ve been diagnosed with Neuroendocrine Tumours – my life is over
Not true. Many patients live a very long time and lead fairly normal lives with the right treatment and support. It’s difficult but I try not to use ‘I can’t’ too much. Read more here.
Myth 14: There are only a handful of Neuroendocrine specialists in the world
Not true. There are many specialists in many countries. Get links to specialists by clicking here
Myth 15: The Ga68 PET scan is replacing the CT and MRI scan in routine surveillance for all NET Patients
Not true. It is actually replacing the Octreotide Scan for particular purposes, or will eventually. Read more by clicking here.
Myth 16: All NET Patients are Zebras
Not true. They are in fact human beings and we should treat them as such. Please don’t call me a zebra, I and many others don’t appreciate it. Please don’t use the term on my social media sites, the comment or post will be removed. Sorry but I refuse to perpetuate this outdated dogma. Read why here:
Myth 17: Multiple Endocrine Neoplasia (MEN) is a type of Neuroendocrine Tumour
Not true. Multiple Endocrine Neoplasia are syndromes and inherited disorders not tumours. You can actually have MEN and not have any tumours. However, these disorders can put people at more risk of developing Neuroendocrine or Endocrine Tumours. Read morehere
Myth 18: Palliative Care means end of life or hospice care
Not true. Palliative care is specialized medical care that focuses on providing patients relief from pain and other symptoms of a serious illness. A multidisciplinary care team aims to improve quality of life for people who have serious or life-threatening illnesses, no matter the diagnosis or stage of disease. Read more here
Myth 19: Serotonin is found in foods
Not true. Serotonin is manufactured in the body. Read more here
Myth 20: NETs cannot be cured
Not true. If caught early enough, some NETs can be treated with curative intent (totally resected with margins) with little or no further follow up. It says this in ENETS and NANETS publications which are authored by our top specialists. If we can’t believe them, who can we believe? Read more here.
Myth 21: Pancreatic Enzyme Replacement Therapy (Creon etc) is only for pancreatic patients
Not true. It’s for any patient who is exhibiting exocrine pancreatic insufficiency. Read more here.
Myth 22: High Grade NETs are Carcinomas
Not entirely true. Grade 3 (high grade) comprises well differentiated tumours and poorly differentiated tumours. Only poorly differentiated tumour are carcinomas. Read more here.
More to follow no doubt
For general cancer myths and the dangers of fake health news, please see my ARTICLE HERE
Thanks for reading
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I recently wrote a blog called Neuroendocrine Cancer – Exciting Times Ahead! I wrote that on a day I was feeling particularly positive and at the time, I wanted to share that positivity with you. I genuinely believe there’s a lot of great things happening. Don’t get me wrong, there’s a lot still to be done, particularly in the area of diagnosis and quality of life after being diagnosed. However, this is a really great message from a well-known NET expert.
In an interview with OncLive, Jonathan R. Strosberg, MD, associate professor at the H. Lee Moffitt Cancer Center in Florida, discussed his presentation on NETs at a recent 2016 Symposium, and shed light on the progress that has been made in this treatment landscape.
OncLive: Please highlight some of the main points from your presentation.
Strosberg: The question I was asked to address is whether we’re making progress in the management of NETs, and I think the answer is unequivocally yes. Prior to 2009, there were no positive published phase III trials.
Since then, there have been 8 trials, 7 of which have reached their primary endpoints. So it’s been a decade of significant improvement. And even though none of these studies were powered to look at overall survival as an endpoint, we’re certainly seeing evidence of improvement in outcomes.
OncLive: What are some of the pivotal agents that you feel have impacted the paradigm in the past several years?
Strosberg: The first group is the somatostatin analogs. We use them to control hormonal symptoms like carcinoid syndrome, but with the CLARINET study, we now know that they substantially inhibit tumor growth.
The next significant drug we use in this disease is everolimus (Afinitor), an oral mTOR inhibitor, which is now approved in several indications based on positive phase III studies. The first was in pancreatic NETs and subsequently, based on the RADIANT-4 trial, it was also approved in lung and gastrointestinal NETs. So that was an important advance.
The next important category of treatment is radiolabeled somatostatin analogs, otherwise known as peptide receptor radiotherapy. The one that’s been tested in a phase III trial is lutetium dotatate, also known as Lutathera. It was tested in patients with progressive midgut NETs and showed a very substantial 79% improvement in progression-free survival, and a very strong trend toward improvement in overall survival, which we hope will be confirmed upon final analysis.
OncLive: Are we getting better at diagnosing and managing the treatment of NETs?
Strosberg: Certainly. I think pathologists are better at making the diagnosis of a NET, rather than just calling a cancer pancreatic cancer or colorectal cancer. They’re recognizing the neuroendocrine aspects of the disease, and doing the appropriate immunohistochemical staining.
We also have better diagnostic tools. We used to rely primarily on octreoscan, and in many cases we still do, but there is a new diagnostic scan called Gallium-68 dotatate scan, also known as Netspot, which has substantially improved sensitivity and specificity. It’s not yet widely available, but it is FDA approved and hopefully will enable better diagnosis as well as staging in the coming years.
And, with the increase in number of phase III studies, we’re developing evidence-based guidelines, which will hopefully lead to more standardization, although knowing how to sequence these new drugs is still quite challenging.
OncLive: With sequencing, what are the main questions that we’re still trying to answer?
Strosberg: If we take, for example, NETs of the midgut, beyond first-line somatostatin analogs, physicians and patients often face decisions regarding where to proceed next, and for some patients with liver-dominant disease, liver-directed therapies are still an option.
For others, everolimus is a systemic option, and then hopefully lutetium dotatate will be an option based on approval of the drug, which is currently pending. Knowing how to choose among those 3 options is going to be a challenge, and I think there will be debates. Hopefully, clinical trials that compare one agent to another can help doctors make that choice. It’s even more complicated for pancreatic NETs. Beyond somatostatin analogs, we have about 5 choices—we have everolimus, sunitinib (Sutent), cytotoxic chemotherapy, liver-directed therapy, and peptide receptor radiotherapy. It’s even more challenging in that area.
OncLive: Are there any other ongoing clinical trials with some of these agents that you’re particularly excited about?
Strosberg: There’s a trial that is slated to take place in Europe which will compare lutetium dotatate with everolimus in advanced pancreatic NETs, and I think that’s going to be a very important trial that will help us get some information on both sequencing of these drugs, as well as the efficacy of Lutathera in the pancreatic NET population, based on well-run prospective clinical trials. I’m particularly looking forward to that trial.
OncLive: Looking to the future, what are some of the immediate challenges you hope to tackle with NETs?
Strosberg: One area of particular need is poorly differentiated neuroendocrine carcinomas. That’s a field that’s traditionally been understudied. There have been very few prospective clinical trials looking at this particular population, and we’re hoping that will change in the near future. There are a number of trials taking place looking at immunotherapy drugs. If these agents work anywhere in the neuroendocrine sphere, they are more likely to work in poorly differentiated or high-grade tumors, in my opinion, given the mutational profile of these cancers. So that’s something I’m particularly looking forward to being able to offer these patients something other than the cisplatin/etoposide combination that goes back decades, and is of short-lasting duration.
See more at: http://www.onclive.com/publications/oncology-live/2016/vol-17-no-24/expert-discusses-recent-progress-in-net-management#sthash.ypkilX2A.dpuf
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Cabozantinib is an oral drug which works by blocking the growth of new blood vessels that feed a tumour. In addition to blocking the formation of new blood cells in tumours, Cabozantinib also blocks pathways that may be responsible for allowing cancers cells to become resistant to other “anti-angiogenic” drugs. It is a type of drug called a growth blocker. Cabozantinib has been studied or is already in research studies as a possible treatment for various types of cancer, including prostate cancer, ovarian cancer, brain cancer, thyroid cancer, lung cancer, and kidney cancer. During my research, I found that it has a connection to Medullary Thyroid Cancer (MTC) which is a type of Neuroendocrine Cancer, frequently associated with Multiple Endocrine Neoplasia (MEN). Cabozantinib, under the brand name of ‘Cometriq’ was approved by the FDA in 2012 for use in MTC. Read more about Cometriq here. It’s also been approved by the FDA for advanced renal cell carcinoma (RCC) (branded as Cabometyx). I also discovered that there is an exclusive licensing Agreement with the manufacturers (Elelixis) and Ipsen (of Lanreotide fame) to commercialize and develop Cabozantinib in regions outside the United States, Canada and Japan
Growth blockers are a type of biological therapy and include tyrosine kinase inhibitors, proteasome inhibitors, mTOR inhibitors, PI3K inhibitors, histone deacetylase inhibitors and hedgehog pathway blockers. Cabozantinib is a tyrosine kinase inhibitor (TKI). They block chemical messengers (enzymes) called tyrosine kinases. Tyrosine kinases help to send growth signals in cells so blocking them stop the cell growing and dividing. Some TKIs can block more than one tyrosine kinase and these are known as multi-TKIs.
So Capozantinib is a tyrosine kinase inhibitor and is therefore a biological therapy and growth blocker just like Everolimus (Afinitor) and Sunitinib (Sutent) – some texts describe thelattero two as chemotherapy but this is just not accurate.
Very technical process but in the simplest of terms, Cabozantinib is designed to disrupt the actions of VEGF (a growth factor) and MET (a growth factor receptor) which promote spread of cancerous cells through the growth of new blood vessels. Whilst we are on this subject, please note Everolimus (Afinitor) is an mTOR inhibitor and Sunitinib (Sutent) is a tyrosine kinase inhibitor. Many people think these drugs are a type of chemo – that is incorrect, these are targeted biological therapies. See more on this by clicking here.
What is the current trial status of Capozantinib?
A Phase III trial is now recruiting entitled “Cabozantinib S-malate in Treating Patients With Neuroendocrine Tumors Previously Treated With Everolimus That Are Locally Advanced, Metastatic, or Cannot Be Removed by Surgery”.
The trial has 172 locations across the US (see link below). The primary study (final data) is scheduled Jan 1st 2021.
A funded piece of research by the NET Research Foundation – check it out here – looks like they are trying to figure out what patients might benefit from Cabozantinib using biomarker data to predict response.
BOSTON — Cabozantinib (Cabometyx) may benefit patients with malignant pheochromocytomas and paragangliomas, according to results of a phase II trial presented here.
Patients receiving cabozantinib (Cometriq) treatment experienced notable tumor shrinkage in the lymph nodes, liver, and lung metastases, according to Camilo Jimenez, MD, of the MD Anderson Cancer Center in Houston, and colleagues.
Additionally, progression-free survival significantly increased after treated to 12.1 months (range 0.9-28) compared with just 3.2 months prior to treatment, they reported at the American Association of Clinical Endocrinologists (AACE) annual meeting.
Cabozantinib treatment was also tied to an improvement in blood pressure and performance status, as well as remission of diabetes among these patients.
“Malignant pheochromocytomas and paragangliomas are frequently characterized by an excessive secretion of catecholamines. [Patients] have a large tumor burden and they have a decreased overall survival,” explained Jimenez. “Tumors are frequently very vascular and frequently associated with bone metastases. In fact, up to 20% of patients who have malignancy of pheochromocytomas and paragangliomas may have predominant bone metastases.”
He added that “an interesting aspect of this tumor is that C-MET receptor mutation have been found in occasional patients with malignant pheochromocytomas and paragangliomas.”
Cabozantinib is an anti-angiogenic tyrosine kinase inhibitor, which also targets RET, MET, and AXL. It is approved for metastatic medullary thyroid cancer, and was more recently approved for first-line treatment of advanced renal cell carcinoma.
“MET pathway is also involved in the development of bone metastases. In fact, cabozantinib is a very effective medications for patients who have bone metastases in the context of cancer of different origins,” Jimenez said.
In order to be eligible for the trial, patients with confirmed pheochromocytoma or paraganglioma had to be ineligible for curative surgery, have ≥3 months life expectancy, no risk for perforation or fistula, and adequate organ functioning. Prior to cabozantinib initiation, patients could not receive chemotherapy or biologic agents within 6 weeks, radiation within 4 weeks, or MIBG within 6 months.
Following histological confirmation of disease progression >1 year according to RECIST 1.1, the trial included 14 patients with measurable disease and eight patients with predominant/exclusive bone metastases. Fifteen patients subsequently enrolled into the trial, six of whom had germline mutations of the SDHB gene.
All participants were all started at an initial daily dose of 60 mg of cabozantinib, which was subsequently reduced down to between 40 to 20 mg due to toxicity in 13 patients based on tolerance.
The majority of these patients with measurable disease experienced some level of disease response. Six patients reported a partial response, defined as over a 30% reduction, while three patients achieved moderate response, marked by a 15%-30% reduction. Five of the patients with predominant bone metastases reported disease stabilization, according to results of an FDG-PET scan. One patient experienced disease progression while on treatment.
Overall, cabozantinib was generally well-tolerated without any grade 4 or 5 treatment-related adverse events reported. Some of the most common adverse events reported included grade mild dysgeusia, hand and foot syndrome, mucositis, fatigue, weight loss, and hypertension, according to the authors.
Primary Source – American Association of Clinical Endocrinologists meeting – AACE 2018; Abstract 142. attended my Medscape writers
I generated this blog article to add value rather than just post the outputs for your own perusal. I hope you find it useful.
Please note that taking part in a clinical trial is a big decision and must be considered carefully in conjunction with your specialists if necessary. This article is not suggesting this trial is right for you. Please check the inclusion and exclusion criteria in the trials document carefully. (Pheo/Para patients see other clinical trial link above)
I’m continually seeing certain drugs for treatment of Neuroendocrine Tumours (NETs) described as chemotherapy. I think there must be some confusion with more modern drugs which are more targeted and work in a different way to Chemotherapy.
I researched several sites and they all tend to provide a summary of chemotherapy which is worded like this: Chemotherapy means:
a treatment of cancer by using anti-cancer medicines called cytotoxic drugs. Cytotoxic medicines are poisonous (toxic) to cancer cells. They kill cancer cells or stop them from multiplying. Different cytotoxic medicines do this in different ways. However, they all tend to work by interfering with some aspect of how the cells divide and multiply. Two or more cytotoxic medicines are often used in a course of chemotherapy, each with a different way of working. This may give a better chance of success than using only one. There are many different cytotoxic medicines used in the treatment of cancer. In each case the one (or ones) chosen will depend on the type and stage of your cancer. Interestingly, there are several statements along the lines of ‘Cytotoxic medicines work best in cancers where the cancer cells are rapidly dividing and multiplying’, a key issue with lower grade NETs.
Well known chemotherapy treatments for NETs include (but are not limited to): Capecitabine (Xeloda), Temozolomide (Temodal), Fluorouracil (5-FU), Oxaliplatin (Eloxatin) Cisplatin, Etoposide (Etopophos, Vepesid), Carboplatin, Streptozotocin (Zanosar). Some of these may be given as a combination treatment, e.g. CAPecitabine and TEMozolomide (CAPTEM).
In the past, any medication used to treat cancer was regarded as chemotherapy. However, over the last 20 years, new types of medication that work in a different way to chemotherapy have been introduced. Many of these new types of medication are known as targeted therapies. This is because they’re designed to target and disrupt one or more of the biological processes that cancerous cells use to grow and reproduce. They are classed as biological therapy. In contrast, chemotherapy medications are mostly systemic in nature and designed to have a poisonous effect on cancerous cells, thus the term ‘cytotoxic’.
The following well known NETs treatment are not really chemotherapy and describing them in this way is not only misleading but may actually cause alarm to other patients. Furthermore, if you check any authoritative NET Cancer specialist or advocate organisation; any general and authoritative cancer site or the manufacturer’s websites; you will not see the drugs below listed within the term chemotherapy.
Somatostatin Analogues e.g. Sandostatin (Octreotide), Somatuline (Lanreotide). Although these drugs have an anti-cancer effect for some, they are in fact hormone inhibitors and are therefore a hormone therapy.
Everolimus (Afinitor). This is a targeted biological therapy or more accurate a mammalian target of rapamycin (mTOR) inhibitor. It is a type of treatment called a signal transduction inhibitor. Signal transduction inhibitors stop some of the signals within cells that make them grow and divide. Everolimus stops a particular protein called mTOR from working properly. mTOR controls other proteins that trigger cancer cells to grow. So everolimus helps to stop the cancer growing or may slow it down.
Sunitinib (Sutent). This is a targeted biological therapy or more accurate a protein (or tyrosine) kinase inhibitor. Protein kinase is a type of chemical messenger (an enzyme) that plays a part in the growth of cancer cells. Sunitinib blocks the protein kinase to stop the cancer growing. It can stop the growth of a tumour or shrink it down.
I can only speculate why some of the confusion exists but I do have some personal experience I can quote too. Firstly I believe it could be easier for some people to describe the new agents as ‘chemotherapy’ rather than explain things such as somatostatin analogues, ‘mammalian target of rapamycin (mTOR) inhibitors’, protein kinase inhibitor or angiogenesis inhibitors. Another reason could be that health insurance companies do not have the correct database structures in place on their IT systems and therefore need to ‘pigeon hole’ drugs into the closest category they can see. Often this is chemotherapy and this only adds to the confusion. In the days when I had health insurance, my Lanreotide injections were coded as chemotherapy on all my bills. I challenged it and this is how they explained the issue.
From ASCO 2019 conference extract: Of the 17 patients enrolled, 16 completed the 12-week trial. One patient was not evaluable due to noncompliance. No DLTs were observed at day 21. The highest dose of 10 mg daily oral everolimus in combination with weekly 60mg/m2 IV fosbretabulin is the RP2D. No grade 4 or 5 toxicities were noted. Grade 3 toxicities were seen in 5 patients; abdominal pain and hyperglycemia (not related to study drug), fatigue (possibly related), decreased lymphocyte count and anemia (related). Several patients had delay in treatment due to grade 2 AE’s (GI symptoms, rash, thrombocytopenia) and one patient was unable to complete treatment due to pneumonitis. All evaluable patients except one had stable disease at 3 months. One patient showed SD but non target lesion demonstrated PD. One patient had > 30% decrease in tumor size but overall sum of lesions showed SD. A detailed table with all grade toxicities and waterfall plot of RR will be presented at the meeting. Ten mg PO daily everolimus plus 60 mg/m2 fosbretabulin IV weekly is the RP2D. Early clinical data suggests clinical activity and stable disease in all but one patient at 3 months. Read full text from ASCO 2019 here.
For further information about the clinical trial, please visit www.clinicaltrials.gov, Study NCT03014297
I will get a better picture but this is what they tweeted from ASCO 2019
added 19 Apr 2017
Mateon Therapeutics, Inc. a biopharmaceutical company developing vascular disrupting agents (VDAs) for the treatment of orphan oncology indications, today announced that the Markey Cancer Center at the University of Kentucky has enrolled the first patient into a new phase 1 study of CA4P in combination with everolimus for the treatment of neuroendocrine tumors.
“The combination of CA4P and everolimus has the potential to decrease the ability of tumor cells to recover between CA4P treatment cycles,” stated Lowell B. Anthony, M.D., Professor of Medicine and Chief, Division of Medical Oncology, Markey Cancer Center, University of Kentucky. “This is the first trial testing this hypothesis in neuroendocrine tumors – with CA4P disrupting the existing tumor blood supply and everolimus preventing a new tumor blood supply from re-forming. Our findings from this trial should lead to a larger clinical study once we have identified the optimal dose and schedule for the combination of these two agents.”
Study MCC-2016-088 is designed to demonstrate whether the addition of CA4P to everolimus may improve tumor control without additional toxicity. Everolimus has been approved by the U.S. Food and Drug Administration for the treatment of advanced pancreatic neuroendocrine tumors and progressive gastrointestinal neuroendocrine tumors, among other indications, and is marketed by Novartis under the tradename AFINITOR®. Mateon has previously demonstrated initial evidence of efficacy for CA4P in patients with neuroendocrine tumors when CA4P was provided as a single agent.
Study MCC-2016-088 is being sponsored, funded, and conducted by the Markey Cancer Center, with Mateon providing the investigational drug. The study is designed as a single center, open label, phase 1 clinical trial for patients with grade 1-3 gastroenteropancreatic neuroendocrine tumors. In the first part of the study, up to 15 patients will be treated with everolimus in combination with two different dosing regimens of CA4P to establish appropriate CA4P dosing levels and evaluate the safety of the drug combination. The second part of the study is designed to enroll 15 additional patients for assessment of additional safety and efficacy data. Patients enrolled in MCC-2016-088 will be treated with CA4P and everolimus for 12 weeks.
For further information about the clinical trial, please visit www.clinicaltrials.gov, Study NCT03014297. (see also ‘added 23 Dec 2016’ below)
added 23 Jan 2017
Mateon Therapeutics, a biopharmaceutical company developing vascular disrupting agents (VDAs) for the treatment of orphan oncology indications, today announced the presentation of final data from Study OX4218 in patients with neuroendocrine tumors (NETs) at a poster session at the ASCO Gastrointestinal Cancers Symposium being held today in San Francisco (20 Jan 17).
Study OX4218 was a multi-center, open label, phase 2 clinical trial to investigate the safety and activity of combretastatin A4-phosphate (CA4P) in the treatment of well-differentiated, low-to-intermediate-grade unresectable, recurrent or metastatic pancreatic or gastrointestinal neuroendocrine tumors/carcinoid (PNETs or GI-NETs) with elevated biomarkers. Following patients’ completion of Study OX4218, patients were eligible to enroll in Study OX4219, a long-term extension study, if they achieved a biomarker or symptom response. In OX4218 patients were treated with CA4P 60 mg/m2 on Days 1, 8, and 15 of a 21-day cycle for 3 cycles, and in OX4219 patients received CA4P maintenance on Day 1 of a 21-day cycle until disease progression or up to one year.
A total of 18 patients were enrolled in OX4218. One patient (6%) experienced significant symptomatic improvement as measured by ECOG Status and had a partial response per investigator-assessed RECIST and an additional 7 patients (39%) had stable disease. In addition, a majority of patients (53%) experienced an improvement in patient-reported quality of life. A statistically significant mean change in biomarkers from baseline, the primary endpoint of the study, was not achieved in OX4218 due to the small sample size along with a high intra- and inter-patient variability observed in the biomarkers. A total of 7 patients were enrolled in OX4219, of which 5 patients (71%) had stable disease, including one that continued for 14 months. The partial response and stable disease analyses, as well as other measures from the trial, suggest that CA4P monotherapy has activity in this indication.
“The results of OX4218 and OX4219 confirm that CA4P monotherapy has efficacy in the indications studied, as we have seen with the investigational drug in a number of other monotherapy trials,” said William D. Schwieterman, M.D., President and Chief Executive Officer of Mateon. “However, we believe that the efficacy of CA4P only becomes compelling when it is used in combination with an anti-angiogenic agent, due to the complementary mechanisms of action for the two agents. Based on the evidence of efficacy observed in this trial, plus an understanding of the benefits of combination therapy, a lead investigator in this trial is sponsoring a 20 patient study in NETs using CA4P in combination with everolimus (AFINITOR®, marketed by Novartis), an anti-angiogenic agent which is already approved and commonly used in this indication.”
Overall CA4P monotherapy was well tolerated. Treatment related adverse events were reported in 77% of subjects. The most common Grade 3-5 AEs (>10%) included: anemia, abdominal pain, fatigue, hypertension, and ALT and AST increases. One Grade 5 adverse event, carcinoid syndrome, was reported and attributed to the underlying disease.
added 23 Dec 2016
There is news of a trial involving this drug which I first published in Jan 2016. The trial is based at Markey Cancer Centre and is led by Dr Lowell Anthony. The trial’s primary objective is to establish the maximum tolerated dose of the combination of Everolimus (Afinitor) plus Fosbretabulin in Neuroendocrine Tumors (Grades 1-3) who have progressed after at least one prior regimen for metastatic disease. Read more here.
The original blog published on 10 Jan 2016 follows:
It’s always nice to hear that another treatment for Neuroendocrine Cancer is in the pipeline. This drug is in the news because it has just been granted designated orphan drug status by the FDA in the US for the treatment of Neuroendocrine Tumours.
My initial thoughts are that it looks promising but it’s very early days.The new drug is formally known as Fosbretabulin Tromethamine or just Fosbretabulin.It also goes by the name of Combretastatin or CA4P which translates to Combretastatin A4-phosphate.In the most basic of terms, it’s a type of vascular disrupting agent (VDA) (note – it’s not chemotherapy).
It appears to be something currently targeted at patients with Advanced Pancreatic or GI Neuroendocrine Tumours with elevated biomarkers. This is not a new drug and has been around for some years. According to Cancer Research UK, it has already been used for advanced and recurrent ovarian and thyroid cancers.
So how does it work? The drug makes the cells that line the smallest blood vessels (capillaries) swell up and this has the effect of blocking the blood flow to a tumour. All tumours need a blood supply so that they can get the oxygen and food they need to survive and Neuroendocrine Tumours can be highly vascular. It follows that if the blood flow to a tumour is blocked, there is a chance that it could stop growing or at best kill the tumour (necrosis). Sounds like the same principles used in Liver Embolization except that this drug has a greater anatomical reach plus a vastly different delivery mechanism via a 10 minute IV infusion.
So why is it a targeted treatment? The drug will only affect blood vessels that supply cancer cells. Cells lining normal blood vessels contain a protein called actin and this protects the blood vessels from the drug’s effects. Cells lining blood vessels that supply a cancer don’t have actin.
Does it work alongside other treatments? Interestingly, it appears to be a recommendation to use the drug in combination with anti-angiogenic drugs (i.e. those that can stop the growth of new blood vessels rather than block the blood supply). Also, according to the manufacturer Mateon, Fosbretabulin has demonstrated broad potential therapeutic value when combined with mainstay oncology modes of treatment including chemotherapy, radiation therapy and the more recent ‘molecularly-targeted therapies’. In fact if you read the trial addition above dated 23 Dec 16, you will see it’s being tested alongside Everolimus (Afinitor).
So when can we expect to see this drug? Phase 2 trials were completed at the end of 2016 (results above). I guess it would still be some years ahead if they wish to proceed. You can see the trial information by clicking here.
I’ll keep this blog live adding to it when I find new or updated information.
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One of the unusual aspects of Neuroendocrine Cancer is that chemotherapy is not normally considered as a ‘standard’ treatment unlike many other cancers. One exception is high grade (Grade 3) where it is often a first and/or second line therapy. Poorly differentiated Neuroendocrine disease is normally labelled as Neuroendocrine Carcinoma (NEC) but worth pointing out there is now a Grade 3 well differentiated classification known as a ‘Grade 3 NET’ rather than Grade 3 NEC. Depending on Ki67 score, there could be differing treatment options for Grade 3 NET and Grade 3 NEC. Read more in my articles Staging and Grading and High Grade.
Many people think Chemotherapy has a short life span due to recent advances in medical science, some citing Immunotherapy as it’s replacement. However, it’s far too early to write off chemotherapy which is still used in many scenarios and remains a tool in the arsenal of cancer treatments and is predicted to do for some time yet. See more informed reporting about this below.
Which Chemo for which Neuroendocrine Cancer type and grade/differentiation?
The type of chemo or the combination of different treatments will often depend on the tumour type and anatomical location involved but may include (but not limited to): Capecitabine (Xeloda), Temozolomide (Temodal), Fluorouracil (5-FU), Oxaliplatin (Eloxatin) Cisplatin, Etoposide (Etopophos, Vepesid), Carboplatin, Streptozotocin (Zanosar). Some of these may be given as a combination treatment, e.g. CAPecitabine and TEMozolomide (CAPTEM). many as a combo treatment. There is a useful article explaining the role of Ki-67 in determining optimal chemotherapy in high grade neuroendocrine tumors.
Cytotoxic chemotherapy is often inadequate for treatment of Grade 1 and 2 (well differentiated) Neuroendocrine tumours which have a low proliferation index. Chemotherapy does not appear to like their slow cytokinetic growth. However, it tends to work better on certain parts of the anatomy than others, e.g. pancreatic NETs and Lung NETs. Of interest is a statistic from NET Research Foundation indicating that 23% of patients who were to be prescribed chemo had their treatment changed to a non-chemo option following a Ga68 PET scan. Read more here.
For second line therapy (including for well differentiated NETs where other conventional treatments are not working), chemo may be given. These include (but not limited to) Capecitabine, Temozolomide, Bevacizumab, Xelox, Folfox. There are other specialist chemos for Mixed Neuroendocrine Non-Neuroendocrine Neoplasms (MiNEN).
‘Horses for Courses’ – Chemo is sometimes used for well differentiated lower grade NETs.
There’s a myth that circulates the NET patient forums along the lines of “chemotherapy does not work for NETs“. That’s not entirely true but most will not get chemotherapy and this can often lead to confusion in those with Stage 4 cancer when asked by others why they are not receiving chemo.
Capecitabine plus Temozolomide (CAPTEM for short) is fast becoming the standarad chemotherapy treatment when it is required with certain lower grade NETs. Dr Robert Fine says the results of the CAPTEM trial showed “tremendous responses in every neuroendocrine tumor”. The treatment elicited a response rate of 45% and a stable disease rate of 52% including those with certain types of NETs and pituitary tumours – types of neuroendocrine tumour that are notoriously ‘chemoresistant’. You can read more about this here (click here) and you can also listen to Dr Fine talking about this on a short You Tube video clip – (click here). Clearly it’s true that it’s not going to work for all.
Other CAPTEM Resources:
There’s a very interesting report on the use of CAPTEM in NETs – (click here)
In Australia, they’re also using a combo treatment of chemo (CAPTEM) and PRRT – I blogged about this click here.
There’s also a useful surgical technique which includes the use of intra-operative chemo, known as “Chinese Dumplings” – I wrote about this click here.
My Oncologist did mention Chemotherapy on my initial meeting, that was a shock and realisation I had something serious. However, that never transpired but I was once scheduled to have a chemo-embolisation (or TACE, Trans-arterial Chemo Embolisation). Clearly TACE is more targeted than conventional and generally systemic chemotherapy techniques. Perhaps that my Oncologist actually meant. The chemo-embolisation never transpired either (long story).
Chemotherapy vs Targeted Biological Agents and Somatostatin Analogues
I often see people describing Somatostatin Analogues (Lanreotide/Octreotide), Afinitor (Everolimus) and Sutent (Sunitinib) as chemo but that’s isn’t technically correct, and I’ve yet to find a NET Specialist or a NET Specialist Organisation who classifies these drugs as chemo. See my article “Chemo or not Chemo” (click here).
Future of Chemo?
A lot is written about how much longer chemo will be around. It gets a bad press – I suspect mainly due to the side effects. There are suggestions that it will eventually be replaced by Immunotherapyand other treatments downstream. However, immunotherapy is really still in its infancy and there remains a lack of long term data on success rates and side effects. I suspect chemo will be around for a while longer, particularly for cancers where it has a track record of curing according to ASCO. Very recently (June 2018), cancer experts said that chemo will be around for a long time yet – read more here
None of the content of this post should be interpreted as advice or a recommendation for chemotherapy. If in doubt about suitability for any form of chemo, or the type you have been prescribed, patients should seek the advice of their treating doctor or NET specialist.