Update June 6th 2021. Novartis reports clinically relevant improvement in median overall survival data in final analysis of pivotal NETTER-1 study with targeted radioligand therapy Lutathera.
New analysis of the NETTER-1 trial data has been published. For those who just need a quick summary, the quote from Dr Jonothan Strosberg is below.
Short PRRT Primer
What is Peptide Receptor Radionuclide Therapy (PRRT)?
For those who are still not sure what it’s all about. This is a non-surgical treatment which is normally administered intravenously. It’s based on the use of somatostatin receptors to attract a ‘radiopeptide’. The radiopeptide is a combination of a somatostatin analogue and a radioactive material. As we already know, somatostatin analogues (i.e. Lanreotide/Octreotide) are a NET cell targeting drug using somatostatin receptors, so when combined with radioactivity, it binds with the NET cells and delivers a high dose of targeted radiation to the cancer while preserving healthy tissue in an attempt to reduce or kill tumours. In general, patients tend to receive up to 4 sessions spaced apart by at least 2 months. PRRT will not work on all NETs and not everyone will be suited to this treatment. In general, for this treatment to be more successful, you must have somatostatin receptors in your tumours. Success rates are not 100% – it should not be considered a cure or ‘magic bullet’. However, the results are said to be pretty good in comparison to other therapies. The NETTER-1 trial data which has led to formal approval in Europe, USA and other areas, can be found here.
A short 4-minute video from the NET Research Foundation is worth a watch if this is new to you. Click here
Who can get LU177 Lutathera?
This is a controversial point, and you need to start with the wording of the various regional/national approvals:
Europe (EU 27/28 countries plus Norway, Liechtenstein and Iceland) – The European Medicines Agency (EMA) approval wording is as follows:
“….. the treatment of unresectable or metastatic, progressive, well differentiated (G1 and G2), somatostatin receptor positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs) in adults”.
USA – The FDA approval wording is as follows:
“….. the treatment of somatostatin receptor positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs), including foregut, midgut, and hindgut neuroendocrine tumors, in adults”.
These approvals remain controversial because the term GEP-NETs technically excludes lung tumours. That’s not to say tumours outside the GEP-NET area cannot get access, it just makes it more difficult to access due to the approvals. The US approval has a much wider scope given the introduction of a Grade 3 well differentiated NET in the latest classification systems. Access criteria in different countries/healthcare locations may be adapted for specific scenarios to suit limited availability and costs.
There can be authorised use of Lu177 Lutathera and other PRRT variants outside of the normal approvals system, so it might be possible to get access to non GEP-NET tumour types. However, even within GEP-NETs, patient selection is not straightforward. Read more in this guidance document from NANETS/SNMMI. There’s also an interesting Italian study into patient selection and also how to monitor the benefits of this therapy during and after treatment completion – click here.
What about Grade 3 (High Grade) Neoplasms?
The main treatment for Grade 3 is chemotherapy, particularly poorly differentiated types. PRRT tends to work better with efficient somatostatin receptors (i.e. somatostatin receptor-positive tumours). The European approval wording only covers Grades 1 and 2. The US FDA approval indicates “somatostatin receptor-positive tumors”. It’s also worth noting that with Grade 3, working somatostatin receptors are more likely to exist in Grade 3 well differentiated NETs, particularly in the lower Ki-67 readings (less than 55%). However, there’s an interesting study from Australia which might be useful to read – check out the abstract here (note the full version is not available free).
2019 Updated data for Grade 3 Neuroendocrine Neoplasms:
“Compared to studies evaluating the efficacy of chemotherapy for NEN patients with a Ki-67 index less than or equal to 55 percent, PRRT has a longer overall survival rate–22 months versus 14 months,” the researchers pointed out. “These results suggest that PRRT, rather than chemotherapy, may be a superior first-line therapeutic option in selected patients with a high level of SSTR expression and a Ki-67 index of less than or equal to 55%.” Read more here. This supports the new thinking behind the revised classification of high-grade tumours published in 2017 – read more here
Another European study stated “This large multicenter cohort of patients with GEP NEN G3 treated with PRRT demonstrates promising response rates, disease control rates, PFS and OS as well as toxicity in patients with mainly progressive disease. Based on these results, PRRT may be considered for patients with GEP NEN G3”.
Click here to read.
Merkel Cell Carcinoma. Although not indicated for this type of Neuroendocrine Neoplasm, there is evidence to suggest that this skin Neuroendocrine Carcinoma does express somatostatin receptors. Read more here.
Now read the clinical trial section below
What about tumours not covered by “GEPNETs”?
This trial in USA is recruiting. Despite the use of “tumor” in the title, it is accepting somatostatin receptor positive Neuroendocrine Carcinomas. Click the text below.
Clinical Trial: Lu-177 DOTATOC (PRRT) in adult subjects with Somatostatin receptor (SSTR) positive Pulmonary, Pheochromocytoma, Paraganglioma, Unknown primary, and Thymic Neuroendocrine Tumors (the PUTNET trial)
What about Pheochromoctyoma/Paraganglioma?
This article discusses the efficacy of PRRT in Pheo/para – click here.
There are actually trials for Pheochromocytoma/Paraganglioma (Pheo/Para). It is known that Pheo/Para can have somatostatin receptor tumours.
1. Study to Evaluate Safety and Dosimetry of Lutathera in Adolescent Patients With GEP-NETs and PPGLs. The objective of this trial is to learn the safety and tolerability of Lu-177-DOTATATE. Also, to see if it improves the length of time it takes for the cancer to return. – read more by clicking here.
2. Study to Evaluate Safety and Dosimetry of Lutathera in Adolescent Patients With GEP-NETs and PPGLs. The objective of this trial is to assess the safety and tolerability. You can read about the trial here.
3. PUTNET trial. See the box above. (….tumours not covered by GEPNETs”)
What about children and adolescents?
Study to Evaluate Safety and Dosimetry of Lutathera in Adolescent Patients With GEP-NETs and PPGLs. The objective of this trial is to learn the safety and tolerability of Lu-177-DOTATATE. Also, to see if it improves the length of time it takes for the cancer to return.
The multicenter trial sponsored by Advanced Accelerator Applications will study the safety and dosage of Lutathera (Lutetium [177Lu] oxodotreotide/dotatate) in patients between 12 to 17 years of age with somatostatin receptor-positive GET-NETs and PPGLs (pheo/para).
read more by clicking here.
What about Carcinoid Syndrome?
Technically, for many people surgery including debulking surgery and/or somatostatin analogues, will help control carcinoid syndrome. However, for some people, breakthrough symptoms till occur
A new study from NET experts in Netherlands, suggests that PRRT with 177Lu-DOTATATE for symptomatic control of refractory Carcinoid Syndrome (i.e. not adequately controlled by somatostatin analogues) is a viable, safe and effective option for patients with stable and recently diagnosed advanced midgut NENs. The study also showed reductions in 5HIAA and I suspect this might be useful to those with very severe effects of carcinoid syndrome with highly elevated 5HIAA.
Read more here.
Peptide receptor radionuclide therapy with 177Lu-DOTATATE for symptomatic control of refractory carcinoid syndrome. Wouter T. Zandee, MD, PhD; Tessa Brabander, MD, PhD; Anela Blaževid, MD; Noémie S. Minczeles, MD; Richard A. Feelders, MD, PhD; Wouter W. de Herder, MD, PhD; Johannes Hofland, MD, PhD. © The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society
July 2021 – New Section – Side Effects of PRRT (Lutathera)
Like many anti-cancer drugs there are side effects. Within the approval system these are carefully documented – for example, see the Lutathera manufacturer’s website – click as appropriate US Patients, European Patients. I suspect there won’t be much difference in other areas.
In 2021, the output from two small studies were published by the Society of Nuclear Medicine and Molecular Imaging. and Mayo Clinic. Both studies indicated there was a small risk PRRT can lead to bowel obstruction in patients with mesenteric or peritoneal disease, likely by inducing inflammation. IMHO, more studies, bigger studies are needed, as there could have been a higher than average of peeps with mesenteric problems over the period data was collected.
Strosberg JR, Al-Toubah T, Pellè E, Smith J, Haider M, Hutchinson T, Fleming JB, El-Haddad G. Risk of Bowel Obstruction in Patients with Mesenteric or Peritoneal Disease Receiving Peptide Receptor Radionuclide Therapy. J Nucl Med. 2021 Jan;62(1):69-72. doi: 10.2967/jnumed.120.242875. Epub 2020 May 22. PMID: 32444368. “Risk of Bowel Obstruction in Patients with Mesenteric or Peritoneal Disease Receiving Peptide Receptor Radionuclide Therapy – PubMed”
The Moffat report – click here
Are there any Guidelines for PRRT?
Until a few years ago, most PRRT was done via clincial trials and early access programs. However, while national guidelines on how PRRT should be delivered do exist, a generic set of formal guidelines has been developed collaboratively by the North American Neuroendocrine Tumor Society (NANETS) and the Society of Nuclear Medicine and Molecular Imaging (SNMMI). Read these here for further information about Lu-177 PRRT including these topics:
- TREATMENT OVERVIEW
- PATIENT SCREENING
- SOMATOSTATIN ANALOG THERAPY
- TREATMENT LOCATION
- ROOM PREPARATION
- PATIENT PREPARATION
- AMINO ACID SOLUTIONS
- ANTIEMETIC MEDICATIONS
- RADIOPHARMACEUTICAL ADMINISTRATION
- DOSAGE MODIFICATIONS FOR ADVERSE REACTIONS
- PATIENT MONITORING AND POTENTIAL REACTIONS
- RADIATION SAFETY
- DOSIMETRY AND POSTTREATMENT IMAGING
Note: the above guidelines may differ from country to country and even within countries due to local regulations in force. Always consult your specialist or treatment centre for the guidelines which apply to your treatment.
Interest point. The above guidelines suggest stopping and starting periods for somatostatin analogues when being treated with PRRT. However, while these guidelines remain in place, a new study in Nov 2021 indicates that small intestine NETs may benefit from an injection of somatostatin analogues at the beginning of each cycle. The conclusion is here:
“SSTR recycling is faster in small-intestinal NETs than in liver, spleen and pancreas. This opens the possibility to protect normal tissues during PRRT by administering a single dose of cold peptide hours before peptide receptor radionuclide therapy (PRRT), and most likely additionally improve the availability and uptake of the therapeutic preparation in the tumors.”
Read the study here. Receptor depletion and recovery in small-intestinal neuroendocrine tumors and normal tissues after administration of a single intravenous dose of octreotide measured by 68Ga-DOTATOC PET/CT | EJNMMI Research | Full Text (springeropen.com)
Can I have PRRT more than the regulated 4 times?
This is complex and will rely on individual healthcare arrangements in place plus in insurance-based systems, willingness of insurance companies to cover costs. However, there is a recently released study covering some data from what is known as “Salvage PRRT“. Salvage PRRT, defined as a re-challenge with one or more 177Lu-DOTATATE therapy cycles after 4 initial PRRT cycles with initial response. Read more here. I have one lady on my social media sites who has had almost a dozen cycles.
There’s another study coming out of NANETS symposium 2020, where the term “re-treatment” is introduced based on the addition of 2 further cycles (total 6) which concluded that retreatment with Lutathera-based PRRT provided an encouraging median PFS in a relatively refractory setting among patients with advanced NETs and it wasn’t really associated with a worsened safety profile compared with initial PRRT.
Understanding the terminology is half the battle in understanding the latest developments. I’ve included Ga-68 PET scans within this section (or in more general terms Somatostatin Receptor PET (SSTR PET)) as the term ‘Theranostics‘ is becoming a commonly used theme. Theranostics is a joining of the words diagnostics and therapy.
LUTATHERA is the radionuclide ‘mix’ for use in Peptide Radio Therapy Treatment (PRRT). You may also see this drug called ‘Lutetium’ or ‘Lu-177 dotatate’, or just ‘Lu-177’ on its own. Yttrium 90 (Y-90) is a radionuclide also used in PRRT.
NETSPOT (USA) or SOMAKIT TOC (Europe) is not PRRT but it is the commercial names for the radiopeptide used in Gallium 68 (Ga-68) PET diagnostic scans.
Together they form a ‘theranostic pair’. Theranostics is apt as together (NETSPOT / SOMAKIT TOC and Lutathera), both target NETs expressing the same somatostatin receptor, with Lutathera intended to kill tumor cells by emitting a different kind of low-energy, short-range radiation than that of the diagnostic version.
Moreover, thanks to the theranostic approach that nuclear medicine allows, Novartis/AAA’s NETSPOT/SomaKit TOC products will be able to determine when Lutathera is the appropriate treatment.
Read more about Theranostics by clicking here.
What’s next for NETs and PRRT including Clinicals Trials?
Some trials are featured in the “What about …..” sections above.
Read the latest news on the NETTER-2 trial here. This is designed to look at the benefits of using PRRT on Grade 2 and Grade 3 patients as a first line treatment.
Other associated PRRT trials are in the pipeline, some based on Lutathera LU177 and other based on new radionuclides:
- two radiopeptides together.
- radiopeptides in conjunction with other chemotherapies (check out my article PRCRT).
- repeated administrations of the radiotherapies.
- other radionuclide-peptide combinations.
- increasing the number of indications for this therapy, including other disease targets. e.g. they are already using it for Prostate Cancer.
- new radionuclides – see my article about the Trial of 177Lu-Edotreotide (Solucin®) COMPETE trial.
- Different nuclear techniques – the currently approved therapy used something called “beta particles”, but alpha particles are gaining ground, see article “PRRT – The Sequel? – Targeted Alpha-emitter Therapy (TAT)”
- The next generation? 177Lu Ops 201 (Satoreotide) (future of this trial is uncertain)
- PRRT liver directed trial: Intra Arterial Lu177 for Neuroendocrine Tumours Liver Metastases (LUTIA)
- Somatostatin Receptor Positive Advanced Bronchial Neuroendocrine Tumors – PRRT vs Everolimus
- Clinical Trial: Lu-177 DOTATOC (PRRT) in adult subjects with Somatostatin receptor (SSTR) positive Pulmonary, Pheochromocytoma, Paraganglioma, Unknown primary, and Thymic Neuroendocrine Tumors
See this great summary from NET Research Foundation of what might be next plus basic facts about PRRT – click here
The future of PRRT delivered by Dr Richard Baum who is the most experienced PRRT doctor on the planet. click here
Where can I get PRRT?
The aim of this section is to update on a regional basis in order to inform an international community of followers and readers.
I wanted a place to review what is happening globally given my following. In many countries, however, I’m dependent on feedback from patients in those countries. Please note this is not intended to be a 100% complete breakdown on everything about PRRT or PRRT centres – it’s a summary. It should be clear from below but please bear that in mind when reading.
This section of this article will cover each region, indicating where PRRT can be obtained (as far as I know). It is not designed to indicate whether this is through public or private facilities (this will depend to too many factors beyond the reach of this article). Please note this is not intended to be a 100% complete breakdown on every single PRRT centre – it’s a summary. This actually should be clear from below but please bear that in mind when reading.
On 29 August 2018. National Institute for Health Care Excellence (NICE) England has formally published that Lutetium (177Lu) oxodotreotide, within its marketing authorisation, is an option for treating unresectable or metastatic, progressive, well-differentiated (grade 1 or grade 2), somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumours (NETs) in adults. CLICK HERE to read the approval. Currently available in the following NHS locations:
- London – at least 4 locations – Royal Free, Guys and St Thomas, University College (UCH), King’s College
- Liverpool – The Royal
- Manchester – The Christie
- Sheffield – Weston Park
- Bristol – Bristol Oncology Centre
- Newcastle – Freeman Hospital
- Coventry – University Hospital
- The Royal Surrey St Lukes Guildford
- University Hospital Southampton
- Medway Maritime Hospital, Gillingham, Kent
- Oxford, Churchill Hospital
On 9 July 2018. The Scottish Medicines Consortium (NICE equivalent) approved lutetium 177Lu (Lutathera) for patients in NHS Scotland. Good news for Scotland once their hospitals have the capability to deliver. Scottish patients would then not need to travel to England for the NHS Scotland funded treatment. Read more here.
It is funded in Wales and Northern Ireland but is currently administered in England with inter NHS budget transfers.
On 7th Feb 2019, Health Canada approved Lutathera™ (lutetium (177Lu) oxodotreotide) for the treatment of unresectable (not removable by surgery) or metastatic, well-differentiated, somatostatin receptor-positive (expressing the somatostatin receptor) gastroenteropancreatic neuroendocrine tumors (GEP-NETs) in adults with progressive disease. The treatment was previously available on a trial basis. Read more here.
Site update to follow but the following trial locations may be up and running first:
- Juravinski Hamilton
- LHSC London
- PMCC Toronto
- Sunnybrooke Toronto
- Cross Cancer Institute, Edmonton
PRRT was approved in USA on 26 Jan 2018. The approval is for the treatment of somatostatin receptor positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs), including foregut, midgut, and hindgut neuroendocrine tumors in adults. CLICK HERE.
The LUTATHERA US website contains a map search which can be found at this link.
Europe (excluding UK which is listed above)
The European Medicines Agency (EMA) “market authorisation” received a positive indication on 20th July followed by EC approval on 29 Sep 2017. The positive indication reads “Lutathera is indicated for the treatment of unresectable or metastatic, progressive, well differentiated (G1 and G2), somatostatin receptor positive gastroenteropancreatic neuroendocrine tumours (GEP NETs) in adults”. Of Course, the decision to fund the drug will be with national approval organisations. Whilst I’m sure there are many more, these well-known centres have been making PRRT available for some years (but please note there are others):
Denmark – ‘Rigshospitalet’ since 2009. They have treated around 250 patients- and given 800 treatments.
Finland – Helsinki: Docrates Cancer Center
France – Hopital Beaujon AP-HP, Clichy (next to Paris)
- Zentralklinik Bade Berka – click here
- Uniklinikum Saarland Homburg,
- Berlin, Klinik für Nuklearmedizin
- Wurzburg – University of Wurzburg
Italy – Milan, European Institute of Oncology
Netherlands – the combined NET centres of the UMCU Utrecht and AVL Amsterdam have an ENET certification and they both do PRRT.
UMCU – Utrecht
(only available in dutch)
AVL – Amsterdam
(only available in dutch)
Rotterdam Treatment Centre – click here
Poland – Poland, Maria Skłodowska-Curie Institute of Oncology, regional branch in Gliwice
Sweden – Department of Endocrine Oncology Uppsala University Hospital – click here
Switzerland – University Hospital Basel, Radiology & Nuclear Medicine Clinic – click here. The University of Zurich also has excellent facilities – click here (call first to see if they accept patients not treated in Zurich)
I’d be interested to hear from countries in Europe with their full list of centres or a link to it.
Australia seems to be ahead of the game or that is what I sense when I read output from there. There’s a good section on the Australian effort – click here.
EDIT. Due to COVID, an interim arrangement was put in place in Auckland. However, in July 2021, it was confirmed this was to become a permanent arrangement. Read more here.
Original info. These guys have had to fight to get some progress on the provision of PRRT. Currently New Zealanders have to go to Melbourne Australia for treatment – almost 50 New Zealanders with NETs are currently raising tens of thousands of dollars to pay for treatment in Australia because the life-prolonging treatment isn’t available locally. But this could change in 2018. Unicorn Foundation New Zealand announced that Pharmac, the New Zealand government agency that decides which pharmaceuticals, have said that PRRT will be funded for patients with medium priority for the treatment of unresectable or metastatic, well-differentiated NETs (irrespective of primary site) that express somatostatin receptors.
– Steve Biko Academic Hospital and the University of Pretoria – Groenkloof Hospital (was called A Little Company of Mary)
– The Wits Donald Gordon Hospital (Private) – Dr L Louw
– JHB General – Dr L Louw (possibly temporary working at Rivolia)
– Umhlanga Molecular Imaging and Therapy Centre of Excellence at Umhlanga Hospital (Private) – Dr Marsha Maharaja
- Cape Town – Tygerberg Hospital
I have been contacted by CNETS India to add this to the list.
PRRT is now available in more than 10 cities in India including Delhi, Mumbai, Chennai, Chandigarh, Lucknow, Pune, Vellore, Vishakapatnam, Ahmedabad, Baroda, Kolkata, Jaipur. Both Lu177 and Actinium 225 / alpha PRRT is available in Delhi and a few other centres. Kind regards Dr Sugandha Dureja.
From patients I’m told the waiting list is long but the cost is much lower than in other countries,
Middle East, Asia, Far East (less India)
Israel – Hadassah Medical Center, Jerusalem – click to read
Lebanon – The American Hospital of Beirut – Dr Ali Shamseddine “We have started using Lu-177 here in Lebanon. So far, we have treated 3 patients, with good response. The operational cost is much less than in Europe”.
Malaysia – Sunway medical Centre, Beacon hospital
Pakistan – check out this article – click here
Singapore – Singapore General Hospital and National University Hospital.
Hong Kong – Queen Elizabeth Hospital and Hong Kong Sanatorium & Hospital.
Philippines – St. Luke’s Medical Center, Global City, Taguig, Metro Manila.
Brazil – Hospital SÍRIO LIBANÊS, SÃO PAULO
General Clinical Trials Disclaimer
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided in the clinical trials document. It’s very important to check the trial inclusion and exclusion criteria before making any contact.
Inclusion of any trial within this blog should not be taken as a recommendation by Ronny Allan.
Subscribe to my newsletter
Top 10 Posts & Pages in the last 48 hours (auto updates)
Thanks for reading.
Sign up for my newsletters – Click Here