Threshold for defining PSMA-positivity prior to 177Lu-PSMA therapy: a comparison of [68Ga]Ga-PSMA-11 and [18F]F-DCFPyL in metastatic prostate cancer.

BACKGROUND: In 2022, the American Food and Drug Administration and the European Medicines Agency approved [177Lu]Lu-PSMA-617 (PLUVICTO™, Novartis AG, Basel, Switzerland) for radionuclide therapy with prostate-specific membrane antigen (PSMA) ligands in metastatic prostate cancer. Theranostics require appropriate patients to be identified by positron emission tomography (PET) prior to radionuclide therapy, usually employing [68Ga]Ga-PSMA-11. Alternatively, several 18F-labelled PSMA-PET tracers are available and may increasingly replace 68Ga-labelled compounds, with respect to their image quality, availability and other practical advantages. However, alternative tracers may differ in uptake behaviour, and their comparability with regard to patient selection for [177Lu]Lu-PSMA therapy has not yet been established. Here, we analysed whether tumour-to-background ratios determined by PET using the 18F-labelled PSMA-specific radiopharmaceutical [18F]F-DCFPyL were comparable to those determined by PET using [68Ga]Ga-PSMA-11. RESULTS: No differences could be observed between [68Ga]Ga-PSMA-11-PET and [18F]F-DCFPyL-PET regarding tumour-to-liver ratios or tumour-to-mediastinum ratios (e. g. tumour-to-liver ratios using maximum SUV of the tumour lesion for ultra-high definition reconstructed PET images with a median of 2.5 (0.6-9.0) on [68Ga]Ga-PSMA-11-PET vs. 2,0 (0.6-11.4) on [18F]F-DCFPyL-PET). However, significant differences were observed in terms of contrast-to-noise ratios, thereby demonstrating the better image quality obtained with [18F]F-DCFPyL-PET. CONCLUSIONS: Our data showed that [18F]F-DCFPyl-PET and [68Ga]Ga-PSMA-11-PET provide comparable tumour-to-liver and tumour-to-mediastinum ratios. Therefore, a tumour uptake of [18F]F-DCFPyL above the liver background, like using [68Ga]Ga-PSMA-11, can be considered as equally suitable for defining PSMA-positivity by a semiquantitative assessment based on the liver background, e. g. prior to radioligand therapy with 177Lu-labelled PSMA ligands. In addition, our data suggest a tending advantage of [18F]F-DCFPyL in terms of lesion detectability.

Ideas of Perfection and the Ethics of Human Enhancement.

Whatever ethical stance one takes in the debate regarding the ethics of human enhancement, one or more reference points are required to assess its morality. Some have suggested looking at the bioethical notions of safety, justice, and/or autonomy to find such reference points. Others, arguing that those notions are limited with respect to assessing the morality of human enhancement, have turned to human nature, human authenticity, or human dignity as reference points, thereby introducing some perfectionist assumptions into the debate. In this article, we ask which perfectionist assumptions should be used in this debate. After a critique of views that are problematic, we take a positive approach, suggesting some perfectionist elements that can lend guidance to the practice of human enhancement, based on the work of Martha Nussbaum's Capability Approach. We suggest that the central capabilities can be used to define the human aspect of human enhancement and thereby allow a moral evaluation of enhancement interventions. These central capabilities can be maximized harmoniously to postulate what an ideal human would look like. Ultimately, the aim of this article is twofold. First, it seeks to make explicit the perfectionist assumptions found in the debate and eliminate those that are problematic. Second, the paper clarifies an element that is often neglected in the debate about human enhancement, the view of the ideal human towards which human enhancement should strive. Here, we suggest that some central capabilities that are essential for an ideal human being can be maximized harmoniously and can therefore serve as possible reference points to guide human enhancement.

Human freedom and enhancement.

Ideas about freedom and related concepts like autonomy and self-determination play a prominent role in the moral debate about human enhancement interventions. However, there is not a single understanding of freedom available, and arguments referring to freedom are simultaneously used to argue both for and against enhancement interventions. This gives rise to misunderstandings and polemical arguments. The paper attempts to disentangle the different distinguishable concepts, classifies them and shows how they relate to one another in order to allow for a more structured and clearer debate. It concludes in identifying the individual underpinnings and the social conditions of choice and decision-making as particularly salient dimensions of freedom in the ethical debate about human enhancement.

Evaluating human enhancements: the importance of ideals.

Is it necessary to have an ideal of perfection in mind to identify and evaluate true biotechnological human "enhancements", or can one do without? To answer this question we suggest employing the distinction between ideal and non-ideal theory, found in the debate in political philosophy about theories of justice: the distinctive views about whether one needs an idea of a perfectly just society or not when it comes to assessing the current situation and recommending steps to increase justice. In this paper we argue that evaluating human enhancements from a non-ideal perspective has some serious shortcomings, which can be avoided when endorsing an ideal approach. Our argument starts from a definition of human enhancement as improvement, which can be understood in two ways. The first approach is backward-looking and assesses improvements with regard to a status quo ante. The second, a forward-looking approach, evaluates improvements with regard to their proximity to a goal or according to an ideal. After outlining the limitations of an exclusively backward-looking view (non-ideal theory), we answer possible objections against a forward-looking view (ideal theory). Ultimately, we argue that the human enhancement debate would lack some important moral insights if a forward-looking view of improvement is not taken into consideration.

Human enhancement and perfection.

Both, bioconservatives and bioliberals, should seek a discussion about ideas of human perfection, making explicit their underlying assumptions about what makes for a good human life. This is relevant, because these basic, and often implicit ideas, inform and influence judgements and choices about human enhancement interventions. Both neglect, and polemical but inconsistent use of the complex ideas of perfection are leading to confusion within the ethical debate about human enhancement interventions, that can be avoided by tackling the notion of perfection directly. In the recent debates, bioconservatives have prominently argued against the 'pursuit of perfection' by biotechnological means. In the first part of this paper, we show that--paradoxically--bioconservatives themselves explicitly embrace specific conceptions of human perfection and perfectionist assumptions about the good human life in order to argue against the use of enhancement technologies. Yet, we argue that the bioconservative position contains an untenable ambiguity between criticising and endorsing ideas of human perfection. Hence, they stand in need of clarifying their stance on human perfection. In the second part of the paper, we ask whether bioliberals in fact (implicitly) advocate a particular conception of perfection, or whether they are right in holding that they do not, and that discussing perfection is obsolete anyway. We show that bioliberals also rely on a specific idea of human perfection, based on the idea of autonomy. Hence, their denial of the relevance of perfection in the debate is unconvincing and has to be revised.