Personalization of treatment response through the use of on-treatment biomarkers is the future of theranostics and marks a key advantage of theranostics treatments over other systemic cancer therapies. Imaging after 177Lu-targeted radionuclide therapy with either planar imaging or SPECT is the standard of care in theranostics to confirm the therapeutic dose delivered and for safety reasons, including dosimetry (1). However, SPECT/CT has the potential for providing significantly more value to patient care than simply estimating safe dose limits. The improvements in SPECT/CT technology and optimizing acquisition protocols means SPECT/CT is now capable of evaluating treatment response. As SPECT/CT can be undertaken after each therapy dose time point, it allows the development of both early and interim response criteria that can help us optimally personalize treatments. Utilizing imaging data from the therapy itself to guide treatment response is an elegant biomarker solution, unique to theranostics, that warrants careful evaluation before routine clinical implementation.
PET using 18F-FDG, 68Ga-DOTA, and 68Ga- or 18F-prostate-specific membrane antigen (PSMA) PET have all been shown to have value as interim response biomarkers, aiding optimization of personalized care for patients on both systemic and theranostics therapies (2–4). Compared with SPECT/CT, PET/CT has significantly higher spatial resolution, allowing evaluation of subcentimeter lesions, accurately restaging patients to a high degree of accuracy. However, there are significant limitations to the use of PET in interim response evaluation. PET is expensive, with limited availability in many countries. It requires separate visits by patients already burdened with heavy timetables while dealing with illness and fatigue. Undertaking multiple-time-point PET imaging in patients on treatment is not feasible at most institutions. In contrast, SPECT/CT requires no additional radionuclide injections, may be performed on widely available SPECT/CT-capable γ-cameras, and may be undertaken at serial time points within a few hours after each theranostic dose. Such advantages mean SPECT/CT should be seriously considered for evaluation of treatment response despite its more limited spatial resolution. Do we need optimal spatial resolution for evaluation of treatment response? Probably not, with identification of newly visualized lesions on serial imaging and progression of larger lesions being more important for clinically relevant disease progression than the detection of small lesions.
Evidence for the use of SPECT/CT in evaluation of treatment response with targeted radionuclide therapy is growing. Pathmanandavel et al., in the prospective 56-patient LuPIN trial utilizing 177Lu-PSMA-617, demonstrated that a change in SPECT-derived total tumor volume between dose 1 and dose 3 177Lu-PSMA SPECT/CT was prognostic for progression-free survival (PFS) (5). Any increase in SPECT/CT tumor volume was associated with a shorter prostate-specific antigen (PSA) PFS of 4.5 versus 7.1 mo for those with either stable or reduced tumor volume (hazard ratio, 4.1 [95% CI, 1.5–11.2]; P = 0.006). A tumor volume increase of 30% or more on SPECT was also associated with shorter PSA PFS (hazard ratio, 3.3 [95% CI, 1.3–8.6]; P < 0.02). Importantly, changes in PSMA SUVmean or SUVmax were not prognostic for either PSA PFS or overall survival.
SPECT/CT can identify patients who will not benefit from 177Lu-PSMA-617 as early as 6 wk after commencing 177Lu-PSMA therapy, immediately after the second cycle of 177Lu-PSMA. Identifying patients who have primary radiation-resistant disease is important as we consider how to best personalize treatments to optimize outcomes. If a patient has primarily radiation-resistant disease with early progression, consideration can be made to change treatment early by either upgrading to α-therapy or changing to an alternative systemic therapy, thereby increasing the chance of getting to another effective line of treatment (Fig. 1). In a clinical registry of 127 patients undergoing 177Lu-PSMA I&T therapy, John et al. demonstrated that any increase in total tumor volume between dose 1 and dose 2 177Lu-PSMA SPECT/CT was associated with significantly shorter PFS. If both PSA and PSMA tumor volume had increased by dose 2, PSA PFS was 2.8 mo compared with 9 mo in those patients who demonstrated a reduction in both SPECT/CT tumor volume and PSA at 6 wk (6). Multiple subsequent retrospective studies have now confirmed that both increased tumor volume or new lesions at 6 wk of treatment are prognostic for short PFS and overall survival (7–9).
Proposed biomarker-guided patient management schema. TTV = total tumor volume.
177Lu-PSMA SPECT/CT changes management in up to 49% of patients undergoing 177Lu-PSMA therapy (9). It does this by allowing better characterization of treatment response than serial PSA alone. Patients with marked reduction in both PSA and SPECT tumor volume have highly radiation-sensitive disease and longer PFS and overall survival than patients with persistently high SPECT tumor volume despite reductions in PSA (Fig. 2) (10). In those patients with progressive disease and a rising PSA, 177Lu-PSMA SPECT/CT helps further characterize the pattern of progression (Fig. 3). Sites of oligometastatic progression on SPECT/CT may benefit from external-beam radiotherapy to those sites of progression and continue treatment. Patients with persistently PSMA-positive disease progression may benefit from transitioning to α-targeted radionuclide therapy to better manage radiation resistance, whereas those with low PSMA or no PSMA expression progression should change to an alternative systemic therapy.
A 94-y-old man with metastatic castration-resistant prostate cancer previously on enzalutamide and deemed not fit for chemotherapy received 2 doses of 177Lu-PSMA I&T 6 wk apart. These SPECT/CT images show reduction in volume from 1,047 to 18 mL, and PSA dropped from 157 to 5.6 ng/mL. Because of these results, patient paused treatment, recommencing 14 mo later at PSA rise. Patient received 6 doses over 3 y, with prolonged treatment pauses due to marked PSA and SPECT tumor volume responses.
A 75-y-old man with progressive metastatic castration-resistant prostate cancer previously treated with docetaxel and enzalutamide was referred for 177Lu-PSMA I&T therapy. Two doses of 177LuPSMA I&T, 8 GBq, were administered at 6-wk intervals. 177Lu SPECT/CT shows multiple new lesions with volume increasing from 377 mL at dose 1 to 495 mL by dose 2. PSA had also risen from 38 to 75 ng/mL in same time frame. Patient commenced cabazitaxel chemotherapy in lieu of further doses of 177Lu-PSMA.
Evidence for the value of SPECT/CT has largely been developed with the 177Lu-PSMA therapy clinical domain, including 67Cu and 212Pb (11), and although it currently shows value in prostate cancer, will likely show value agnostic of the receptor targeted. Further work should be done to evaluate the use of SPECT/CT for treatment response in prospective trials across the theranostics landscape and into effective quantification tools to better guide clinical decision making. Composite biomarker-guided therapy to better personalize and improve patient outcomes is the glowing future of theranostics.
Footnotes
Published online Jan. 2, 2025.
- © 2025 by the Society of Nuclear Medicine and Molecular Imaging.
REFERENCES
- Received for publication September 1, 2024.
- Accepted for publication November 14, 2024.
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