EANM procedure guideline for the treatment of liver cancer and liver metastases with intra-arterial radioactive compounds.

Primary liver tumours (i.e. hepatocellular carcinoma (HCC) or intrahepatic cholangiocarcinoma (ICC)) are among the most frequent cancers worldwide. However, only 10-20% of patients are amenable to curative treatment, such as resection or transplant. Liver metastases are most frequently caused by colorectal cancer, which accounts for the second most cancer-related deaths in Europe. In both primary and secondary tumours, radioembolization has been shown to be a safe and effective treatment option. The vast potential of personalized dosimetry has also been shown, resulting in markedly increased response rates and overall survival. In a rapidly evolving therapeutic landscape, the role of radioembolization will be subject to changes. Therefore, the decision for radioembolization should be taken by a multidisciplinary tumour board in accordance with the current clinical guidelines. The purpose of this procedure guideline is to assist the nuclear medicine physician in treating and managing patients undergoing radioembolization treatment. PREAMBLE: The European Association of Nuclear Medicine (EANM) is a professional non-profit medical association that facilitates communication worldwide among individuals pursuing clinical and research excellence in nuclear medicine. The EANM was founded in 1985. These guidelines are intended to assist practitioners in providing appropriate nuclear medicine care for patients. They are not inflexible rules or requirements of practice and are not intended, nor should they be used, to establish a legal standard of care. The ultimate judgment regarding the propriety of any specific procedure or course of action must be made by medical professionals taking into account the unique circumstances of each case. Thus, there is no implication that an approach differing from the guidelines, standing alone, is below the standard of care. To the contrary, a conscientious practitioner may responsibly adopt a course of action different from that set out in the guidelines when, in the reasonable judgment of the practitioner, such course of action is indicated by the condition of the patient, limitations of available resources or advances in knowledge or technology subsequent to publication of the guidelines. The practice of medicine involves not only the science but also the art of dealing with the prevention, diagnosis, alleviation and treatment of disease. The variety and complexity of human conditions make it impossible to always reach the most appropriate diagnosis or to predict with certainty a particular response to treatment. Therefore, it should be recognised that adherence to these guidelines will not ensure an accurate diagnosis or a successful outcome. All that should be expected is that the practitioner will follow a reasonable course of action based on current knowledge, available resources and the needs of the patient to deliver effective and safe medical care. The sole purpose of these guidelines is to assist practitioners in achieving this objective.

The EANM guideline for radiosynoviorthesis.

PURPOSE: Radiosynoviorthesis (RSO) using the intraarticular application of beta-particle emitting radiocolloids has for decades been used for the local treatment of inflammatory joint diseases. The injected radiopharmaceuticals are phagocytized by the superficial macrophages of the synovial membrane, resulting in sclerosis and fibrosis of the formerly inflamed tissue, finally leading to reduced joint effusion and alleviation of joint pain. METHODS: The European Association of Nuclear Medicine (EANM) has written and approved these guidelines in tight collaboration with an international team of clinical experts, including rheumatologists. Besides clinical and procedural aspects, different national legislative issues, dosimetric considerations, possible complications, and side effects are addressed. CONCLUSION: These guidelines will assist nuclear medicine physicians in performing radiosynoviorthesis. Since there are differences regarding the radiopharmaceuticals approved for RSO and the official indications between several European countries, this guideline can only give a framework that must be adopted individually.

Persistent Hematologic Dysfunction after Peptide Receptor Radionuclide Therapy with 177Lu-DOTATATE: Incidence, Course, and Predicting Factors in Patients with Gastroenteropancreatic Neuroendocrine Tumors.

Peptide receptor radionuclide therapy (PRRT) may induce long-term toxicity to the bone marrow (BM). The aim of this study was to analyze persistent hematologic dysfunction (PHD) after PRRT with 177Lu-DOTATATE in patients with gastroenteropancreatic neuroendocrine tumors (GEP NETs). Methods: The incidence and course of PHD were analyzed in 274 GEP NET patients from a group of 367 patients with somatostatin receptor-positive tumors. PHD was defined as diagnosis of myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), myeloproliferative neoplasm (MPN), MDS/MPN, or otherwise unexplained cytopenia (for >6 mo). Using data from The Netherlands Cancer Registry, the expected number of hematopoietic neoplasms (MDS, AML, MPN, and MDS/MPN) was calculated and adjusted for sex, age, and follow-up period. The following risk factors were assessed: sex, age over 70 y, bone metastasis, prior chemotherapy, prior external-beam radiotherapy, uptake on the [111In-DTPA0]octreotide scan, tumor load, grade 3-4 hematologic toxicity during treatment, estimated absorbed BM dose, elevated plasma chromogranin A level, baseline blood counts, and renal function. Results: Eleven (4%) of the 274 patients had PHD after treatment with 177Lu-DOTATATE: 8 patients (2.9%) developed a hematopoietic neoplasm (4 MDS, 1 AML, 1 MPN, and 2 MDS/MPN) and 3 patients (1.1%) developed BM failure characterized by cytopenia and BM aplasia. The median latency period at diagnosis (or first suspicion of a PHD) was 41 mo (range, 15-84 mo). The expected number of hematopoietic neoplasms based on The Netherlands Cancer Registry data was 3.0, resulting in a relative risk of 2.7 (95% confidence interval, 0.7-10.0). No risk factors for PHD could be identified for the GEP NET patients, not even bone metastasis or estimated BM dose. Seven patients with PHD developed anemia in combination with a rise in mean corpuscular volume. Conclusion: The prevalence of PHD after PRRT with 177Lu-DOTATATE was 4% in our patient population. The median time at which PHD developed was 41 mo after the first PRRT cycle. The relative risk for developing a hematopoietic neoplasm was 2.7. No risk factors were found for the development of PHD in GEP NET patients.

From imaging to dosimetry and biological effects.

The essential steps are explained in calculating a radiation dose for radionuclide therapy from imaging data. As the dose alone is a meaningless value, its consequences in tumour cell kill efficiency and normal tissue damage are explained. The influence of dose rate and inhomogeneous dose distributions are discussed.

[177Lu-DOTAOTyr3]octreotate: comparison with [111In-DTPAo]octreotide in patients.

The somatostatin analogue [DOTA0,Tyr3]octreotate has a nine-fold higher affinity for the somatostatin receptor subtype 2 as compared with [DOTA0, Tyr3]octreotide. Also, labelled with the beta- and gamma-emitting radionuclide lutetium-177, this compound has been shown to have a very favourable impact on tumour regression and animal survival in a rat model. Because of these reported advantages over the analogues currently used for somatostatin receptor-mediated radiotherapy, we decided to compare [177Lu-DOTA0,Tyr3]octreotate (177Lu-octreotate) with [111In-DTPA0]octreotide (111In-octreotide) in six patients with somatostatin receptor-positive tumours. Plasma radioactivity after 177Lu-octreotate expressed as a percentage of the injected dose was comparable with that after 111In-octreotide. Urinary excretion of radioactivity was significantly lower than after 111In-octreotide, averaging 64% after 24 h. The uptake after 24 h, expressed as a percentage of the injected dose of 177Lu-octreotate, was comparable to that after 111In-octreotide for kidneys, spleen and liver, but was three- to fourfold higher for four of five tumours. The spleen and kidneys received the highest absorbed doses. The doses to the kidneys were reduced by a mean of 47% after co-infusion of amino acids. It is concluded that in comparison with the radionuclide-coupled somatostatin analogues that are currently available for somatostatin receptor-mediated radiotherapy, 177Lu-octreotate potentially represents an important improvement. Higher absorbed doses can be achieved to most tumours, with about equal doses to potentially dose-limiting organs; furthermore, the lower tissue penetration range of 177Lu as compared with 90Y may be especially important for small tumours.

Monte Carlo modeling of radiation dose distributions in intravascular radiation therapy.

Radiation dose distributions are developed for balloon and wire sources of radioactivity within coronary arteries. The Monte Carlo codes MCNP 4B and EGS4 were used to calculate dose distributions for photons and electrons at discrete energies around such sources, with and without the presence of a high-density atherosclerotic plaque. An interactive computer program was developed which then calculates dose distributions for many radionuclides by applying the emission spectra to the discrete energy grids calculated by the Monte Carlo codes, weighting appropriately for electron energy and abundance. Results for Re-186 and Re-188 balloon sources are shown in comparison to an Ir-192 wire source. The program provides dose distributions as well as estimates of activity levels needed to deliver prescribed doses to the vessel wall at selected distances from the lumen in a selected time interval. In addition, dose calculations are presented in this paper for other organs in the body, from photon radiation as well as from possible loss of liquid activity into the bloodstream in the case of a balloon rupture. These results, especially the interactive computer program permitting easy comparison of various radionuclides and their physical characteristics, will greatly facilitate the comparison process and aid in the selection of the best candidate(s) for clinical use.

Re-evaluation of absorbed fractions for photons and electrons in spheres of various sizes.

UNLABELLED: Absorbed fractions for unit density spheres in an infinite unit density medium, previously calculated for photon emitters and electron emitters, were reevaluated with the Monte Carlo codes EGS4 and MCNP4B. METHODS: Activity was assumed to be distributed uniformly throughout the spheres, and absorbed fractions for self-irradiation were calculated at discrete photon and electron energies. RESULTS: For electrons, the codes were in very good agreement with each other (+/-5%) and with published values, except at higher energies in the very smallest spheres, where some differences exceeded 10%. For photons, the codes were again in good agreement with each other but produced results that varied considerably from published MIRD values. For energies <1 MeV and sphere sizes <50 g, the absorbed fractions determined using the Monte Carlo codes were typically 20%-40% higher than values in MIRD 3 and 8. For energies >1 MeV, the Monte Carlo values were sometimes lower than those in the MIRD documents. Recommended values, generally the average results from the 2 Monte Carlo codes, are given for all sphere sizes and energies for both electrons and photons. CONCLUSION: The absorbed fractions calculated using the Monte Carlo codes should replace the older values and are helpful in evaluating tumor doses, doses to small organs, and other situations in which a uniform distribution of activity throughout a spherical structure of unit density can be assumed.

Clinical dosimetry of an epithermal neutron beam for neutron capture therapy: dose distributions under reference conditions.

PURPOSE: The aim of this study was to asses the dose distribution under reference conditions for the various dose components of the Petten clinical epithermal neutron beam for boron neutron capture therapy (BNCT). METHODS AND MATERIALS: Activation foils and a silicon alpha-particle detector with a 6Li converter plate have been used for the determination of the thermal neutron fluence rate. The gamma-ray dose rate and the fast neutron dose rate have been determined using paired ionization chambers. Circular beam apertures of 8, 12 and 15 cm diameters have been investigated using a 15 x 15 x 15 cm3 solid polymethyl-methacrylate phantom, a water phantom of the same dimensions and a 30 x 30 x 30 cm3 water phantom at various phantom to beam-exit distances. RESULTS: The effect of phantom to beam-exit distance could be modeled using an inverse square law with a virtual source to beam-exit distance of 3.0 m. At a reference phantom to beam-exit distance of 30 cm, three-dimensional dose and fluence distributions of the various dose components have been determined in the phantoms. The absolute thermal neutron fluence rate at a reference depth of 2 cm in the 15 cm water phantom increased by 43% when the field size was increased from 8 to 15 cm. Simultaneously the gamma-ray dose rate increased by 46% while the fast neutron dose rate increased by only 5%. CONCLUSION: A reference treatment position at 30 cm from the beam exit allows convenient patient positioning with a relatively small increase in irradiation time compared to positions very close to the beam-exit. A more homogeneous distribution of thermal neutrons over a target volume, a higher absolute thermal neutron fluence rate and a lower contribution of the fast neutron dose to the total dose will result in improved treatment plans when using a 12 cm or 15 cm field compared to a 8 cm field. The dose distributions will be used as benchmark data for treatment planning systems for BNCT.

Dose monitoring for boron neutron capture therapy using a reactor-based epithermal neutron beam.

The aims of this study were (i) to determine the variation with time of the relevant beam parameters of a clinical reactor-based epithermal neutron beam for boron neutron capture therapy (BNCT) and (ii) to test a monitoring system for its applicability to monitor the dose delivered to the dose specification point in a patient treated with BNCT. For this purpose two fission chambers covered with Cd and two GM counters were positioned in the beam-shaping collimator assembly of the epithermal neutron beam. The monitor count rates were compared with in-phanton reference measurements of the thermal neutron fluence rate, the gamma-ray dose rate and the fast neutron dose rate, at a constant reactor power, over a period of 2 years. Differences in beam output, defined as the thermal neutron fluence rate at 2 cm depth in a phantom, of up to 15% were observed between various reactor cycles. A decrease in beam output of about 5% was observed in each reactor cycle. An unacceptable decrease of 50% in beam output due to malfunctioning of the beam filter assembly was detected. For safe and accurate treatment of patients, on-line monitoring of the beam is essential. Using the calibrated monitor system, the standard uncertainty in the total dose at depth due to variations with time of the beam output parameters has been reduced to a clinically acceptable value of 1% (one standard deviation).

Dose homogeneity in boron neutron capture therapy using an epithermal neutron beam.

Simulation models based on the neutron and photon Monte Carlo code MCNP were used to study the therapeutic possibilities of the HB11 epithermal neutron beam at the High Flux Reactor in Petten. Irradiations were simulated in two types of phantoms filled with water or tissue-equivalent material for benchmark treatment planning calculations. In a cuboid phantom the influence of different field sizes on the thermal-neutron-induced dose distribution was investigated. Various shapes of collimators were studied to test their efficacy in optimizing the thermal-neutron distribution over a planning target volume and healthy tissues. Using circular collimators of 8, 12 and 15 cm diameter it was shown that with the 15-cm field a relatively larger volume within 85% of the maximum neutron-induced dose was obtained than with the 8- or 12-cm-diameter field. However, even for this large field the maximum diameter of this volume was 7.5 cm. In an ellipsoid head phantom the neutron-induced dose was calculated assuming the skull to contain 10 ppm 10B, the brain 5 ppm 10B and the tumor 30 ppm 10B. It was found that with a single 15-cm-diameter circular beam a very inhomogenous dose distribution in a typical target volume was obtained. Applying two equally weighted opposing 15-cm-diameter fields, however, a dose homogeneity within +/- 10% in this planning target volume was obtained. The dose in the surrounding healthy brain tissue is 30% at maximum of the dose in the center of the target volume. Contrary to the situation for the 8-cm field, combining four fields of 15 cm diameter gave no large improvement of the dose homogeneity over the target volume or a lower maximum dose in the healthy brain. Dose-volume histograms were evaluated for the planning target volume as well as for the healthy brain to compare different irradiation techniques, yielding a graphical confirmation of the above conclusions. Therapy with BNCT on brain tumors must be performed either with an 8-cm four-field irradiation or with two opposing 15- or 12-cm fields to obtain an optimal dose distribution.

Determination of dose components in phantoms irradiated with an epithermal neutron beam for boron neutron capture therapy.

The application of activation foils, thermoluminescent detectors, and ionization chambers has been investigated for the determination of the different dose components in phantoms irradiated with a mixed gamma-ray and epithermal neutron beam for boron neutron capture therapy. The thermal neutron fluence has been determined using a set of AuAl and MnNi activation foils. TLD-700 and a Mg(Ar) ionization chamber have been used for the determination of the gamma-ray dose. The dose from epithermal neutrons has been determined using a TE(TE) ionization chamber. The detector characteristics and the relative sensitivities of the various detectors to the different dose components in the phantom have been determined. The following accuracies (1 standard deviation) in the determination of the different components have been obtained: thermal neutron fluence rate: 5%; gamma-ray dose rate: 7%; epithermal neutron dose rate: 15%. These values make these detectors suitable for obtaining the complete set of clinical dosimetry data required for patient dose assessment.

Monitoring of blood-10B concentration for boron neutron capture therapy using prompt gamma-ray analysis.

The aim of the present study was to monitor the blood-10B concentration of laboratory dogs receiving boron neutron capture therapy, in order to obtain optimal agreement between prescribed and actual dose. A prompt gamma-ray analysis system was developed for this purpose at the High Flux Reactor in Petten. The technique was compared with inductively coupled plasma-atomic emission spectrometry and showed good agreement. A substantial variation in 10B clearance pattern after administration of borocaptate sodium was found between the different dogs. Consequently, the irradiation commencement was adjusted to the individually determined boron elimination curve. Mean blood-10B concentrations during irradiation of 25.8 +/- 2.2 micrograms/g (1 SD, n = 18) and 49.3 +/- 5.3 micrograms/g (1 SD, n = 17) were obtained for intended concentrations of 25 micrograms/g and 50 micrograms/g, respectively. These variations are a factor of two smaller than irradiations performed at a uniform post-infusion irradiation starting time. Such a careful blood-10B monitoring procedure is a prerequisite for accurately obtaining such steep dose-response curves as observed during the dog study.

A scintillation spectrometer for direct comparison of neutron energy spectra at high and low rates.

The energy spectrum of the HB11 beam at HFR, Petten, has previously been measured by proton and alpha recoil in hydrogen and helium gas proportional counters at power levels of a few kW. There is some doubt whether the spectrum remains the same at the much higher power of 45 MW required for therapeutic fluxes. In order to test this point, a scintillation detector has been developed at the Paul Scherrer Institute, Villingen, Switzerland. While the device is again based on the proton recoil reaction, a combination of mm-sized plastic scintillators and fast electronics will allow it to operate at both a few kW and 45 MW, permitting direct comparison of energy spectra at these very different power levels. Results of preliminary tests at LFR, Petten, are presented.

Determination of the gamma-ray dose in an epithermal neutron beam.

Neutron beams used for Boron Neutron Capture Therapy (BNCT) are always accompanied by photons. These two irradiation components have different relative biological effectiveness. Therefore it is necessary to determine the neutron and photon absorbed dose in the mixed field separately. All gamma-ray detectors however are also sensitive for neutrons. In this work preliminary results are presented using TLD-700 chips, a Mg(Ar) ionisation chamber and a GM-counter to determine the gamma-ray component in a mixed beam of gamma-rays and neutrons. The results show a good agreement between the GM-counter and the ionisation chamber, indicating a small relative neutron sensitivity (ku) for these detectors. The sensitivity of TLD-700 for thermal neutrons however gives rise to a detector response for which a correction is necessary. The uncertainty however in the relative gamma-ray sensitivity (hu) of the detectors is at this moment too large to determine accurate values of the relative neutron sensitivities.

An investigation of the possibilities of BNCT treatment planning with the Monte Carlo method.

The neutron fluence distribution inside two types of water phantom have been calculated with the Monte Carlo programme MCNP for the epithermal neutron beam at the Petten Low Flux Reactor. Comparison between the calculated and the measured neutron fluence distributions showed a reasonable agreement. The influence of beam and phantom geometry on the neutron fluence distribution has been calculated. An increase of the field size leads to a somewhat deeper position of the maximum of the thermal neutron fluence distribution in the cylindrical phantom. The possible use of beam modifying devices like wedges and blocks has been tested with this model. Blocks have been modelled that can locally reduce the fast neutron skin dose by 70%.