Exceptional Response to Lu-177 FAP 2286 Radioisotope Therapy in CNS Haemangiopericytoma: A Novel Therapeutic Breakthrough

INTRODUCTION

Solitary fibrous tumour (SFTs) are rare soft tissue tumours arising from mesenchymal cells, accounting for less than 2% of soft-tissue sarcomas.^[1] Intracranial involvement of solitary fibrous tumour is even more rare, with an incidence of less than 1% of all central nervous system (CNS) tumours. SFTs are graded from 1 to 3 under the 2021 WHO classification, with higher grades (2 and 3) having a greater likelihood of malignant behaviour, including higher recurrence and metastasis rates. Grade 3 SFTs, in particular, show a significantly worse prognosis.^[2] The optimal treatment strategy for CNS SFTs is maximally safe resection followed by adjuvant radiotherapy (RT), which offers good local control. In spite of this, higher-grade tumours or those with submaximal resection show local recurrence as well as distant failure. Currently, there are no established treatment options for recurrent cases, prompting the exploration of multiple therapeutic targets.^[3]SFTs are characterised by a substantial tumour stroma containing cancer-associated fibroblasts (CAFs) embedded within it. CAFs express Fibroblast Activation Protein (FAP) on their cell membranes, which are integral to cellular proliferation, migration, and neoangiogenesis. In recent decades, small inhibitory molecules have been developed that can be conjugated with radioisotopes of choice for both diagnostic imaging and therapeutic applications.^[4,5] FAP theranostics represents a distinctive methodology for the diagnosis and treatment of SFTs, wherein Gallium-68 labelled FAP molecules are utilised for diagnostic purposes and assessment of disease extent, followed by the same molecules being labelled with therapeutic isotopes such as Lutetium-177 or Yttrium-90 to target tumour sites accurately. Numerous studies have documented its efficacy and safety. However, its application in CNS SFTs is seldom addressed in the literature.^[6-9]

In this report, we present a unique case of CNS SFT that demonstrated recurrence following maximal safe resection and adjvant radiotherapy.

CASE REPORT

A 37-year-old female presented with one episode of seizures (generalised tonic - clonic) followed by a brief episode of unconsciousness. Baseline MRI revealed a lobulated extraaxial T2 iso to hypointense soft tissue lesion [Fig 1A] in the right parasellar region in the brain parenchyma, along with intense homogenous post-contrast enhancement and dural tail [Fig 1B, red arrow] along the right tentorium cerebelli. Preliminary diagnosis of meningioma was made. Patient underwent right pterional craniotomy, trans-sylvian approach, and subtotal resection of the lesion. Histopathological diagnosis was haemangiopericytoma/solitary fibrous tumour, WHO grade 3, CD34-positive, with a MIB-1 index of 10-12%. In view of aggressive and rare histology with significant residual disease, the patient was planned for adjuvant radiation therapy with a dose of 55.8 Gy in 31 fractions. The patient was kept on regular clinical-radiological follow-up with stable disease for 3 years. She was then lost to follow-up for a year and later presented with recurrent disease on MRI brain imaging. Since the patient had already undergone surgical debulking and RT, the recurrent tumour was not amenable to surgery or reradiation. The patient was referred to as Lutetium177 FAP 2286 therapy as a compassionate treatment option. A Gallium-68 FAP 2286 PET/CECT scan was performed to ascertain the feasibility of Lutetium177 FAP 2286 therapy.

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Fig 1: (A) MRI brain showing lobulated extra axial T2 iso to hypointense soft tissue lesion in the right parasellar region in brain parenchyma, along with (B) Intense homogenous post contrast enhancement and dural tail (red arrow) along the right tentorium cerebelli. MRI: Magnetic resonance imaging

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Fig 2A reveals baseline Gallium 68 FAP 2286 PET/CECT Maximum Intensity Projection (MIP) with focal intense FAP 2286 uptake in the brain, corresponding fused transaxial images reveal intense FAP 2286 uptake [Fig 2B] with SUVmax 126.9 in a homogeneously enhancing right parasellar mass measuring 2.6x2.1x2cm (TXAPXV) [Fig 2C]. Inferiorly, the mass was reaching till the right cavernous sinus [Fig 2D and E]. No extracranial metastasis was noted elsewhere in the whole body. Patient underwent two sessions of Lutetium177 FAP 2286 therapy (Dose ~ 7.4GBq/200mCi in each session) with a gap of 6-8 weeks between each session. Fig 2F reveals Gallium 68 FAP 2286 PET/CECTMIP image with focal uptake of FAP 2286 in the brain. Corresponding fused transaxial image [Fig 2G and H] shows FAP 2286 uptake with SUVmax 19.1 in enhancing residual lesion involving right parasellar region, measuring 2x1.5x1.8cm [Transverse x Anteroposterior x Vertical (T x AP x V)]. Previously seen FAP uptake and contrast enhancement along the lesion, inferiorly involving the right cavernous sinus, had significantly reduced [Fig 2I and J]. Overall, there was a significant reduction in the FAP 2286 expression (80%) and size of the tumour (20%) following 2 sessions of FAP therapy. The patient was followed up with haematological and biochemical tests at 2-4 weeks and 6-8 weeks to assess the toxicities. The patient did not develop any grade 3 or higher toxicity.

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Fig 2: FAP2286 baseline and response assessment scan. (A) Baseline maximum intensity projection (MIP) with focal intense FAP 2286 uptake in the brain; (B) Corresponding fused transaxial images reveal intense FAP 2286 uptake in a (C) Homogeneously enhancing right parasellar mass; (D and E) Inferiorly, the mass was reaching till the right cavernous sinus. Patient underwent two sessions of Lutetium177 FAP 2286 therapy; (F) Reveals an MIP image with focal uptake of FAP 2286 in the brain (red arrow); (G-J) Corresponding fused transaxial image shows FAP 2286 uptake in enhancing residual lesion involving the right parasellar region. FAP: Fibroblast activation protein

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DISCUSSION

Solitary fibrous tumour with WHO grade 3 is an extremely rare histological entity with an incidence of less than 1%.^[1]Considering the aggressive histology, these tumours almost invariably recur either at local sites or have extracranial metastases. Optimal management of CNS SFT/HPC includes maximal safe resection, with or without adjuvant radiotherapy. Adjuvant radiotherapy is administered for haemangiopericytoma (HPC) classified as grades 2 and 3 with the intent to control the local disease and extend the survival.^[3] Recently, risk stratification for CNS SFTs was published, in which authors have concluded that postoperative adjuvant treatment in the form of radiotherapy has significantly improved survival in intermediate and high-risk grade 3 SFTs with any extent of resection.^[10] Although treatment strategies in an upfront setting are well-established, there is no consensus or treatment guideline in recurrent settings.

Few retrospective studies and case series highlighting the use of chemotherapy in recurrent settings are seen, with no significant benefit. In a retrospective analysis of 15 patients with recurrent SFTs treated with cyclophosphamide, doxorubicin, and vincristine, partial response was seen in 40%, with the rest showing progressive disease. They showed modest efficacy in the outcomes, with a median survival of 14 months, with acceptable toxicities.^[11] In another retrospective study with temozolomide plus bevacizumab, only 14.3% (2/14) achieved a partial response.^[12] These results indicate that the targeted therapies may not be sufficiently effective, particularly in cases that require rapid tumour shrinkage and symptom relief. Hence, there is an unmet need for newer targets to be explored with better efficacy and tolerability.

Radioisotope therapy is an emerging treatment approach for solid tumours, capable of delivering radiation to targeted tumour cells while limiting damage to surrounding tissue. The efficacy and safety of radioisotope therapy with Lu177 DOTATATE in neuroendocrine tumours and PSMA therapy in prostate cancers are well established. However, other solid tumours lack specific targets.^[13,14]

FAP labelled with therapeutic radioisotopes is being extensively studied for efficacy and safety in various solid tumours. It has shown promising results in tumours with desmoplasia, poor differentiation, or fibrous stroma. Since the tumour growth and spread are determined by these factors, FAP has emerged as a target for treatment, more so in the recurrent/refractory setting.^[15] Since intracranial tumours can be subjected to limited radiotherapy regimes and since chemotherapy drugs show poor penetration to the blood-brain barrier, the onus of exploring a safe yet target-specific treatment option is high. In a cohort of 21 patients, including 5 (24%) whose SFTs had the highest FAP expression, disease control (evaluated with Response Evaluation Criteria in Solid Tumours (RECIST)) was seen in 8 (50%) of 16 patients, which was associated with improved survival.^[9] Another study evaluated the efficacy of Y90-FAPi46 in 3 metastatic SFTs, which led to near-complete responses with no high-grade toxicities.^[16]

The above-mentioned studies had included predominantly extracranial SFTs; ours is a unique case where a patient had primary CNS involvement and had shown local recurrence. Since FAP 2286 therapy was planned, pretreatment PET/CT was also performed with Gallium68 FAP 2286, which showed high expression in the tumour with SUVmax 126.9. The patient had received 2 sessions of Lu177 FAP2286 therapy with a dose of ~7.4GBq per session. Toxicity assessment was performed at 1 week, 4-6 weeks, and 6-8 weeks post each session. There was no demonstrable single grade 3/higher haematological/non-haematological toxicity. On response assessment, FAPi PET/CT, there was a significant reduction in FAP expression depicted by SUVmax along with morphological partial response as per RECIST 1.1 criteria. Our findings concur with the existing literature regarding the potential role of FAP radioisotope therapy in SFTs.

CONCLUSION

To conclude, radioisotope therapy with Lu177 FAP 2286 is a promising treatment option in haemangiopericytomas and its long term efficacy and safety should be explored further in trial settings.