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
Hasn’t the therapy has been in use for some time?
This therapy has actually been in use in Europe and some other places for over 10 years but on a limited scale and until recently were never formally approved by national drug agencies. Despite this long use, the EU approval in 2017 was actually the very first for PRRT anywhere in the world. This was quickly followed by FDA approved in the US. In the meantime, I constantly see stories of patients travelling to Switzerland, Germany, Netherlands, Sweden, Great Britain and others; many at their own cost. However, it does indicate one thing, there is a huge unmet need in that many patients do not have access to the best treatments in their own country. I see this daily through many private messages.
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 GEPNET 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.
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.
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.
Case Rep Oncol 2019;12:98–103 Merkel Cell Carcinoma https://doi.org/10.1159/000496335
What about Pheochromoctyoma/Paraganglioma?
This article discusses the efficacy of PRRT in Pheo/para – click here. There’s actually still a trial for Pheochromocytoma/Paraganglioma (Pheo/Para). It is known that Pheo/Para can have somatostatin receptor tumors so a useful trial. The aim of the trial is to assess the safety and tolerability. You can read about the trial 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.
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?
LATEST ON EXPANDED NETTER-1 TRIAL DATA. “Novartis has announced presentation of a new analysis of Lutathera (lutetium Lu 177 dotatate) NETTER-1 data at the 2018 European Society for Medical Oncology (ESMO) congress examining the impact of Lutathera treatment on patients with low, medium or high liver tumor burden. The data show that Lutathera treatment results in significant improvement in progression free survival (PFS) regardless of the extent of baseline liver tumor burden (LTB), elevated alkaline phosphatase (ALP) liver enzyme or presence of large (>30mm diameter) lesion in patients with progressive midgut neuroendocrine tumors (NETs) compared to octreotide LAR alone.”
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.
- e.g. new radionuclides – see my article about the Trial of 177Lu-Edotreotide (Solucin®) COMPETE trial.
- See article “PRRT – The Sequel? – Targeted Alpha-emitter Therapy (TAT)”
- The next generation? 177Lu Ops 201 (Satoreotide)
- PRRT liver directed trial: Intra Arterial Lu177 for Neuroendocrine Tumours Liver Metastases (LUTIA)
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 probably 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 2 locations – Royal Free, Guys and St Thomas
- 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 is in place in Aukland. I have a suspicion it will remain permanently – to be confirmed. In the meantime, read 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.
- Pretoria – Steve Biko Academic Hospital and the University of Pretoria
- Johannesburg – The Wits Donald Gordon Hospital
- Durban – Umhlanga Molecular Imaging and Therapy Centre of Excellence at Umhlanga Hospital
- Cape Town – Tygerberg Hospital
Middle East, Asia and the Far East
Azerbaijan – Nuclear Medicine Centre in Baku, Lu-177-DOTATATE and Ас-225-DOTATATE. Click here.
Turkey – Istanbul, Dr.Levent Kabasakal.
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”.
|Ali Shamseddine, MD, CHB||Professor and Head of Divisionfirstname.lastname@example.org|
India – Mahatma Gandhi Cancer Hospital, Visakhapatnam. Recently started radionuclide therapy. Although only currently available privately, some patients have been sponsored by the companies that they work for. Point of contact is Dr. K. Raghava Kashyap. I’ve been assured by CNETS India that many locations have PRRT capability – contact them direct please. Also – TATA Memorial Hospital Mumbai (waiting time is long, but cost is low: $200) and there are private clinics in Pune (cost is $1500) and Bengaluru (cost is around $6000). (Info from Russian patient group).
Kuwait – Kuwait Cancer Control Center (KCCC) – read article here.
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
Thanks for reading