Nearly double the patients and dramatic changes over 14 years of UK MRT: Internal Dosimetry Users Group survey results from 2007 to 2021

Introduction The Internal Dosimetry Users Group has regularly surveyed UK molecular radiotherapy (MRT) activity in the UK for the past decade. Combined with data from a previous survey 1 we present results from 2007 and consecutive years from 2011 to 2021. Data were gathered in the same manner as previous surveys 2–4 from 39 UK centres (1 from Northern Ireland, 1 from Wales, 3 from Scotland, 34 from England, 3 privately run, 36 NHS centres), 7 more than in our most recent publication 4, collectively administering 64 614 treatments over the surveyed period. Previous publications of ours 2–4 have focussed on MRT for malignancies, here we will also present data from 2018 onwards on MRT use in benign conditions. Treatments identified were Na131I Radioiodine (RAI) for thyroid cancer, 131I-metaiodobenzylguanidine (131I-mIBG) and peptide receptor radionuclide therapy (PRRT) for neuroendocrine tumours (NETs), 89Sr-chloride, 153Sm-EDTMP and 223Ra-Chloride for bone metastases, MRT for haematological malignancies, selective internal radionuclide therapy (SIRT) for liver metastases, radio-labelled prostate specific membrane antigen (PSMA) therapies, RAI for benign thyroid conditions, radio-labelled colloid use for radiosynoviortheses and various agents used in small trials. Data from the last 4 years also include a breakdown, where available, between treatments given to adult or paediatric patients. Results and discussion From 2007 to 2021 we have seen an 87% increase in the number of cancer patients treated and a 231% increase in treatments given, as well as several sudden changes year on year in overall workload as shown in Fig. 1. Whilst established therapies with reliable sources of funding appear primarily subject to clinical demand, which may wax with increasing incidence, or wane as newer treatments take over, the workloads from newer therapies can be volatile and appear particularly sensitive to;Fig. 1: Total numbers of molecular radiotherapy patients treated (upper) and treatments given (lower) in each year of the survey for the 39 participating centres. mIBG, 131I-metaiodobenzylguanidine; PRRT, peptide receptor radionuclide therapy; PSMA, radio-labelled prostate specific membrane antigen therapy; RAI, radioiodine; SIRT, selective internal radionuclide therapy. changes to funding changes in clinical evidence regulatory approval, examples of which will be discussed below in relation to each form of MRT. When a change in these factors is anticipated for a treatment, we can perhaps use the data presented here to anticipate the subsequent changes in demand, and consequent pressures on workload, as will be discussed in the case of 177Lu-PSMA. Our data also show the impact on MRT of the COVID-19 pandemic on workload in 2020 and how different therapies recovered into 2021. Na131I radioiodine (RAI) for thyroid cancer Incidence of thyroid cancer has risen steadily over the past decade, increasing by 65% between 2006–2008 and 2016–2018 5. Our data on the use of Na131I Radioiodine (RAI) to treat thyroid cancer show a rise of 31% over the same period, but not following the same, steady trend as the incidence data, as seen in Fig. 2 and Table 1. Unlike other treatments discussed below, funding, evidence and regulatory approval are not limiting factors as the therapy is cheap and has been used successfully for decades. Provided that centres have adequate and sufficient facilities, the dominant driver on rates of treatment is likely rates of referrals, driven itself by factors specific to each individual site. Otherwise, the data show no obvious trend. Table 1 - Treatment statistics for centres administering radioiodine treatments for thyroid cancer Year Total treatments administered Centres administering Treatments per centre Mean/median SD/range 2007 1314 30 44/33 32/5–150 2011 1617 34 48/40 32/1–162 2012 1767 34 52/40 36/3–158 2013 1666 34 49/37 34/6–157 2014 1693 34 50/46 33/4–160 2015 1643 35 47/41 36/4–162 2016 1750 35 50/38 31/6–128 2017 1891 35 54/41 40/9–152 2018 1725 35 49/36 35/9–127 2019 1745 35 50/41 34/7–119 2020 1498 36 42/33 28/5–114 2021 1719 36 48/39 35/8–156 Fig. 2: Numbers of radioiodine treatments for thyroid carcinoma with the number of centres administering.The one exception is the impact of the COVID-19 pandemic. In March 2020 a statement issued on behalf of the National Cancer Research Institute (NCRI) Thyroid Cancer Subgroup on the use of RAI during the COVID-19 pandemic 6 supported halting RAI treatments for differential thyroid cancer patients at that time. Our data show a 14% drop from 2019 to 2020 and a near complete recovery in 2021 to 99% of the number of treatments given in 2019. Paediatric RAI treatments (data available from 2018–2021) were given in 9 centres averaging 2.9% of all RAI treatments for thyroid cancer across the survey group. Neuroendocrine cancer 131I-mIBG and PRRT were used to treat similar numbers of patients at the beginning of this surveyed period. Whilst NET incidence in the UK has increased 7, the use of 131I-mIBG has steadily declined, being given in fewer centres, in ever-decreasing numbers as seen in Fig. 3 and Table 2. 131I-mIBG was administered to paediatric patients (data available from 2018–2021) in three centres in total but predominantly in one, consisting of 22.6% of all 131I-mIBG treatments. The impact of the COVID-19 pandemic on 131I-mIBG treatments is hard to discern over the general downward trend given the low numbers involved. Table 2 - Treatment statistics for centres administering 131I-mIBG. 131I-mIBG, 131I-metaiodobenzylguanidine Year Total treatments administered Centres administering Treatments per centre Mean/median SD/range 2007 148 17 9/8 7/1–25 2011 120 19 6/5 5/1–21 2012 135 18 8/5 7/1–30 2013 103 18 6/5 4/1–15 2014 108 14 8/7 6/1–27 2015 87 15 6/5 4/1–14 2016 72 13 6/3 6/1–23 2017 79 15 5/4 5/1–18 2018 78 12 7/3 9/1–32 2019 54 12 5/4 3/1–10 2020 48 10 5/4 4/1–13 2021 64 12 5/5 4/1–16 Fig. 3: Total numbers of patients treated, treatments given and centres administering 131I-mIBG. 131I-mIBG, 131I-metaiodobenzylguanidine.PRRT treatment numbers by contrast have increased tenfold over the survey period with significant changes year on year within this time frame, as shown in Fig. 4 and Tables 3 and 4, consistent with the factors identified above. 177Lu-Dotatate, available commercially as Lutathera (Novartis, Basel, Switzerland) use rose steadily up to 2015 when it was cut from the Cancer Drugs Fund (CDF) in November of that year 8. Numbers rose again and more sharply following positive results from the NETTER-1 trial (ClinicalTrials.gov ID NCT01578239) 9, EMA marketing authorisation in 2017 10 and subsequent National Institute of Clinical Excellence (NICE) approval in August 2018 11. The use of 90Y-PRRT, having started as the dominant radiopharmaceutical, has declined over the survey period as centres previously administering it have switched to 177Lu-PRRT, and most new services have only used the 177Lu based agent. 2021 saw a halt in availability of cold kits for in house labelled 90Y-Dotatate 12, effectively halting its use for PRRT in the UK. Paediatric patients were treated with PRRT in only one centre, their treatments constituting 0.9% of all PRRT treatments given between 2018 and 2021. Table 3 - Treatment statistics for centres administering 90Y-PRRT Year Total treatments administered Centres administering Treatments per centre Mean/median SD/range 2007 124 3 41/42 36/5–77 2011 156 4 39/19 44/14–105 2012 104 6 17/15 17/1–44 2013 107 5 21/21 15/6–36 2014 109 6 18/17 12/2–38 2015 107 6 18/14 15/3–40 2016 94 5 19/15 14/5–40 2017 101 4 25/23 27/2–53 2018 84 2 42/42 14/32–52 2019 71 2 36/36 49/1–70 2020 35 2 18/18 23/1–34 2021 0 0 0/0 0/0–0 PRRT, peptide receptor radionuclide therapy. Table 4 - Treatment statistics for centres administering 177Lu-PRRT Year Total treatments administered Centres administering Treatments per centre Mean/median SD/range 2007 6 1 6/6 0/6–6 2011 149 7 21/21 19/1–53 2012 264 11 24/13 23/1–57 2013 433 12 36/27 40/2–144 2014 467 13 36/26 36/4–147 2015 614 17 36/24 50/2–215 2016 543 17 32/16 44/3–173 2017 376 15 25/7 39/1–133 2018 485 15 32/13 46/2–152 2019 1263 18 70/49 76/2–320 2020 1232 20 62/44 64/2–273 2021 1365 20 68/61 60/6–279 PRRT, peptide receptor radionuclide therapy. Fig. 4: Numbers of patients treated (pts), treatments (tx) given and centres administering peptide receptor radionuclide therapy using 90Y and 177Lu labelled radiopharmaceuticals.PRRT treatment numbers appear the least impacted by the COVID-19 pandemic within our survey as they fell only 5% in 2020 and grew again in 2021 reaching their highest level to date. Bone metastases MRT use for bone metastases has changed dramatically over the surveyed period. In 2007 this field consisted of mostly one-off administrations (one treatment per patient) of 89Sr-chloride and 153Sm-EDTMP treatments to palliate bone pain. These treatments have decreased steadily in usage over the surveyed period, eventually not being used at all in 2021, as shown in Fig. 5 and Tables 5 and 6. However, in 2013 223Ra-Chloride was shown through the ALSYMPCA trial (NCT00699751) 13 to not only control bone pain but also give a 2.8-month survival benefit to patients with castration-resistant metastatic prostate cancer (mCRPC) as compared to placebo. This was evident even at interim analysis after which the trial was cut short 13. The patients treated in this trial are visible in our data from 2007 to 2011. The commercially available product Xofigo (Bayer, Leverkusen, Germany) was briefly included on the CDF between 2014 and 2015 14 leading to a sharp increase in its use, before gaining NICE approval in 2016 15. This propelled its use so as to treat more than 6 times as many patients, with 22 times as many treatments, at its peak in 2017 as were ever treated in one year with the other bone seeking agents combined as seen in Fig. 6 and Table 7. Table 5 - Treatment statistics for centres administering 89Sr-chloride for bone metastases Year Total treatments administered Centres administering Treatments per centre Mean/median SD/range 2007 156 20 8/5 8/1–33 2011 119 18 7/4 7/1–26 2012 104 20 5/4 4/1–13 2013 29 11 3/2 2/1–7 2014 21 11 2/1 1/1–4 2015 15 7 2/1 2/1–6 2016 4 4 1/1 0/1–1 2017 3 2 2/2 1/1–2 2018 4 2 2/2 0/2–2 2019 0 0 0/0 0/0–0 2020 0 0 0/0 0/0–0 2021 0 0 0/0 0/0–0 Table 6 - Treatment statistics for centres administering 153Sm-EDTMP for bone metastases Year Total treatments administered Centres administering Treatments per centre Mean/median SD/range 2007 36 4 9/8 7/3–18 2011 36 6 6/5 6/1–18 2012 39 4 10/8 9/1–23 2013 40 7 6/4 5/1–15 2014 13 4 3/2 3/1–8 2015 11 4 3/2 2/1–6 2016 2 2 1/1 0/1–1 2017 6 1 6/6 0/6–6 2018 2 1 2/2 0/2–2 2019 4 2 2/2 0/2–2 2020 0 0 0/0 0/0–0 2021 0 0 0/0 0/0–0 Table 7 - Treatment statistics for centres administering 223Ra-Chloride for bone metastases Year Total treatments administered Centres administering Treatments per centre Mean/median SD/range 2007 32 2 16/16 10/9–23 2011 72 3 24/10 28/6–56 2012 23 3 8/6 5/4–13 2013 70 4 18/10 19/6–45 2014 943 16 59/52 57/1–222 2015 2713 21 129/150 87/2–276 2016 3627 24 151/172 79/22–302 2017 4305 24 179/173 106/2–366 2018 3576 26 138/142 79/11–291 2019 2621 27 97/94 51/10–193 2020 2558 28 91/85 57/1–241 2021 2715 30 91/73 60/2–246 Fig. 5: Numbers of patients treated (pts), treatments given (tx) and number of centres administering 89Sr and 153Sm radiopharmaceuticals for bone metastases.Fig. 6: Numbers of patients treated (pts), treatments given (tx) and number of centres administering 223Ra-Chloride for bone metastases.In 2017 the Medicines and Healthcare products regulatory Agency, and in 2018 the European Medicines Agency (EMA), issued recommendations against the use of 223Ra-Chloride alongside the combination of the hormone therapy abiraterone acetate (Zytiga, Janssen Biotech, Pennsylvania, USA) and the steroid prednisone/prednisolone. This followed interim analysis of the ERA 223 trial (NCT02043678) 16,17 which indicated an increased risk of bone fractures in patients receiving these treatments together. The full results of ERA 223 18 further supported this conclusion and the use of 223Ra-Chloride dropped considerably up to 2019, but remained relatively steady in 2020 and 2021 despite the COVID-19 pandemic. PSMA for prostate cancer 177Lu-PSMA was first reported by responders to our survey in 2018 (Fig. 7 and Table 8), consisting of patients treated within the VISION trial (NCT03511664) which ceased recruitment in 2021. Results from the trial were published later that year 19 and showed a 4-month survival benefit for mCRPC patients treated with 177Lu-PSMA in addition to standard of care. By the end of 2021 the treatment was only available in the UK privately, via trials or through the early access to medicines scheme 20. 177Lu-PSMA, under the brand name Pluvicto (Novartis, Basel, Switzerland), has been granted marketing authorisation by the EMA 21 and at the time of writing is being reviewed by NICE with the final conclusion expected in October 2023 22. While under NICE review the future for 177Lu-PSMA in the UK, in terms of demand and our capacity to meet it, remains uncertain. Table 8 - Treatment statistics for centres administering 177Lu-PSMA for prostate cancer Year Total treatments administered Centres administering Treatments per centre Mean/median SD/range 2018 1 1 1/1 0/1–1 2019 223 8 28/20 26/4–80 2020 239 8 30/2 47/1–131 2021 216 6 36/24 45/2–117 PSMA, prostate specific membrane antigen. Fig. 7: Number of patients treated (pts), treatments given (txs) and centres administering 177Lu and 227Th labelled PSMA for prostate cancer. PSMA, prostate specific membrane antigen.Experience with 223Ra-Chloride can serve to give us an indication, if not a precise prediction, of the demand that might be expected with 177Lu-PSMA. As discussed above, following NICE approval of 223Ra-Chloride, centres rapidly began giving many times more treatments than were given with pre-existing equivalent products. However, whilst patients treated with 223Ra-Chloride and 177Lu-PSMA have overlapping characteristics, as seen in the demographics of the ALSYMPCA and VISION trials 11,17, 177Lu-PSMA can be given to patients who have visceral as well as bone metastases. Furthermore, several trials are underway which could broaden the range of patients who might be shown to benefit from 177Lu-PSMA, such as PSMAfore (NCT04689828), PSMAddition (NCT04720157) and SPLASH (NCT04647526). As such the exact eligibility criteria determined by NICE for 177Lu-PSMA, if approved, will have a considerable impact on the size of the demand, which could well be greater than that experienced with 223Ra-Chloride. Based on our data it would seem unlikely that the UK has the capacity to meet such demand. In 2021 within the surveyed group 177Lu-PSMA was being given, in all but one case, in centres already treating with 177Lu-Dotatate. To meet a swell in demand for 177Lu-PSMA would create conflict for capacity in high volume PRRT centres such as these. Capacity both in terms of staffing and facilities but also limits in Environment Agency (EA) permits for radioactive waste accumulation and disposal. Whilst lower volume centres may be able to expand their workload within their EA limits, they would require considerable investment in facilities, staffing and training, including supporting diagnostics (a guide to which can be found in recent EANM guidance 23). NHS commissioning decisions surrounding 177Lu-PSMA will therefore play a major role on the UK’s ability to meet the demand for the treatment. In the case that capacity cannot meet demand, whether only initially or in the long term, this could lead to difficult decisions surrounding eligibility. 177Lu based agents have the benefit over primarily alpha emitters such as 223Ra-Chloride of convenient imaging and the potential to perform dosimetry. The importance of which has been recognised in legislation 24, guidelines from several UK legislative entities 25,26 as well as by many professional groups 27–30, particularly for this therapy. Provision of a dosimetry service will similarly require investment in facilities, equipment, staff and their training but would help stratify patients, if patients for the treatment and its will not be 227Th labelled PSMA was given by one centre in this group as within the clinical trial also shown in Fig. 7. and other small volume treatments treatments as identified in our previous publications a small of based clinical trials for radiopharmaceuticals (Fig. The and only is the use of to treat or Data for were within our likely an up to after which centres were and from the given we can that given were for Treatments for both have declined sharply over recent years and from 2020 MRT treatments given for haematological and other not included in Fig. 8 are the treatments labelled as in Fig. being small trial based treatments for with receptor positive with and cancer with Wales, internal radionuclide therapy internal radionuclide therapy (SIRT) use in the UK has been relatively over the surveyed period as seen in Fig. 9 and Tables 9 and being used to treat patients with metastases of cancer, it was available for a time through the from which it was cut in followed by a period of through where it was available in numbers in a number of centres from 2013 to 2017 Results of trials of both 90Y Wales, and later and the commissioning not show a survival benefit with these treatments for the SIRT, not including has NICE approval for a more of patients with carcinoma Treatment numbers dropped after relatively steady from 2018 onwards including during the COVID-19 pandemic. Table 9 - Treatment statistics for centres administering treatments using Year Total treatments administered Centres administering Treatments per centre Mean/median SD/range 2007 23 2 2011 9 2012 14 2013 14 2014 14 17/15 2015 15 2016 14 2017 14 2018 13 2019 11 8/6 2020 9 2021 9 SIRT, selective internal radionuclide therapy. Table 10 - Treatment statistics for centres administering treatments using Year Total treatments administered Centres administering Treatments per centre Mean/median SD/range 2007 1 1 1/1 0/1–1 2011 9 2 5/5 2012 10 2 5/5 2013 22 8 2014 12 5/4 4/1–16 2015 15 8/7 2016 13 7/4 2017 10 4/1–15 2018 64 6 2019 9 7/4 2020 6 2021 0 0 0/0 0/0–0 SIRT, selective internal radionuclide therapy. Fig. Total number of treatments given and centres administering selective internal radionuclide therapy using and for benign have only been included in our survey from 2018 onwards and not form of the data included in Fig. but are shown in Fig. 10 and Table is relatively in the UK and within our survey group lead to over Na131I treatments in 2018 and 2019, up the of MRT for benign conditions. The COVID-19 pandemic to have a impact on this treatment than other in this Whilst in treatment during the of the pandemic were supported by the UK professional as with the use of radioiodine for thyroid cancer, treatment rates fell by in 2020 and only recovered in 2021. This as compared to a drop of only in RAI for in 2020 followed by a recovery in 2021 to Whilst the in treatment numbers in 2020 for this benign is perhaps as compared to treatments for malignancies, the recovery in 2021 perhaps to an of COVID-19 on the benign thyroid treatment Table 11 - Treatment statistics for centres treating benign Treatment Year Total treatments administered Centres administering Treatments per centre RAI benign thyroid 2018 36 2019 36 2020 34 2021 34 90Y 2018 7 2019 7 6/3 2020 23 7 5/1–15 2021 27 8 2/1–7 2018 16 3 2019 11 2 6/6 2020 10 2 5/5 2021 17 3 6/5 RAI, Fig. Number of treatments given and centres administering radiopharmaceuticals for benign are in small numbers in a similarly small number of centres whilst data are appear to have also in numbers to the COVID-19 pandemic. In a of 39 UK centres, MRT was used to treat 87% more cancer patients in 2021 than in with 231% more treatments. of new therapies by funding, clinical evidence and regulatory In this the of these were seen most for 177Lu-PRRT, 223Ra-Chloride and 177Lu-PRRT and grew in over several years despite in funding as trials were publication of these trials and subsequent regulatory decisions their usage with 177Lu-PRRT by from 2018 to 2019 and high whilst declined to a of its 2016 peak by 2021. 223Ra-Chloride usage to regulatory approval was likely to trial patients with a increase over a period of over three followed by a similarly sudden as with from 2017 to 2019 to of its peak steady The impact of the COVID-19 pandemic is visible as a in workload in 2020 for not treatment with most or in 2021. The was seen in the use of radioiodine for treatment of where treatment numbers by and fell short of a full recovery in 2021. This survey evidence of changes which many will have experienced or that of considerable and sudden in therapy that this data help for investment in and given the identified NHS staffing in MRT as well as This will be to with this and demand, in for treatments with a as we have seen with 223Ra-Chloride and may to a greater with 177Lu-PSMA. The of alongside a for of how these treatments are given, and a to the potential of dosimetry.