Recent phase III trials with immune-checkpoint inhibitors (ICIs) for advanced non–small cell lung cancer (NSCLC) included a small number of patients with stable and previously treated brain metastases.1,2 Systemic pseudoprogression, defined as initial radiological enlargement of lesions followed by spontaneous decrease in size or stabilization, due to immune-cell infiltrate, is reported to occur in approximately 5% of NSCLC patients.3–5 The Immunotherapy Response Assessment for Neuro-Oncology criteria have been developed to evaluate response to immunotherapy in the brain. Based on the Immunotherapy Response Assessment for Neuro-Oncology criteria, suspicion of progressive disease within 6 months after the start of immunotherapy (eg, tumor progression or appearance of new lesions) requires confirmation of tumor progression with further follow-up imaging, while immunotherapy should be continued until true progression is confirmed.6 One case of pseudoprogression of brain metastases under immunotherapy has been described in a melanoma patient.7 Pseudoprogression may also occur with gliomas after effective treatment.8–11 High-dose radiotherapy as radiosurgery or stereotactic radiotherapy may induce pseudoprogression in 2% to 30% of cases.12 Moreover, higher rates of symptomatic radiation necrosis have been reported after stereotactic radiotherapy in patients receiving immunotherapy.13
PET using 18F-FDG as radiotracer is indicated for whole-body assessment of NSCLC patients but is not as useful for brain metastases, owing to high physiologic background activity there. O-(2-(18F)-fluoroethyl)-L-tyrosine PET (18F-FET PET) might discriminate pseudoprogression from real progression of brain lesions, based on uptake ratios and dynamic uptake patterns.14 FET uptake occurs through large neutral amino acid transporters (LATs)15 (Fig. 1), which are expressed on tumor cells and immune cells. Fluoroethyltyrosine is transported by LAT2, which is not expressed in inflammatory cells, but to a high extent on tumor cells (Fig. 2). Thus, FET is selectively taken up by tumor cells, which16–18 advocates FET as a valuable tracer for the discrimination of neoplastic and inflammatory lesions.19,20
The aim of this study was to evaluate the ability of 18F-FET PET to distinguish pseudoprogression from real progression of brain metastases in NSCLC patients treated with radiotherapy and immunotherapy.
PATIENTS AND METHODS
Study Design and Patients
We evaluated the use of 18F-FET PET in cases with documented progression of brain metastases on MRI in a retrospective cohort of 53 patients with NSCLC receiving ICIs and radiotherapy of brain metastases at the University Hospital of Zürich between June 2015 and January 2019. Our study was approved by the local ethics committee (EK-ZH-2017-00152 and EK-ZH-2018-01919) and is in accordance with local laws and regulations.
All MRIs were performed as standard of care between 6 and 8 weeks after the last radiotherapy, including the following pulse sequence set: T2-weighted, FLAIR-weighted, susceptibility-weighted, T1-weighted with and without gadolinium contrast and diffusion-weighted images (Skyra Magnetom 3 T [Siemens, Forchheim, Germany]; Ingenia 3 T [Philips, Best, The Netherlands]).
18F-FET PET examinations were acquired using a Discovery 690 Standard scanner (GE Healthcare, Waukesha, WI) or a Signa PET/MR scanner (GE Healthcare). A standardized dose of 130 MBq of 18F-FET was injected. The dynamic 18F-FET PET acquisition started either immediately (PET/MR) or at 20 minutes after tracer injection (PET/CT), using eight or four 5-minute frames, respectively. For assessing the dynamic 18F-FET uptake pattern, the 4 frames from 20 to 40 minutes were plotted, following the recommendation of the 2018 joint Response Assessment in Neuro-oncology/European Association of Neuro-Oncology/European Association of Nuclear Medicine guidelines.21–24 The dynamic FET uptake pattern, SUVmax, and mean and maximum target-to-background ratio (TBRmean, TBRmax), as well as time-to-peak (TTP) were analyzed. Based on previous publications,25,26 the following parameters were considered to indicate progression rather than pseudoprogression: TBRmean greater than 1.95 with 18F-FET washout or plateau uptake pattern or TBRmax greater than 2.55, regardless of uptake pattern, as well as a shorter TTP. Follow-up MRI was routinely performed 4 to 8 weeks after 18F-FET PET.
Forty-one (77.4%) patients had adenocarcinoma, 9 (17%) had squamous cell carcinoma, 2 (3.8%) had undifferentiated carcinoma, and 1 (1.9%) had large cell neuroendocrine carcinoma. Thirty-three patients (62.3%) were treated with nivolumab, 12 (22.6%) with pembrolizumab, 5 (9.4%) with ipilimumab-nivolumab, 2 (3.8%) with atezolizumab, and 1 (1.9%) with nivolumab and anti–LAG-3 antibody. Twenty-three patients (43.4%) were alive at the last follow-up, and 30 (56.6%) died due to NSCLC. Among these 23 alive patients, 11 (47.8%) had a metabolic complete remission of systemic disease, 10 (43.5%) were in partial remission, and 2 (8.7%) had progressive disease at the end of follow-up. The median overall survival from the beginning of immunotherapy was 17.7 months (95% confidence interval, 13.4–22.1 months). The median overall survival among the 23 alive patients was 20.7 months (range, 2.49–44.3 months).
All patients underwent radiotherapy for brain metastases. Thirty-two (60.4%) received a single course, 16 (30.2%) received 2 courses, and 5 (9.4%) received 3 or more, with a total of 80 treatments performed. Forty-three treatments (53.7%) consisted of radiosurgery, 25 (31.3%) of hypofractionated stereotactic radiotherapy, and 12 (15%) of whole-brain radiotherapy.
From the cohort of 53 patients, an MRI after radiotherapy showed in 30 patients (56.6%) progression of at least 1 treated metastases, and in 18 (34.0%) cases a partial response based on the Response Assessment in Neuro-oncology–Brain Metastases criteria. Of the 30 patients with MRI-documented progression, 18F-FET PET was performed in 11 subjects, between 2 and 4 weeks after the MRI. The decision of acquiring an 18F-FET PET was based on the absence of neurological symptoms or presence of systemic response and physicians' decision. No additional MRI criteria were used. In 9 of 11 patients (81.8%), 18F-FET PET suggested pseudoprogression rather than progression, which was confirmed by MRI 4 to 8 weeks later. In 1 of 11 patients (9.1%), 18F-FET PET suggested true progression, which was, however, not confirmed by follow-up MRIs during 20 months.
In the remaining subject (9.1%), 18F-FET PET results were inconclusive because of borderline TBRmax and a plateau pattern in the dynamic images; this case was confirmed as true progression at follow-up (Figs. 3A–D, Figs. 4A–C).
Of the 19 patients, where no 18F-FET PET was performed, follow-up MRI showed pseudoprogression in 5 cases (26.3%) (Fig. 4).
Altogether, from 30 patients with initial MRI-based diagnosis of progression, 50% had a pseudoprogression (Fig. 5). The median follow-up time after 18F-FET PET was 7.8 months (range, 2.3–47 months). During this period, follow-up MRIs were performed at least every 3 months. 18F-FET PET parameters are listed in Table 1.
Suspicion of progression of brain metastases may lead to discontinuation of an effective therapy, for example, immunotherapy, or provoke unneeded interventions. In our cohort of 30 patients with initially suspected progression in MRI, 23 were alive at the end of follow-up, thereof 11 (47.8%) had a complete remission of systemic disease and 10 (43.5%) were in good partial remission under continuing treatment with ICIs at the end of follow-up. It is therefore of paramount importance to use tools that accurately identify pseudoprogression in patients undergoing immunotherapy.
Pseudoprogression of brain lesions, observed as radiological enlargement followed by spontaneous decrease in size or stabilization, may occur after effective treatment, such as immunotherapy, radiation therapy, or a combination of both. In our cohort, all patients received both immunotherapy and brain irradiation; hence, observed pseudoprogressions in our cohort may be regarded as radiation necrosis. Martin et al13 have reported higher rates of radiation necrosis in patients undergoing brain-directed radiotherapy and simultaneous systemic immunotherapy.
The MRI-based assessment of irradiated brain metastases is challenging. Metastases typically cause a disruption of the blood-brain barrier, leading to contrast enhancement on MRI. The same mechanism is responsible for contrast enhancement of radionecrosis, making the differentiation between real progression and pseudoprogression difficult.
Perfusion-weighted MRI with dynamic susceptibility contrast technique is one of the most important methods to discriminate progression from radionecrosis.18 The relative cerebral blood volume was shown useful in the distinction of active tumor lesions and radionecrosis, with tumor exhibiting higher relative cerebral blood volume. Nevertheless, hypoxia due to radiation necrosis may also induce neoangiogenesis, making a proper distinction difficult.27 MRI spectroscopy using ratios of choline/creatine and/or choline/N-acetyl aspartate may contribute to a better distinction of radionecrosis, but is limited in small lesions and in the posterior fossa.18,28 A combination of 18F-FET PET and perfusion-weighted MRI was shown to improve the accuracy of glioma grading compared with MRI alone.29 Specific literature data on the use of this combined technique for radiation necrosis vs vital brain metastases are currently lacking.
18F-FET PET data are acquired dynamically during a comparably long time of at least 20 minutes. A continuous slow accumulation of tracer typically represents a disrupted blood-brain barrier, with the radiotracer being trapped in the interstitium. On the other hand, a rapid early uptake followed by washout of activity represents active transport, requiring vital tumor tissue.
In our series, pseudoprogression occurred in 50% of patients, who were previously diagnosed as progressive on MRI. This is a fundamental information for clinicians who may safely continue treatment without additional intervention on brain metastasis. In our study, 18F-FET PET, where performed, identified 90% of patients with pseudoprogression.
The limitations of our study are the comparably small number of patients and the clinical preselection of subjects who underwent 18F-FET PET, which relied on systemic response and absence of neurological symptoms. Another limitation is that we do not report on perfusion-weighted MRI. This is owing to our study design, because MRI (partly perfusion-weighted MRI) was used as identifier of progression before 18F-FET PET.
Our study indicates that the response assessment of brain metastases might require a closer investigation, as the expected rate of pseudoprogression in patients treated with both radiotherapy and immunotherapy is much higher compared with the rate expected after radiotherapy alone. This is the first study to investigate the role of 18F-FET PET in NSCLC patients treated with immunotherapy and radiotherapy for brain metastases, providing new insights about intracranial response and strong evidence for the use of this diagnostic tool. Based on our data, we have designed a prospective clinical trial comparing the use of MRI and 18F-FET PET in this population of patients.
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