177Lutetium-based peptide receptor radionuclide therapy for treating neuroendocrine tumours: a health technology assessment
Health technology assessment
|Published
The Commission Forum representing the four National Regional Health Authorities (RHA) in Norway (Bestillerforum RHF) asked the Norwegian Institute of Public Health (NIPH) to conduct a full health technology assessment (HTA) of 177Lu-PRRT.
Key message
Peptide receptor radionuclide therapy (PRRT) using 177Luthetium (177Lu-PRRT) has become an established treatment modality, which increasingly is being used for subgroups of patients with neuroendocrine cancers (tumours) or neoplasias (NET/NEN).
So far, Norwegian patients have been sent abroad for treatment, as 177Lu-PRRT has not been available in Norway. The Commission Forum representing the four National Regional Health Authorities (RHA) in Norway (Bestillerforum RHF) has therefore asked the Norwegian Institute of Public Health (NIPH) to conduct a full health technology assessment (HTA) of 177Lu-PRRT. Included in this assessment is the radiopharmaceutical Lutathera® (177Lu-DOTATATE) has recently been approved by the European Medicines Agency (EMA) with market exclusitivity. Our assessment of clinical effectiveness, side-effects and adverse events is based on nine studies, i.e. one RCT with 229 patients and eight observational studies with 1,200 participants in total. Main findings are the following:
Clinical effectiveness
- 177Lu-PRRT probably reduces overall mortality, and is likely to increase both general and progression-free survival, however the evidence is too sparce to draw any definitive conclusion.
- Tumour response rates, assessed using the RECIST-criteria are likely to improve with 177Lu-PRRT.
- It is uncertain to what extent 177Lu-PRRT causes myeloplastic syndrome and acute leukemia, but the risk might be around 1%.
Safety
- Provided that the Radiation Protection Regulations are followed, the use 177Lu-PRRT with 177Lu-DOTATATE, including Lutathera®, is considered to be justified.
Health economic evaluation
- In terms of prices and suppliers, it is not be possible to use today’s prices and suppliers, given that Lutathera® has marked exclusitivity. The mean cost per patient per year when 177Lu-PRRT is carried out in Norway is estimated between 492, 000 and 870, 000 NOK, depending on organisation and possible discount on Lutathera®.
- Total costs for establishing the treatment in Norway is estimated to be between 25,928,000 and 44,763,000 NOK the first year and between 24,595,000 and 43,518,000 NOK the following years , while the total costs for treating abroad are slighly lower, as it is expected that more patients will be offered the treatment if available in Norway.
- The major cost-driver is the price of Lutathera®, which is independent of the treatment being established in Norway or patients still being treated abroad.
Ethics
- The treatment is expensive and might therefore challenge the principle of equal use of limited health care resources, although the number of eligible patients per year is low. On the other hand, it is not often a palliative cancer treatment with relatively few side-effects may extend life-time to up to three years.
Summary
Background
Peptide receptor radionuclide therapy (PRRT) using 177Luthetium (177Lu-PRRT) has become an established treatment modality, which increasingly is being used for subgroups of patients with neuroendocrine cancers (tumours) or neoplasias (NET/NEN).
Clinical experience indicates that selected patients profit from the treatment. Since 2002, an increasing number of Norwegian patients (approx. 20-50 per year) have been sent to Sweden or Denmark to get their treatment, as the treatment has not been available in Norway so far. Now it is being considered to establish PRRT in Norway. Therefore, the Commission Forum representing the four National Regional Health Authorities (RHA) in Norway (Bestillerforum RHF) has asked the Norwegian Institute of Public Health (NIPH) to perform a full health technology assessment (HTA) of 177Lu-PRRT.
Neuroendocrine tumours (NET) have their origin from hormone-producing cells, and in principle they may arise from most organs in the body. The majority however has its origin in the digestive tract. Approximately 370 cases yearly are diagnosed with NET in Norway, which corresponds to an incidence of 7.2 per 100,000 inhabitants per year. Median age at diagnosis is 65 years. Surgery is the only potentially curative treatment for NET.
The last decade treatments using nuclear medicine, in particular PRRT have been increasingly used in subgroups of patients with NET. This treatment modality appear to have better effect than the other existing treatment alternatives. The radioactive peptide will then bind to tumour cells via the somatostatin receptor, and the complexe is internalised into the cytolsol, where it emits killing β (beta)-rays, thereby killing completely or parts of the tumour. β-rays have short range, hence emission to the surrounding tissues is limited. The radiopharmaceutical Lutathera® which includes 177Lu-DOTATATE has recently been approved by the European Medicines Agency (EMA) with market exclusitivity.
Clinical effectiveness
We carried out a literature search for publications that included the combination of population (patients with neuroendocrine cancer) and intervention (177Lu-PRRT) without any restrictions in terms of study design, in the databases Cochrane library, Embase, HTA (CRD), MEDLINE, PubMed (NOT MEDLINE), Epistemonikos, SveMed+, Web of Science. Our assessment of clinical effectiveness, side-effects and adverse events is based on these nine studies, which include one RCT and eight observational studies including 1,200 participants in total.
Overall, the evidential material is sparce and with low to moderate quality. Estimates on the effect of 177Lu-PRRT in terms of overall mortality and survival are uncertain, but number of deaths reported 20 months after randomisation in the one RCT included showed lower mortality in the intervention group (RR=0.52 with 95% CI 0.29-0.95). According to one of the observation studies, expected extended life-time could be between 40 and 72 months and depends on the type of NET. Moreover, preliminary results from the RCT indicated a higher percentage of progression-free patients 20 months after randomisation in the group treated with 177Lu-PRRT (MD=54.4% with 95% CI 43.1-65.7%). Tumour response rates assessed using the RECIST-criteria are likely to improve with 177Lu-PRRT compared to octreotide. Results from the RCT indicated that 18% of the patients treated with 177Lu-PRRT had partial or full remission compared to 3% in the control group (MD=15% with 95% CI 7.5-22.5%), a finding supported by all the three observational studies that had assessed this outcome. Few serious adverse events and side-effects were related to the intervention. Both in the RCT and in the observational studies the most prominent ones were related to the bone marrow and kidney functions. As the events were rare in the included studies, it is still uncertain to what extent 177Lu-PRRT causes myeloplastic syndrome and acute leukemia, but the risk might be around 1%.
We have searched for ongoing studies in the registries ISRCTN and ClinicalTrials.gov. Most likely in the near future more evidence will be generated as at least 16 studies are ongoing. Many of them are planned to be completed within a few years, and among them are three RCTs comparing 177Lu-PRRT with sunitinib, everolimus and capecitabine / temozolomide.
Safety
Hospitals carrying out treatments with 177Lu-PRRT must have procedures for the treatment and time for preparing and administrating the radiopharmaceutical. In addition to emit “curative” β-rays, 177Lu also emit potentially damaging γ (gamma)-rays, but these have lower radiation energy than γ (gamma)-rays emitted by 131I, that is already in use today. 177Lu has lower potentially harmful gamma-ray energy than 131I (iodine) that is already in use in Norwegian hospitals. Therefore, guidelines for handling 131I might as well be used for handling 177Lu.
Provided that the Radiation Protection Regulations are followed, the use of 177Lu-DOTATATE is considered to be justified, as the expected benefit from the treatment should be taken into account in light of the potential harm radiation may cause for the patient, personnel, care givers, surroundings and the environment.
Organisation
The organisational consequences of introducing 177Lu-PRRT into the Norwegian health care services are discussed based on the assessment elements on organisational issues from the mini-HTA template and the EUnetHTA HTA Core Model. The documentation base is from references identified through the literature search and the source has been the mini-HTA carried out by the University Hospital of Oslo (OUS) which was basis for a request to the South-East Regional Health Authority to introduce 177Lu-PRRT in OUS in addition to CarciNor (patient association).
The neuroendocrine cancer patient group is relatively small and heterogenous, and the most challenging in terms of organisation is related to the clinical examination and diagnosis, and the selection of the patients suited for 177Lu-PRRT. Hospitals making the decision on whether patients show be offered the treatment or not, must have the necessary multidisciplinary and experience competence both in diagnosing and treating patients with this type cancer. It is likely that the most practical would be to have the decision making and the treatment at the same hospital. A centralization of examination, diagnosis and treatment (but not necessarily follow-up) towards only a few centres would therefore seem appropriate.
Health economic evaluation
The cost-minimization analysis (CMA) includes costs related to different possible organisation alternatives in the country, as well as costs related to treating patients abroad. Based on information NIPH has received so far, it will not be possible to maintain in Norway the today’s practice of PRRT abroad in terms of prices and suppliers. The recent market approval of Lutathera®, and its status as orphan drug, will affect the use of radiopharmaceuticals in PRRT in Sweden and Denmark, which will be replaced by Lutathera®. In Norway as well, only Lutathera® will be allowed to use in this treatment. Data used in our evaluation are collected mainly from university hospitals in Norway where 177Lu-PRRT is planned to be established, i.e. Oslo University Hospital, Haukeland University Hospital (Bergen), St. Olavs Hospital and the University Hospital of North Norway, as well as from the foreign offices of the Regional Health Authorities and Uppsala University Hospital. Estimated costs were dependent on organisation and the price of Lutathera®. We have used the list price and two possible discounts, i.e. 25% and 50% in our evaluation.
The mean cost per patient per year when 177Lu-PRRT is carried out in Norway is estimated between 492,000 and 870,000 NOK, while the mean cost is estimated between 612,000 and 938,000 NOK if patients are treated abroad. Total costs for establishing 177Lu-PRRT in Norway is estimated between 25,928,000 and 44,763,000 NOK the first year, and between 24,595,000 and 43,518, 000 NOK the following years. Total costs for treatment abroad is estimated between 26,295,000 and 40,322,000 NOK per year, as it is likely that an increased number of Norwegian patients will have access to the treatment if established in Norway. Total costs for treating patients abroad, where 177Lu-DOTATATE has been prepared so far in own hotlab (i.e. not used Lutathera®) is estimated to 18,653,000 NOK, while the mean cost is estimated to 434,000 NOK per patient per year.
Ethics
We have chosen to discuss ethical questions we think might be relevant in this context, based on a series of selected questions (check-list) presented in our method handbook.
Additionally, we have retrieved information from the literature we considered useful to shed light on ethical aspects related to the type of treatment assessed in this report.
In general there are few ethical challenges related to the treatment of patients with neuroendocrine cancer with 177Lu-PRRT, which appear to be rather non-controversial. However, due to the risks for the patient and the surroundings related to the treatment, one should consider the trade-off between the possible benefit in terms of extended life-time and possibly better quality of life, against possible injuries or side-effects PRRT may cause. Health carers are therefore ought to explain the issue, so the patient can take an informed decision about his/her treatment.
The treatment is expensive and might therefore challenge the principle of equal use of limited health care resources, although the number of eligible patients per year is low. On the other hand, it is not often we encounter a palliative cancer treatment with relatively few side-effects, which may extend life-time to up to three years.
Discussion
Differences in total costs between establishing 177Lu-PRRT in Norway and 177Lu-PRRT abroad are mainly due to the assumption of a higher patient volume when the treatment is established in Norway.
The most important cost-driver is the high price of the radiopharmceutical both in the case of establishment of 177Lu-PRRT in Norway and in the case where the patients are treated abroad. Currently, it is not known what the final price after price negociations will be, and we are not aware of any ongoing negociation(s). Therefore, prices we have been operating with in our analyses include theoretical levels of discounts. Nevertheless, the price of the radiopharmaceutical will probably increase considerably in the future compared with the price today, where Lutathera® is not being used, and thereby increase the total costs for the treatment regardless of localisation. It will be crucial for the validity of this economic evaluation that the purchase price of Lutathera® in Norway will be within the same range as in Sweden and/or Denmark, as larger differences in price will most likely affect the decision on establishing 177Lu-PRRT at the national level in Norway.
177Lu-PRRT and other targeted radionuclide treatments are within an area where a lot research is going on, and most likely many of these radiopharmaceuticals will be developed in the future. This type of treatment should therefore be seen in a larger context considering beneficial synergy effects in terms of establishing and further developing nuclear medical diagnostics and treatments.
