In a prospective observational cohort of patients with mCRPC at various stages of the disease who underwent 68Ga-PSMA-617 PET/CT, we observed a significant tumour sink effect in healthy tissues, i.e., the more the tracer is sequestered by the tumour, the less it is available to accumulate in these tissues. As introduced earlier, we believe that the most significant clinical implication of the tumour sink effect is that, in PSMA RPT, patients with a large tumour burden will likely be undertreated, from a dosimetry perspective, when a fixed activity is administered, such as per the currently approved regime of 177Lu-PSMA-617 [2]. Indeed, the tumour sequestration spares organs at risk (i.e., the parotid, the kidney, and the bone marrow, for which blood is often considered a dosimetric surrogate) from radiation exposure by removing a portion of the radiopharmaceutical from the blood stream. Consequently, when they are treated with a one-size-fits-all RPT regime, patients with a larger tumour burden, who tend to be more symptomatic and in greater need of therapeutic efficacy, may not receive the maximum injected activity – hence tumour absorbed dose – that they could tolerate. However, these are the patients who could potentially benefit the most from dosimetry-based, personalised RPT, especially since they have a poor prognosis [3, 21]. Further research validating the tumour sink effect on healthy tissues dosimetry in patients treated with PSMA RPT is warranted, paving the way to clinical trials of personalised PSMA PRT.

The sink effect is not limited to PSMA theranostics. We previously reported on the tumour sink effect in patients with neuroendocrine tumour undergoing 68Ga-DOTATATE PET/CT [4]. Our initial results, using a renal dosimetry-based regime of peptide receptor radionuclide therapy with 177Lu-DOTATATE, showed that it is possible to safely escalate administered activity and tumour absorbed dose in most patients, including those with larger tumour burden [22]. This approach could be translated to PSMA RPT. However, caution is advised in cases of sink effect resulting from extensive bone metastasis, which is more prevalent in prostate cancer than in neuroendocrine tumour patients. Indeed, while in such cases the bone marrow would receive lower self-dose and cross-dose from the blood, the cross-dose from bone tumour infiltration may be high, counteracting the bone marrow sparing by the sink effect. On the other hand, patients with extensive soft-tissue metastasis (with or without limited bone disease) clearly have the potential to draw more benefits from personalised RPT without risking undue toxicity. Further research is warranted on how to best use PSMA PET (e.g., TLF and/or healthy tissue uptake) to predict specific absorbed doses and, ultimately, to personalise the first cycle of PSMA RPT [23].

Others have reported on the sink effect on PSMA PET and we have summarized key features and results of their studies in Table 5. Unlike other researchers who analysed retrospective series, we derived our results from a prospective cohort. We used 68Ga-PSMA-617 in the 3TMPO study, a PSMA radioligand that is less commonly used in the clinics than 68Ga-PSMA-11 and 18F-DCFPyL, but which has a similar biodistribution [24, 25]. Thus, our results supplement those of others, confirming that the sink effect can be observed with all these urea-based radioligands, including 68Ga-PSMA-617, which shares the same pharmaceutical moiety as 177Lu-PSMA-617. Others have mainly used the MTV metric, or a visual categorical equivalent, to quantify or stratify tumour sequestration. While MTV is likely the most significant driver of the sink effect, intensity of uptake is the other defining dimension thereof. In this respect, Burgard et al. used TLA, the product of MTV and SUVmean, which is a more comprehensive metric for the purpose [13]. However, both MTV and TLA are contingent on knowledge of body weight to determine the relative magnitude of the tumour burden (e.g., for a given MTV or TLA, the tumour is twice as burdensome for a 50 kg patient than for a 100 kg patient). Instead, we propose TLF as a simplified, more interpretable, and direct metric of the tumour sink effect that is independent of weight and may facilitate interpatient comparisons [15]. In principle, TLF directly represents the proportion by which the healthy tissue uptake would be decreased because of cancer load. As for the metric of organ uptake, we primarily used %IA/cm3 rather than SUVmean, as others did, because the former is more directly related to the specific absorbed dose (i.e., Gy/GBq, or Gy per a fixed activity) when extrapolating to RPT. Indeed, assuming equal biokinetics, the specific absorbed doses in the tissues of patients of varied body weight will be proportional to %IA/cm3 but not to SUV. Notably, all but one group observed a statistically significant relationship describing a tumour sink effect in at least one healthy tissue of interest with direct relevance to PSMA RPT. Werner and al. were the exception and this is likely because their analysis was restricted to patients with low-volume disease (< 100 cm3) [12]. Observation of a meaningful sink effect obviously requires inclusion of patients with a large tumour burden.

A larger volume of distribution and a faster excretion from the body of virtually any radiopharmaceutical will inevitably contribute to lowering its concentration in blood and tissues. Accordingly, in patients with neuroendocrine tumours, we have found that body habitus and renal function were factors affecting the biodistribution and dosimetry of DOTATATE compounds in tissues of interest including the kidney [4, 26, 27]. In prostate cancer patients, using quantitative SPECT at ~ 48 h after 177Lu-PSMA-I&T RPT, we found that body habitus and renal function were both significantly and negatively correlated with specific absorbed dose estimates for the bone marrow and the kidney [14]. In accordance with our data, Violet et al. showed a significant absorbed dose reduction in parotid glands with increasing BSA [5]. In this study, we observed a strong correlation between body habitus indices or eGFR and activity concentration of 68Ga-PSMA-617 in the blood (as a surrogate for bone marrow), but not in the kidney. We hypothesize that at an early imaging timepoint (~ 60 min. for PET/CT), more complex and competing rapid kinetics at the renal cell level, superimposed over excreted activity into nephron tubules, may blur the relationships between apparent renal activity concentration and these patient characteristics. Moreover, the correlation between body habitus indices and renal SUVmean was revealed as significantly positive (Supplemental Table 1), pointing at body weight as an overestimated volume of distribution for 68Ga-PSMA-617, which does not exhibit a particular tropism for fatty tissues. This also raises concerns about the use of tumour SUV cutoffs for patient selection for RPT (e.g., SUVmax ≥ 20 in at least one lesion and ≥ 10 in all other lesions in the TheraP trial) [28], as overweight patients would technically be favoured over underweight patients in terms of access to the RPT. Normalizing SUV by LBW or BSA may help to reduce this bias [29, 30], although the use of a SUV ratio (e.g., uptake relative to the liver) may be preferable as it is independent of body habitus. We are currently conducting more in-depth analyses regarding these issues, which will be the topic of upcoming publications.