As an aggressive malignancy arising from epithelial cells of the lung, diagnosis of small cell lung cancer (SCLC) is usually established by CT followed by histologic confirmation or 18F-FDG PET to assess widespread disease.1 Although treatment-naive SCLC is sensitive to the immune checkpoint inhibitor atezolizumab plus chemotherapy (CTx), most patients experience relapse within 1 year.2 Other therapeutic options in advanced disease include external beam radiation (RTx) of the thorax,3 whereas prophylactic cranial irradiation to avoid occurrence of brain metastases is linked to severe adverse effects including neurotoxicity.3 Moreover, tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors have also achieved encouraging outcome benefits but are also associated with an increased risk of malignant transformation, ultimately leading to acquired resistance.4–6 Thus, despite this plethora of therapeutic options in patients with SCLC, novel targets or more effective sequencing strategies of existing treatments are intensively sought, for example, by a comprehensive imaging readout.
Among others, somatostatin receptor (SSTR) subtype 2 is linked to adverse outcome in SCLC, whereas downregulation of this receptor profile is associated with an increasing rate of apoptosis in neuroendocrine neoplasm (NEN) cell lines.7 Despite such encouraging results, less than 50% of harvested SCLC specimens revealed relevant SSTR expression,7 and thus, identification of those high-risk individuals would be of importance, preferably by providing a noninvasive whole-body assessment of the current receptor status. Somatostatin receptor–directed PET radiotracers such as (1,4,7,10-tetraazacyclododecane-N,N′,N″,N‴-tetraacetic acid-d-Phe(1)-Tyr(3)-octreotide/-octreotate ([68Ga]DOTATOC/-TATE)) may provide such an elaborated receptor profiling,8,9 which then allows to schedule patients for peptide receptor radionuclide therapy (PRRT) using β-emitting equivalents.10,11 Of note, such image-piloted strategies in the context of SCLC have already resulted in partial response or even stable disease in selected cases.8,11
Despite those encouraging results for diagnosis and treatment, the added clinical value of SSTR PET/CT for SCLC has not been elucidated yet, including change in management after hybrid imaging or the rate of controlled disease once those therapeutic modifications have been implemented. In the present study investigating one of the largest cohorts of SCLC patients imaged with [68Ga]DOTATOC to date, we first compared the diagnostic performance of the CT portion relative to SSTR PET, thereby allowing to determine the incremental value of hybrid imaging in the workup of SCLC. In addition, we aimed to determine the rate of therapeutic changes after conducting PET/CT. Last, we also assessed the beneficial effects of PET/CT-triggered treatment modifications on disease stabilization and overall survival (OS).
MATERIALS AND METHODS
As this was a retrospective investigation, the local ethics committee of the University Hospital Würzburg waived the need for further approval (waiver no.: 2021041503). Somatostatin receptor–directed PET/CT was performed because of suspected tumor progression potentially requiring a change in therapy or to determine a rationale for PRRT. Informed consent on diagnostic procedures was obtained from all subjects involved in the study.
One hundred patients (37 female patients) between 41 and 91 years old (62.0 ± 9.4 years) with a histologically confirmed SCLC were included. Patients were referred to our department for staging (4/100 [4%]) or restaging (96/100 [96%]). Parts of this cohort have been investigated,8 but without performing a head-to-head comparison between PET and CT, without assessing change in management triggered by hybrid imaging or determining its impact on disease control and OS.
Imaging Procedures and Analysis
All patients received SSTR-directed PET/CT with an average activity of 120 ± 24 MBq [68Ga]DOTATOC, and imaging was then performed at 1 hour postinjection. PET/CT was conducted either on a Siemens Biograph mCT 64 or 128 (Siemens Healthineers, Erlangen, Germany). Whole-body imaging was performed from the complete skull to midthigh. All PET images were reconstructed iteratively as implemented by the manufacturer (Siemens Healthineers). For further details, refer to Serfling et al.12 In brief, we applied a 3D mode (200 × 200 matrix, 3 iterations, minimum 21 subsets, Gaussian filtering 2 mm). For CT, the following parameters were used: reference tube current 35 mAs (low-dose scans; 160 mAs, full dose scans), minimum 100-keV tube voltage, minimum 0.8 pitch, and rotation time of 0.5 second, along with reconstructed axial slice thickness, 3.0–5.0 mm.13 Assessments of CT, SSTR PET, and hybrid imaging were conducted by an expert reader and verified by a second experienced observer in inconclusive cases, and superiority of the respective image modality was then determined, as described by Rowe et al.14
Treatment Modifications After SSTR-Directed PET/CT
After molecular imaging, treatment changes were determined by assessing treatment modifications before and after SSTR-directed imaging. Change in existing CTx regimen or initiation of novel CTx, PRRT, or TKI was subsumed as systemic treatment, whereas active surveillance or RTx was classified as nonsystemic therapy.
Impact of Management Change on Outcome
Assessing the impact of management change on outcome, we also investigated first follow-up imaging after SSTR PET/CT. In this regard, we used RECIST criteria 1.1, and stable, partial, or complete response was then subsumed as controlled disease.12,15
Descriptive statistics are presented as mean ± SD. Kaplan-Meier curves and log-rank comparisons were used to compare OS in subjects allocated to the no-change versus change groups (including systemic and nonsystemic treatment modifications). Overall survival was defined until date of death or last available clinical follow-up in our electronic health archive. We present the median in days with respective hazard ratios (HRs) and 95% confidence interval (95% CI). P < 0.05 was considered statistically significant. GraphPad Prism (9.3, GraphPad Software, San Diego, Calif) was used to conduct the herein described statistical analyses.
SSTR PET/CT Identified Tumor Involvement in All Subjects, Whereas SSTR PET Alone Provided Additional Information on Skeletal Disease
Somatostatin receptor PET/CT detected the following sites of disease. On a patient-based level, hybrid imaging identified tumor involvement in all 100 subjects (100%). An organ-based assessment revealed that 84 of 100 (84%) had a primary tumor, 80 of 100 (80%) had lymph node (LN) involvement, and 40 of 100 (40%) were affected with liver lesions, followed by osseous tumor sites in 39 of 100 (39%) and lung metastases in 14 of 100 (14%).
In a head-to-head comparison of PET versus CT, the latter imaging component was slightly superior in the detection of the primary (CT, 43/84 [51.2%] vs SSTR PET, 34/84 [40.5%]), whereas in the remaining 7 of 84 (8.3%), both imaging modalities revealed equal findings. Conventional imaging was also superior in the detection of LN (CT, 31/80 [38.8%] vs SSTR PET, 14/80 [17.5%]; equal, 35/80 [43.7%]) and liver metastases (CT, 29/40 [72.5%] vs SSTR PET, 8/40 [20%]; equal, 3/40 [7.5%]). In contrast, SSTR PET was superior for the diagnosis of skeletal metastases (CT, 12/39 [30.8%] vs SSTR PET, 19/39 [48.7%]; equal, 8/39 [20.5%]). For pulmonary metastases, the low number of findings did not allow for a comprehensive head-to-head comparison. Figure 1 displays a lesion-based distribution for CT and PET, respectively.
SSTR PET/CT Triggered Change in Management, Leading to Systemic Treatments in the Majority of Cases
In 41 of 100 (41%), no change in treatment was recorded after conducting SSTR PET/CT, with CTx in 29 of 41 (70.7%), RTx in 6 of 41 (14.6%), surveillance in 4 of 41 (9.8%), and TKI in 2 of 41 (4.9%).
Fifty-nine of 100 (59%) experienced change in treatment after conducting SSTR PET/CT. Of those individuals, 44 of 59 (74.6%) received systemic treatment after hybrid imaging, with the remaining 15 of 59 (25.4%) scheduled for nonsystemic therapy. In the latter group, 13 of 15 (86.7%) received local RTx and active surveillance in 2 of 15 (13.3%). Individuals scheduled for systemic treatment after PET/CT, however, mainly received PRRT in 28 of 44 (63.6%), followed by novel CTx initiation in 10 of 44 (22.7%), change in CTx regimen in 3 of 44 (6.8%), and initiation of TKI in the remaining 3 of 44 (6.8%). Figure 2 provides an overview of patients without and with change in treatment, with the latter group divided into systemic versus nonsystemic treatment after hybrid imaging.
PET/CT-Triggered Changes Achieved Disease Control, But Did Not Prolong OS When Compared With Subjects Not Experiencing Treatment Modifications
Among the entire cohort, follow-up imaging was available in 84 of 100 (84%) patients, and disease control was achieved in 24 of 84 (28.6%).
Within the subgroups with and without treatment changes, controlled disease was achieved as follows: Among those 59 subjects of whom treatment was altered, 53 of 59 (89.8%) also had available follow-up. Within this subgroup, the respective disease control rate was 14 of 53 (26.4%). In 41 patients with no recorded change after SSTR PET/CT, 31 of 41 (75.6%) had available follow-up, and disease control rate was then 10 of 31 (32.3%).
However, when compared with subjects with no change (171 days), patients with change to systemic treatment did not exhibit longer OS (155 days; HR, 0.94; 95% CI, 0.53–1.67; P = 0.83). This also applied to individuals changed to nonsystemic treatment (210 days; HR, 0.67; 95% CI, 0.34–1.34; P = 0.22 vs no change; Fig. 3). Figure 4 displays 2 subjects who experienced change in management after conducting SSTR PET/CT. Patient in Figure 4A was scheduled for systemic therapy (initiation of PRRT), whereas patient in Figure 4B received nonsystemic treatment (RTx) after molecular imaging. Overall survival was comparable among both patients.
Investigating one of the largest cohorts of patients affected with SCLC, complementary information on the current disease status was achieved by both imaging components of SSTR PET/CT, thereby providing a comprehensive readout of the locoregional and extrathoracic disease burden. In addition, hybrid imaging triggered change in management in more than half of the cases, which led to disease stabilization in more than one-fourth of the subjects. Of note, in the subgroup experiencing change in management, most patients were then scheduled for systemic treatment, mainly PRRT. However, independent of the initiated treatment (systemic vs nonsystemic), survival was comparable to subjects without change after PET/CT. Taken together, implemented management changes based on hybrid imaging achieved disease control without prolonging survival. Nonetheless, the high number of individuals selected for PRRT based on PET/CT may trigger novel therapeutic strategies, for example, by targeting SSTR and oncogenic transcription using recently approved targeted therapies.2,16 In this regard, achieved synergistic antitumor effects may then also increase survival, which is currently not accomplished by respective monotherapies.11,17
Among neuroendocrine malignancies, approximately 20% accounts for pulmonary NEN, with SCLC representing the largest subgroup.18,19 Also referred to as neuroendocrine carcinomas,19 SCLCs are characterized by a mitotic count of >10 per 2 mm2 (average of 40) according to the World Health Organization.18,20 Such highly aggressive NEN types, however, are characterized by varying expression of SSTR, irrespective if primaries are located in the digestive21 or pulmonary system.7,22 In our study, SSTR PET was superior relative to CT for assessing tumor burden in the skeleton. This is in line with a head-to-head comparison between [68Ga]DOTATOC PET and CT, which enrolled a mixed cohort of digestive and pulmonary NENs and also reported on superior accuracy for bone lesions by the molecular imaging component.23 As a possible explanation, skeletal alterations may appear rather subtle and thus may be more likely missed on morphological imaging.22,23 Nonetheless, in patients affected with SCLC, hybrid imaging achieves synergistic diagnostic accuracy, thereby providing a complementary, whole-body readout of the current disease status.
Somatostatin receptor–directed PET/CT is also used to identify subjects eligible for PRRT in a theranostic setting using radiolabeled, “hot” somatostatin analogs.10 In our investigation, the majority of patients with systemic treatment changes received PRRT after imaging, further demonstrating the added clinical benefit of SSTR PET/CT to triage patients for therapy beyond staging purposes. Nonetheless, a substantial portion of subjects was not scheduled for PRRT based on imaging, and thus, we also aimed to determine the clinical value of SSTR PET/CT in those individuals not receiving “hot” somatostatin analogs. In this regard, we divided patients into subgroups who had experienced either no change or change in management after hybrid imaging, with the latter group further allocated into systemic versus no systemic treatment. Beyond PRRT, other systemic therapies included CTx, or TKI, whereas the group allocated into no systemic treatment included active surveillance or local RTx. Surprisingly, although disease control was achieved in a substantial portion of patients, individuals allocated to the no-change group experienced comparable survival benefits relative to subjects receiving systemic or nonsystemic therapies after imaging. Thus, despite an optimal readout based on hybrid imaging even in the skeleton, triggered management changes were not associated with longer survival. Those findings, however, may be partially explained by the limited treatment options in SCLC when those PET/CTs were conducted. Recent years, however, have witnessed the introduction of novel targeted therapies, including the selective inhibitor of RNA polymerase II lurbinectedin. This marine-derived drug has recently received accelerated approval of the US Food and Drug Administration based on results of a single-arm trial,16 but failed to prolong OS when compared with best supportive care based on physician's choice.18 Although the vast majority of our patients had received SSTR PET/CT for restaging in a relapsed setting after second-line therapy and thus may have been eligible for lurbinectedin, this drug was not available at time of imaging in our study. This also applies to atezolizumab, which is nowadays used as first-line treatment in patients with SCLC.2 Thus, future studies may also determine the impact of hybrid imaging as a therapeutic decision aid in subjects for whom those novel drugs would be available. Moreover, within the systemic therapy group, a substantial fraction of patients (>63%) were scheduled for PRRT, thereby demonstrating that SSTR PET/CT can identify a relevant number of patients eligible for such a theranostic strategy. As such, future studies may also determine whether SSTR-targeted molecular imaging may allow to initiate combined-therapeutic strategies to achieve synergistic, tumor-targeting effects, for example, PRRT plus lurbinectedin. In this regard, such a “dual hit” of selective inhibition of SSTR and oncogenic transcription may then also prolong survival, which is currently not achieved by those therapies alone.11,17 Limitations of the present investigation include the low number of analyzed subjects, in particular for the different subgroups. Thus, future studies enrolling a larger number of individuals are needed, preferably based on a sample size analysis.
In SCLC patients scheduled for SSTR PET/CT, hybrid imaging provides a complementary readout of the current disease status, with SSTR PET providing superior performance in the skeleton. Somatostatin receptor–targeted PET/CT also led to management changes in 59% of the cases, which achieved disease control in 26% of the subjects. Individuals experiencing no change in treatment after imaging, however, demonstrated comparable survival relative to the change group, which was also independent from the type of initiated treatment (systemic vs no systemic therapy). Further research is needed to evaluate the beneficial impact of SSTR-directed PET/CT, for example, to determine the impact of hybrid imaging on patients who will be scheduled for recently introduced, second-generation, targeted therapies. Last, within the subgroup experiencing systemic treatment alterations after PET/CT, the highest portion of patients was scheduled for PRRT, thereby favoring a more widespread adoption of this therapeutic option in the clinic. As such, future studies may also determine whether such image-guided strategies targeting SSTR may then achieve synergistic antitumor effects, for example, when combined with novel, targeted drugs such as lurbinectedin. Those combined concepts may then overcome limitations of respective monotherapies, which currently do not achieve longer survival.
The authors thank Dr Dirk Mügge, Adelebsen, for statistical advice.
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