A Retrospective Interventional Cohort Study to Assess the Safety and Efficacy of Sandostatin LAR(octreotide) for Treatment of Recurrent and/or Refractory Meningiomas CURRENT STATUS: POSTED

Meningiomas are the most common adult primary intracranial tumors in the United States. Despite, high recurrence rate of atypical and malignant subtypes, there is no approved drug indicated specifically for meningioma. Majority of meningiomas exhibit high density (70%) of somatostatin receptors subtypes, and somatostatin analogs have been under close investigation as a potential treatment option for management of progressive or recurrent meningiomas. The aim of this study was to evaluate efficacy and safety of Sandostatin LAR (octreotide) in patients with progressive and/or recurrent meningioma. Methods This study is the largest study to date that provides additional evince to support current treatment guideline for management of progressive and/or recurrent meningiomas by the National Comprehensive Cancer Network (NCCN) [1]. Additional prospective, larger scale randomized trials are needed to validate effectiveness of Sandostatin LAR (octreotide) in meningioma. Furthermore, our study provides a diverse patient population, and includes Hispanics (25.5%) and Asians (22.7%). retrospective The consisted


Introduction
Meningiomas are dural-based tumors that arise from an arachnoid layer or meningothelial cells. They are the most common primary adult CNS tumors, and account for 36.8 % of all primary brain tumors [2]. Most meningiomas are histologically classified as World Health Organization (WHO) grade I tumors (benign, 81.3%) with an indolent course. WHO grade II (atypical, 16.9%) and WHO grade III (anaplastic, 1.7%) tumors classified as high-grade tumors and known to be more aggressive with increased risk of recurrence [3].
If indicated based on tumor size or tumor progression, patients with WHO grade I meningiomas undergo complete surgical resection [4]. Approximately 5% of completely resected benign meningiomas, 30% of partially resected benign meningiomas and 40% of atypical meningiomas recur within 5 years after surgery [5]. Despite surgical resection and radiation therapy that is standard of care for WHO grade II and III meningiomas, patients have higher recurrence risk of 29-52% and 50-94%, respectively [6]. Depending on tumor location, invasion of surrounding structures, age and medical comorbidities of the patient, surgical intervention is not always possible. Chemotherapy or biologics are then considered as an alternate treatment option. However, there is no FDA approved drug indicated specifically for meningioma, and patients with atypical, anaplastic, recurrent or invasive meningiomas are often left with limited options.
The National Comprehensive Cancer Network (NCCN) guideline identified three drug classes that showed some benefits for treatment of meningioma in retrospective analysis or small phase II trials: vascular endothelial growth factor (VEGF) signaling pathway inhibitors, alpha-interferons, and somatostatin receptor agonists [1,7]. Since the majority of meningiomas exhibit a high density (70%) of somatostatin receptors subtypes (SSTR1-SSTR5), it is not surprising that somatostatin analogs have been under close investigation as a potential treatment option [8,9].
Somatostatin is an a cyclic tetradecapeptide hormone that is produced in hypothalamus and released into systemic circulation, where it exhibits its exocrine and endocrine inhibitory functions by targeting pituitary, pancreas and gastrointestinal tract [10]. It also has been implicated in the induction of apoptosis and inhibition of angiogenesis [11]. Since naturally occurring somatostatin has a short halflife, somatostatin analogs were developed to achieve a longer half-life (lanreotide, pasireotide, and octreotide).
Sandostatin LAR (octreotide) is another long acting somatostatin analogue approved by the FDA for treatment of acromegaly, severe diarrhea/flashing episodes associated with metastatic carcinoid tumors, and vasoactive intestinal peptide (VIP) secreting tumors [12]. Given that Sandostatin LAR (octreotide) was shown to significantly decrease cell proliferation in 88% of meningiomas with more prominent inhibition in a group expressing a high level of SSTR2a, one of the most frequently expressed receptors in meningiomas, investigative work was initiated to assess its efficacy for treatment of meningiomas [8,13].
A prospective pilot study showed that 31% of patients with recurrent meningiomas demonstrated a partial radiographic response and 44% achieved progression free survival (PFS) at 6 months with minimal side effects after undergoing treatments with Sandostatin LAR (octreotide) [14]. Even though a phase II study conducted to evaluate the efficacy and safety of Sandostatin LAR (octreotide) did not demonstrate a significant benefit, 2 patients experienced prolonged stability of previously progressive tumors [15]. Studies that investigated the effect of Sandostatin LAR (octreotide) in patients with a progressive benign residual or recurrent meningioma of the skull base, showed that somatostatin analog can arrest progression and stabilized disease [16].
Numerous case reports and clinical studies highlighted potential benefit of Sandostatin LAR (octreotide) for treatment of meningioma, but due to small sample size, no statistical significance was achieved. Thus, our retrospective interventional cohort study with a bigger sample size provides supporting evidence to consider Sandostatin LAR (octreotide) as a potential candidate for meningioma based treatment taken into an account its tolerability and safety profile.

Materials And Methods
The following study was a retrospective interventional cohort analysis conducted at the University of California Medical Center (UCIMC) between January 2010 and June 2017. The study cohort consisted of patients with recurrent and/or progressive WHO grade I, II or III meningiomas who received treatment with Sandostatin LAR (octreotide). All information related to patients' demographics, cancer type, response to treatment, therapies previously received, and Karnofsky performance scores (KPS) were collected [17]. The primary objective of this study was to determine efficacy of Sandostatin LAR (octreotide) in patients with recurrent and/or progressive meningiomas. Six months PFS6 was defined as a primary endpoint, and OS was a secondary endpoint. Safety and toxicity of Sandostatin LAR (octreotide) were assessed as well.

Patients Eligibility
Patients were required to be ≥ 18 years old with recurrent and/or progressive meningioma expressing sandostatin receptors confirmed by positive 111 Indium ( 111 In) -octreotide positron emission tomography (PET) or positive immunohistochemistry analysis. Patients were determined to be poor candidates for surgical resection, stereotactic radiosurgery or radiation therapy based on tumor location, increased risk factors for postoperative morbidity and mortality, or individual preference for noninvasive approach, or were shown to have recurrence despite surgical or radiation therapy. There was no limit on the number of prior surgeries, radiation or radiosurgery treatments. Patients were excluded if metastatic lesions were found on octreotide PET scan or informed consent was not obtained.

Treatment Plan
In order to confirm meningioma and its response to treatment with Sandostatin LAR (octreotide) the vast majority of patients underwent a 111 In-octreotide PET scan. For patients who were unable to undergo a 1111 In-octreotide PET scan, meningioma was confirmed by immunohistochemical analysis.
A MRI or CT scan was done prior to first drug administration, and was repeated every 2 to 3 months thereafter for an evaluation of tumor status. Patients received deep intragluteal injections of Sandostatin LAR (octreotide) monthly, and were treated until disease progression or intolerability. The dose of Sandostatin LAR (octreotide) was gradually increased from 30 mg to 40 mg per injection if tolerated. Patients were followed for any adverse reactions to the drug. The treatment was stopped if the patient met any of the following criteria: MRI or CT showed tumor progression, serious adverse events, physician discretion, patient's choice to discontinue treatment, death, or lost to follow up. The institutional review board approved the study, and all patients that participated provided written informed consent.

Statistical Methods
Data was analyzed by using the IBM SPSS statistical program package (PAWS statistics v18.0). Data was grouped into categories based on demographics, WHO tumor grades, KPS scores and treatment characteristics, and analyzed using descriptive statistics. The PFS was calculated from the date of initial treatment with Sandostatin LAR (octreotide) until the date of death or disease progression.
Patients who did not experience disease progression were censored. The OS was estimated from the date of initial treatment with Sandostatin LAR (octreotide) to the date of death or last known date to be alive. Subjects that have not died were censored at the last known date to be alive. Survival curves were estimated by generating Kaplan-Meier methods. PFS and OS were compared between WHO tumor grades, ethnicities and races. The log rank test was used to compare the survival distributions of the groups. P-value < 0.05 for all analyses was considered significant. Best radiographic response was determined based on 2010 the Response Assessment in Neuro-Oncology (RANO) Working Group [18]. Results from our treatment group were compared to results from previous published studies using Sandostatin LAR (octreotide) for treatment of meningioma and compared to other studies using interferon-alpha, bevacizumab, sunitinib, vatalanib, imatinib, imatinib/ hydroxyurea, and erlotinib/ gefitinib.

Safety and Toxicity
Adverse events were reported by patients and/or providers when clinically significant abnormal laboratory, or physical examination findings were identified requiring intervention. Adverse events were recorded from the first date of Sandostatin LAR (octreotide) administration until death or 12 months follow up. The relationship of the adverse event to Sandostatin LAR (octreotide) was also evaluated. It was considered to be a related event when there was an evidence to suggest the relationship between the drug and the adverse event. An unrelated event was thought to be an adverse event, possibly caused by an underlying disease or biologically improbable event. Safety results were evaluated via descriptive statistics to identify frequency, type, and severity of adverse events.
Treatment related toxicities were evaluated using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 [19]. All patients who received Sandostatin LAR (octreotide) were evaluable for toxicity, and toxicity results were then compared to other clinical studies.

Patients Characteristics
A total of 44 patients with recurrent or progressive WHO grade I (75.0%), II (11.4%) and III (13.6%) meningiomas were enrolled in this study, including 5 with atypical and 6 with anaplastic meningiomas ( were generated to analyze the overall PFS and PFS stratified by WHO tumor grade (Fig. 1A, Fig. 1B).
The median OS for all tumor grades has not been yet reached, thus it could not be reported (  (Fig. 1C, Fig.   1D).

Discussion
Currently, there are no FDA approved therapies for management of surgically inaccessible or radiation-refractory recurrent meningiomas. In 2018, the Central Nervous System NCCN guideline recommended somatostatin analogues as valuable therapeutic options for management of progressive or recurrent meningiomas [1]. These recommendations were derived from limited studies evaluating various somatostatin analogues (somatostatin, pasireotide, octreotide and Sandostatin LAR). Our study, on the other hand, is the largest reported retrospective analysis to date of meningioma patients with recurrent and/or progressive disease treated with Sandostatin LAR (octreotide).
Comprehensive review of our study and previously reported data are summarized in Table 5 [21]. Overall, our data shows longer PFS compared to the other clinical studies. Reported toxicities were consistent across clinical studies with diarrhea, nausea, vomiting and transminities being the most common events. Prior studies had less than 25 patients that resulted in low statistical power.
Our clinical study provides additional evidence to support the rationale for a larger phase study to assess the efficacy of Sandostatin LAR (octreotide). Compared to other therapeutics, octreotide Sandostatin LAR (octreotide) had longer median PFS, PFS6 and safer profile (Table 6.0). There were no observed CTCAE grade 4 or grade 5 adverse events. There was only one grade 3 adverse event in our study that identified the patient who was hospitalized with pancreatitis after developing cholelithiasis. Sandostatin LAR (octreotide) was subsequently discontinued in this patient. Erlotinib demonstrated a favorable safety profile compared to all the other drugs, however, median PFS was lower than patients who received Sandostatin LAR (octreotide).
It is important to note, that the CNS NCCN guideline classifies somatostatin analogue, as a level 2A category for patients with progressive recurrent meningioma while interferon alpha, sunitinib and bevacizumab, and everolimus combination were given 2B category [1]. Category 2A evidence is based on lower-level evidence with uniform NCCN consensus that the intervention is appropriate, while category 2B evidence that is also based on lower level of evidence was only granted experts consensus. These recommendations are not surprising, as scientific literature review indicates that somatostatin analogues including Sandostatin LAR (octreotide) are better tolerated therapies with good efficacy as evidenced by longer PSF and PFS6.
Specifically, phase II clinical trial that included 36 patients with high-grade meningioma who received sunitibin showed efficacy of that treatment based on PFS6 of 42%, median PFS of 5.2 months and median OS of 24.6 months [22]. However, considerable toxicity was observed with 1 grade 5, 1 grade 4 and 2 grade 3 intratumoral hemorrhages, 1 grade 4 and 1 grade 3 thrombic microangiopathy attributed to known side effect profile of VEGF inhibitors. By comparison all studies on somatostatin analogues including this report indicate well tolerability and minimal side effects with diarrhea being the most commonly reported side effect.
The phase II clinical study evaluated efficacy of combination of everolimus and bevacizumab in 17 patients with progressive recurrent meningiomas (WHO tumor grade I,II and III) showed that this regiment was well tolerated, and produced stable diseases in 88% of patients with median PFS as 22 months, PFS as 69% and median OS of 23.8 months [23]. No grade 5 or grade 4 toxicities were reported, but four patients (22%) discontinued treatment due to grade 3 toxicities such as proteinurea, colitis and thrombocytopenia. Important to note, that since the sample size was small, additional work in indicated. In comparison, our study is the largest study that included 44 patients providing more conclusive results.
A retrospective case series evaluated treatment with interferon alpha for patients with high grade meningiomas that showed progression after surgery, radiotherapy, or prior systemic chemotherapy [24]. The study revealed the median PFS of 12 weeks and PFS6 of 17% without radiographical response and moderate toxicity. Unfortunately, given that overall PFS and PFS6 were below benchmark criteria of PFS of 26% for atypical and malignant meningiomas proposed by the Response Assessment in Neuro-Oncology (RANO) Working Group 2014, it appears to be an unlikely candidate for use for treatment of progressive recurrent meningiomas [25].
Thus, based on available clinical data, Sandostatin LAR (octreotide) should be given preferential choice for managing patients with progressive and/or recurrent meningiomas. Nevertheless, this was a retrospective study with several limitations, imposed by the type of the study. Comparison of Sandostatin LAR (octreotide) to other therapeutics were hindered, as all the studies have different methodologies, size, patient population or objectives. In addition, our study did not include a control, and prior reported studies were used for comparison. Despite the stated limitations, our study is the largest study to date that provides rationale and supports further investigation of Sandostatin LAR (octreotide) for the treatment of progressive or recurrent meningiomas. Additional prospective, larger scale randomized trials are needed to validate the effectiveness of Sandostatin LAR (octreotide) in meningioma.

Supplementary Files
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