A multidisciplinary expert panel convened to formulate state-of-the-art recommendations for optimisation of selective internal radiation therapy (SIRT) with yttrium-90 (90Y)-resin microspheres. A steering committee of 23 international experts representing all participating specialties formulated recommendations for SIRT with 90Y-resin microspheres activity prescription and post-treatment dosimetry, based on literature searches and the responses to a 61-question survey that was completed by 43 leading experts (including the steering committee members). The survey was validated by the steering committee and completed anonymously. In a face-to-face meeting, the results of the survey were presented and discussed. Recommendations were derived and level of agreement defined (strong agreement ≥ 80%, moderate agreement 50%–79%, no agreement ≤ 49%). Forty-seven recommendations were established, including guidance such as a multidisciplinary team should define treatment strategy and therapeutic intent (strong agreement); 3D imaging with CT and an angiography with cone-beam-CT, if available, and 99mTc-MAA SPECT/CT are recommended for extrahepatic/intrahepatic deposition assessment, treatment field definition and calculation of the 90Y-resin microspheres activity needed (moderate/strong agreement). A personalised approach, using dosimetry (partition model and/or voxel-based) is recommended for activity prescription, when either whole liver or selective, non-ablative or ablative SIRT is planned (strong agreement). A mean absorbed dose to non-tumoural liver of 40 Gy or less is considered safe (strong agreement). A minimum mean target-absorbed dose to tumour of 100–120 Gy is recommended for hepatocellular carcinoma, liver metastatic colorectal cancer and cholangiocarcinoma (moderate/strong agreement). Post-SIRT imaging for treatment verification with 90Y-PET/CT is recommended (strong agreement). Post-SIRT dosimetry is also recommended (strong agreement). Practitioners are encouraged to work towards adoption of these recommendations.

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International recommendations for personalised selective internal radiation therapy of primary and metastatic liver diseases with yttrium-90 resin microspheres

Radioembolization is an established treatment for chemoresistant and unresectable liver cancers. Currently, treatment planning is often based on semi-empirical methods, which yield acceptable toxicity profiles and have enabled the large-scale application in a palliative setting. However, recently, five large randomized controlled trials using resin microspheres failed to demonstrate a significant improvement in either progression-free survival or overall survival in both hepatocellular carcinoma and metastatic colorectal cancer. One reason for this might be that the activity prescription methods used in these studies are suboptimal for many patients. In this review, the current dosimetric methods and their caveats are evaluated. Furthermore, the current state-of-the-art of image-guided dosimetry and advanced radiobiological modeling is reviewed from a physics’ perspective. The current literature is explored for the observation of robust dose-response relationships followed by an overview of recent advancements in quantitative image reconstruction in relation to image-guided dosimetry. This review is concluded with a discussion on areas where further research is necessary in order to arrive at a personalized treatment method that provides optimal tumor control and is clinically feasible.

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The physics of radioembolization

The new European Council Directive 2013/59 (http://eur-lex. europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX: 32013L0059&from=EN), to be translated into national legislations before 6 February 2018, in article 56 (Optimisation) states: BFor all medical exposure of patients for radiotherapeutic purposes, exposures of target volumes shall be individually planned and their delivery appropriately verified, taking into account that doses to non-target volumes and tissues shall be as low as reasonably achievable and consistent with the intended radiotherapeutic purpose of the exposure^. No doubt this statement holds for nuclear medicine therapy, since in article 4 of the same, directive definition 81 states that Bradiotherapeutic^ means pertaining to radiotherapy, including nuclear medicine for therapeutic purposes. The directive thus asks for dosimetry, as is routinely implemented in radiotherapy, using external beam or brachytherapy sources. However, in nuclear medicine therapy, absorbed dose planning is rarely performed. One of the main reasons is the amount of work needed for internal dosimetry that includes multiple whole-body counts or scintigraphy and sometimes blood samples over some days after administration. The Bintended purpose^ in all therapeutic exposures is treatment efficacy against malignant disease. The optimization principle (as low as reasonably achievable, ALARA) of article 56, when applied in a therapy situation, states that absorbed doses to nontarget tissues should be kept reasonably low, but not so low as to lose efficacy. We think that this applies above all to the fight against life-threatening cancer. As a consequence, we believe that to adhere to the optimization principle in oncological patients, nuclear medicine therapy should be based on individualized dosimetry.

/pdf/the-conflict-between-treatment-optimization-and-registration-1u7mltd20l.pdf

The conflict between treatment optimization and registration of radiopharmaceuticals with fixed activity posology in oncological nuclear medicine therapy

A guide to 90Y radioembolization and its dosimetry.

Towards clinical translation of FLASH radiotherapy

90Y-microsphere selective internal radiation therapy (SIRT) is a valuable treatment in unresectable hepatocellular carcinoma (HCC). Partition-model predictive dosimetry relies on differential tumor-to-nontumor perfusion evaluated on pretreatment 99mTc-macroaggregated albumin (MAA) SPECT/CT. The aim of this study was to evaluate agreement between the predictive dosimetry of 99mTc-MAA SPECT/CT and posttreatment dosimetry based on 90Y time-of-flight (TOF) PET/CT. Methods We compared the 99mTc-MAA SPECT/CT results for 27 treatment sessions (25 HCC patients, 41 tumors) with 90Y SIRT (7 glass spheres, 20 resin spheres) and the posttreatment 90Y TOF PET/CT results. Three-dimensional voxelized dose maps were computed from the 99mTc-MAA SPECT/CT and 90Y TOF PET/CT data. Mean absorbed dose ([Formula: see text]) was evaluated to compute the predicted-to-actual dose ratio ([Formula: see text]) in tumor volumes (TVs) and nontumor volumes (NTVs) for glass and resin spheres. The Lin concordance ([Formula: see text]) was used to measure accuracy ([Formula: see text]) and precision (ρ). Results Administered activity ranged from 0.8 to 1.9 GBq for glass spheres and from 0.6 to 3.4 GBq for resin spheres, and the respective TVs ranged from 2 to 125 mL and from 6 to 1,828 mL. The mean dose [Formula: see text] was 240 Gy for glass and 122 Gy for resin in TVs and 72 Gy for glass and 47 Gy for resin in NTVs. [Formula: see text] was 1.46 ± 0.58 (0.65-2.53) for glass and 1.16 ± 0.41 (0.54-2.54) for resin, and the respective values for [Formula: see text] were 0.88 ± 0.15 (0.56-1.00) and 0.86 ± 0.2 (0.58-1.35). DR variability was substantially lower in NTVs than in TVs. The Lin concordance between [Formula: see text] and [Formula: see text] (resin) was significantly better for tumors larger than 150 mL than for tumors 150 mL or smaller ([Formula: see text] = 0.93 and [Formula: see text] = 0.95 vs. [Formula: see text] = 0.57 and [Formula: see text] = 0.93; P Conclusion In 90Y radioembolization of HCC, predictive dosimetry based on 99mTc-MAA SPECT/CT provided good estimates of absorbed doses calculated from posttreatment 90Y TOF PET/CT for tumor and nontumor tissues. The low variability of [Formula: see text] demonstrates that pretreatment dosimetry is particularly suitable for minimizing radiation-induced hepatotoxicity.

http://jnm.snmjournals.org/content/57/11/1672.full.pdf

Partition Model–Based 99mTc-MAA SPECT/CT Predictive Dosimetry Compared with 90Y TOF PET/CT Posttreatment Dosimetry in Radioembolization of Hepatocellular Carcinoma: A Quantitative Agreement Comparison

A reemergence of research implementing radiation delivery at ultra-high dose rates (UHDRs) has triggered intense interest in the radiation sciences and has opened a new field of investigation in radiobiology. Much of the promise of UHDR irradiation involves the FLASH effect, an in vivo biological response observed to maintain anti-tumor efficacy without the normal tissue complications associated with standard dose rates. The FLASH effect has been validated primarily, using intermediate energy electron beams able to deliver high doses (>7 Gy) in a very short period of time (<200 ms), but has also been found with photon and proton beams. The clinical implications of this new area of research are highly significant, as FLASH radiotherapy (FLASH-RT) has the potential to enhance the therapeutic index, opening new possibilities for eradicating radio-resistant tumors without toxicity. As pioneers in this field, our group has developed a multidisciplinary research team focused on investigating the mechanisms and clinical translation of the FLASH effect. Here, we review the field of UHDR, from the physico-chemical to the biological mechanisms.

Understanding the FLASH effect to unravel the potential of ultra-high dose rate irradiation.

PURPOSE To present the acceptance and the commissioning, to define the reference dose, and to prepare the reference data for a quality assessment (QA) program of an ultra-high dose rate (UHDR) electron device in order to validate it for preclinical animal FLASH radiotherapy (FLASH RT) experiments and for FLASH RT clinical human protocols. METHODS The Mobetron® device was evaluated with electron beams of 9 MeV in conventional (CONV) mode and of 6 and 9 MeV in UHDR mode (nominal energy). The acceptance was performed according to the acceptance protocol of the company. The commissioning consisted of determining the short- and long-term stability of the device, the measurement of percent depth dose curves (PDDs) and profiles at two different positions (with two different dose per pulse regimen) and for different collimator sizes, and the evaluation of the variability of these parameters when changing the pulse width and pulse repetition frequency. Measurements were performed using a redundant and validated dosimetric strategy with alanine and radiochromic films, as well as Advanced Markus ionization chamber for some measurements. RESULTS The acceptance tests were all within the tolerances of the company's acceptance protocol. The linearity with pulse width was within 1.5% in all cases. The pulse repetition frequency did not affect the delivered dose more than 2% in all cases but 90 Hz, for which the larger difference was 3.8%. The reference dosimetry showed a good agreement within the alanine and films with variations of 2.2% or less. The short-term (resp. long-term) stability was less than 1.0% (resp. 1.8%) and was the same in both CONV and UHDR modes. PDDs, profiles, and reference dosimetry were measured at two positions, providing data for two specific dose rates (about 9 Gy/pulse and 3 Gy/pulse). Maximal beam size was 4 and 6 cm at 90% isodose in the two positions tested. There was no difference between CONV and UHDR mode in the beam characteristics tested. CONCLUSIONS The device is commissioned for FLASH RT preclinical biological experiments as well as FLASH RT clinical human protocols.

https://aapm.onlinelibrary.wiley.com/doi/pdf/10.1002/mp.14885

Commissioning of an ultra-high dose rate pulsed electron beam medical LINAC for FLASH RT preclinical animal experiments and future clinical human protocols.

Nicolas Cherbuin

Papers

Partition Model–Based 99mTc-MAA SPECT/CT Predictive Dosimetry Compared with 90Y TOF PET/CT Posttreatment Dosimetry in Radioembolization of Hepatocellular Carcinoma: A Quantitative Agreement Comparison

Understanding the FLASH effect to unravel the potential of ultra-high dose rate irradiation.

Commissioning of an ultra-high dose rate pulsed electron beam medical LINAC for FLASH RT preclinical animal experiments and future clinical human protocols.