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Advances in Radiotherapy
& Nuclear Medicine LuPSMA response patterns on PSMA PET

Table 4. Repeatability of TLW response pattern, SUV max, in identifying subtypes of progressive disease, including
SUV mean and tumor volume. Results presented as estimates progression with high versus low PSMA expression, and
with 95%CI) and p-values in brackets oligo-progressive disease. If progressive sites are identified
early, the treatment plan may be adjusted, for example, by
Measurement Absolute test‑retest Repeatability
difference* estimate adding a radiation sensitizer, changing the radionuclide,
SUVmax 0.67 (−0.47–1.82) (0.25) 0.96 (0.94–0.97) applying local treatment of oligo-progressive sites, or
utilizing an alternative systemic therapy. Heterogeneity
SUVmean 0.08 (−0.07–0.22) (0.31) 0.97 (0.96–0.98) of PSMA expression may be a mechanism of treatment
Tumor volume (mL) 10.33 (11.02–31.69) (0.34) 0.96 (0.94–0.97) resistance to Lu-PSMA-617. 22-26 In this cohort, we found
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TLW response pattern NA 0.93 (0.87–0.97) that the mean difference between SUV and SUV mean was
max
Note: * Indicates adjusted for lesion type. greater in “progressors” than in “responders,” indicating
Abbreviations: CI: Confidence intervals; NA: Not available; greater heterogeneity of PSMA expression in “progressors.”
SUVmax: Maximum standardized uptake value; SUVmean: Mean Combination approaches, such as 177 Lu-PSMA-617 with
standardized uptake value; TLW: Traffic light workflow.
enzalutamide as demonstrated in the ENZAp study, may be
used to overcome heterogeneous PSMA expression. 27
lesions were defined as those with a ≥30% increase in
either volume or PSMA SUV . “Progressors” in this cohort had a lower pre-treatment
max PSMA SUV and a smaller decline in PSMA SUV
Previous research has explored whole-body PSMA PET following treatment, reflecting less treatment-induced
max
max
quantitation for response assessment after Lu-PSMA-617 PSMA-avid cell death in these participants. Many sites
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therapy. However, measures such as TTV may misclassify of disease had persistently high PSMA SUV following
patients with mixed responses. 5,17-19 In this cohort, 43% treatment, with 61% of “progressors” above the LuPIN
max
(16/37) of participants had a decline in TTV despite having trial entry criteria. Persistently high PSMA expression may
new or progressing lesions on TLW. This study identified indicate radiation resistance, which might be overcome
that TLW response category is independently associated by alpha-emitting radioligands. 28-31 Further pre-clinical
with OS, with a trend toward worse survival in “low- and clinical work examining the radiobiology of prostate
volume progressors,” those with predominant treatment cancer treated with Lu-PSMA-617 is needed to support
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response but new or small-volume progressing lesions.
this hypothesis.
Within this cohort, TLW and RECIP 1.0 performed
This study used the TLW to assess post-treatment
similarly in prognostic models for OS (C-index, 0.70 and imaging; however, it may be more valuable to implement
0.75, respectively). Importantly, under RECIP 1.0 criteria, the TLW earlier in the treatment course as an early marker
51% (19/37) of participants were categorized as RECIP-SD. of response to guide treatment decisions. Ideally, response
However, TLW revealed that all these participants had assessment would be undertaken following cycle 1 or 2,
new lesions, with 16 of 19 showing new lesions despite allowing for a prompt change in treatment. If access to
reductions in TTV. This suggests that RECIP 1.0 does not 68 Ga-PSMA PET is limited, use of 177 Lu-single photon
capture the complexity of treatment response and may not emission CT for response analysis may be a lower-cost
sufficiently guide subsequent treatment decisions.
option. 32,33 Currently, the implementation of imaging
In contrast, TLW enables characterization of both analysis workflows such as TLW is limited by the cost
responding and progressive lesions. “Responders” (9/37) of software and clinician time to perform analyses, but
had higher pre-treatment PSMA SUV and greater post- automation of workflows continues to improve.
max
treatment declines in PSMA SUV , consistent with prior Further investigation of the prognostic potential of
max
studies showing that higher PSMA expression (SUV the TLW will require larger prospective cohorts. Our
max
and SUV mean ) is associated with improved response rates sample size limited the assessment of key subgroups,
to 177 Lu-PSMA-617 therapy. 20,21 The observed decline such as patients with visceral metastases. In addition, to
in SUV reflects treatment-induced death in PSMA- avoid multiple testing in a small sample size, we did not
max
expressing prostate cancer cells. investigate multiple thresholds to define “low-volume” and
Most patients (28/37) in this cohort had a mixed response “high-volume” disease progression. A larger sample size
to Lu-PSMA-617 therapy, with at least one site of progressive would allow further investigation to optimize these cutoffs.
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disease. TLW was able to recognize and characterize these Our study only included participants who completed post-
mixed responses, showing differences in OS between “high- treatment imaging, introducing potential survival bias
volume progressors” and “low-volume progressors.” I and limiting the generalizability of the observed treatment
addition, the lesion-specific data extracted from TLW assists response spectrum.

Volume 3 Issue 3 (2025) 50 doi: 10.36922/ARNM025110011