Anlotinib plus Temozolomide for Recurrent Glioma: A Single-Center, Retrospective Study of 30 cases

doi:10.21203/rs.3.rs-4373518/v1

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Anlotinib plus Temozolomide for Recurrent Glioma: A Single-Center, Retrospective Study of 30 cases

https://doi.org/10.21203/rs.3.rs-4373518/v1

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Objective

To determine the efficacy and tolerability of Anlotinib plus temozolomide (TMZ) as a first-line treatment for recurrent malignant glioma (rMG).

Methods

A total of 30 eligible patients who relapsed from the standard chemoradiotherapy regimen (TMZ and radiotherapy) or had macroscopic residual tumor after surgery because of tumor located in the eloquent brain areas were enrolled in this study between March 2018 and January 2021. Patients were subjected to a concurrent treatment of Anlotinib (12mg qd, 14 days on with 7 days off) and TMZ (200mg/m², 5 days on with 23 days off) until disease progression or intolerable toxicity. Efficacy was evaluated using Response Assessment in Neuro-Oncology(RANO) criteria for high-grade glioma. Safety was assessed using NCI-CTCAE 4.0. Survival was estimated with the Kaplan-Meier curve and log-rank test.

Results

Until April 2023, our median follow-up time was 28.1 ± 5.07 months(95% CI:18.20-38.06m). The median OS(from recurrence to death or end of follow-up) was 17.87 ± 4.29 m(95%CI: 9.46-26.28m). 1-year, 1.5 year, 2-year OS rates were were 60.0%, 46.7% and 36.7% respectively. The median PFS(from the treatment of Anlotinib and TMZ to the endpoint) was 7.83 ± 0.82m(95%CI, 6.22-9.44m). 6-month, 1-year PFS rates were 63.3%, 36.7%, respectively. In the univariate analysis, patients of WHO Ⅱ group have a longer mOS and mPFS than that of WHO Ⅲ and Ⅳ group(Ⅱ: 30.45 ± 4.32m, Ⅲ: 15.07 ± 5.72m, Ⅳ: 9.21 ± 1.90m, P = 0.035). Patients ≤ 55 had a longer mPFS compared with those > 55 years old(12.97 ± 1.71m vs. 7.33 ± 1.95m. p = 0.010), but failed to reach statistical difference in OS(19.90 ± 6.29m vs. 10.53 ± 1.68m, p = 0.106). While their gender, 1p/19q and IDH mutation are not independent negative predictors on OS or PFS. In the multivariate analysis, age, pathological grade and IDH mutation all failed to serve as an independent negative predictor of PFS or OS in recurrent glioma.

Conclusion

Anlotinib combined with TMZ was effective for recurrent glioma in terms of OS and PFS, and was well tolerated in patients. Further randomized controlled clinical studies are needed to confirm the efficacy of Anlotinib combined with TMZ for the treatment of rMG.

Biological sciences/Cancer

Health sciences/Oncology

Central nervous system

Recurrence

Malignant Glioma

Anlotinib

Temozolomide

Malignant glioma (MG) is the most common primary brain tumor. Currently, the standard treatment for MG is surgery combined with postoperative radiotherapy (RT) and chemotherapy. The prognosis of MG is closely correlated with the pathological classification and World Health Organization (WHO) grade level. The median survival time (OS) for GBM patients is only 13 to 16 months, and the 2-year survival rate is only 26.9% ^[1]. Unfortunately, intracerebral relapse is almost inevitable ^[2]. During recurrence, some tumors display new genetic mutations and can progress to a more aggressive state, thus making treatment of recurrent gliomas more difficult ^[3]. It was reported that survival after relapse and retreatment of MG is 6–8 months ^[4], and the median time to the second progression is 14 weeks ^[5].

For patients with recurrent MG, current treatment options are limited ^{[2, 6–7]}. Given that the growth of GBM is dependent on the formation of new blood vessels, inhibitors targeting tumor vasculature are promising therapeutic agents for rMG^[8].

Anlotinib is a multitarget tyrosine kinase inhibitor that was originally designed to inhibit VEGFR2/3, FGFR1–4, PDGFR α/β, c-Kit, and Ret. Anlotinib can inhibit tumor angiogenesis and tumor cell growth. Anlotinib has been reported to have a good and acceptable adverse effect in the treatment of non-small cell lung cancer, metastatic renal cell carcinoma, and sarcoma ^{[9, 10]}. Anlotinib has been approved by the National Medical Products Administration for use in advanced non-small-cell lung cancers. Preclinical results revealed that Anlotinib could significantly inhibit FGFR1–4, especially FGFR2 ^[11]. However, to the best of our knowledge, only a few articles have reported on the use of Anlotinib in the treatment of patients with MG ^{[12, 13]}. Therefore, in the present article, we reported on the efficacy and security of Anlotinib for rMG.

Patient Selection

This retrospective study was approved by the Institutional Research Ethics Committee of the First Affiliated Hospital of Nanjing Medical University(NO:2021-SR-193). The study population consisted of patients with rMG who did not respond well to standard surgery plus chemoradiotherapy regimen (TMZ and radiotherapy) at the First Affiliated Hospital of Nanjing Medical University between March 2018 and January 2021. The inclusion criteria were as follows: (1) age of 18–70 years; Karnofsky performance scale (KPS) of ≥ 60; (2) histologically confirmed diagnosis of malignant gliomas, World Health Organization Grade Ⅱ, Ⅲ or IV; (3) measurable or evaluable disease by magnetic resonance imaging (MRI) confirmation and a minimum life expectancy of 8 weeks; (4) progressive disease (relapse) on MRI defined by Response Assessment in Neuro-Oncology (RANO) criteria after the standard Stupp protocol or with macroscopic residual tumor after surgery because of tumor located in the eloquent brain areas; (5) adequate bone marrow function (leukocyte count ≥ 4000/µL, neutrophil count ≥ 1500/µL, platelet count ≥ 100,000/µL, hemoglobin ≥ 8.0 g/dL), liver function (total bilirubin ≤ 34 µmol/L and aspartate and alanine aminotransferase ≤ 120 U/L), and renal function (serum creatinine ≤ 150 µmol/L, 24 hrs urine protein ≤ 3.4 g).

The exclusion criteria were following: (1) extracranial metastatic disease, (2) Gliadel wafer treatment, (3) severe cardiopulmonary insufficiency, (4) status epilepticus, (5) pregnancy, (6) gastrointestinal bleeding, (7) uncontrolled blood pressure with medication (> 140/90 mm Hg), (8) swallowing difficulties, and (9) HIV positivity and treatment of antiretroviral therapy.

Drug Administration

Anlotinib was provided by Chiatai TianQing Pharma Co., Ltd. A starting dose of Anlotinib was administered 12 mg p.o. once daily (14 days on with 7 days off) on a 21-day cycle. Drug doses were withheld and/or reduced for intolerance grade 2 or grade 3–4 toxicity. A maximum of 3 dose-level reductions was permitted (12 mg, then 10 mg, then 8mg). The dosage was modified to 10 mg and then 8mg if patients experienced grade 2 hematologic adverse events, hand, and foot syndrome, proteinuria, grade 3/4 hypertension, or other grade 3/4 adverse events. Anlotinib was administered until disease progression, unacceptable toxicity, or death. TMZ was administrated to patients with a dosage of 200 mg/ m² (5 days on with 23 days off) on a 28-day cycle.

Efficacy and Adverse Events

All the lesions were measurable. The baseline evaluation included MRI, questionnaires on health-related quality of life, neurocognitive testing, blood routine, renal and liver function, urinalysis, and electrocardiogram. Efficacy was measured by RANO criteria, and the brain MR examination was conducted every 1–3 months. The primary endpoint was PFS and OS. OS₁ was defined as the time from surgery to death or the end of follow-up. OS₂ was defined as the time from recurrence to death or end of follow-up in all patients, OS₃ was defined as the time from the beginning of intervention treatment to death or the end of follow-up. PFS was defined as the time from the beginning of intervention treatment to PD or end of follow-up.

Adverse events (AEs) were estimated with National Cancer Institute-Common Terminology Criteria Adverse Events version 4.0 (NCI-CTCAE 4.0) at regular intervals during each cycle. Physical examination, hematology, biochemistry tests, and electrocardiograms were used to monitor AEs. Medical and clinical monitoring of the study, as well as data management, was conducted by the authors. Clinical laboratory assessments were performed by local laboratories.

Statistical analysis

OS and PFS were analyzed with Kaplan-Meier analysis and log-rank test. Survival differences were compared using a log-rank test. Multivariable analyses were conducted using the Cox proportional hazards regression model to investigate the effects of different survival factors. A 2-sided P value of less than .05 indicated a statistically significant finding for all analyses. Statistical analyses were carried out with SPSS 20.0 version. Patient characteristics and AEs were described with counts and percentages in frequency tables, respectively.

Characteristics of Patients

The characteristics of the patients are summarized in Table 1. A total of 30 patients with rMG who received Anlotinib and TMZ between September 2017 and December 2020 were included in this study. All of them were evaluated in the analysis. Among these patients, 46.7% (14) were females, and 53.3% (16) were males. The median age was 53.53 years; 66.7% (20) were grade Ⅳ MG (GBM), 20% (6) were grade Ⅲ MG, 13.3% (4) were grade Ⅱ MG. Of the 30 glioma patients, 16(52.8%) recurrence occurred within no more than 6 months, 10 (33%) within 6–12 months, 4(13.2%) occurred after more than 12 months. After the follow-up time until 26 April 2023, 19 patients(70%) died, and 9 patients(30%) survived, with a median follow-up time of 28.1 ± 5.07 months(95% CI:18.20-38.06m).

Table 1

Patient Demographics and Baseline Characteristics
Characteristic	N0.(%)	%
Age, median(range), y	53.53 ± 11.038
Gender
Male	16	53.3
Female	14	46.7
Histopathologic diagnosis
WHO Ⅱ	4	13.3
WHO Ⅲ	6	20.0
WHO Ⅳ	20	66.7
Age
< 50	12	40%
≧ 50	18	60%
Time from the initial diagnosis to recurrence
≤ 6m	16	52.8%
6-12m	10	33%
> 12m	4	13.2%
IDH1 Mutant
Negative	17	56.7%
Positive	7	23.3%
Unknown	6	20%
1p/19q Mutant
Negative	13	43.3%
Positive	6	20.0
Unknown	11	36.7%
Dead
Yes	21	70%
No	9	30%

Figure 1A-D show Kaplan-Meier curves of OS and PFS of 30 patients calculated from different start points to death/recurrence or end of follow-up. In Fig. 1A, the median OS₁ (calculated from surgery to death or end of follow-up) was 28.13 ± 5.07m(95% CI, 18.2-38.06m) as estimated by the Kaplan-Meier method. Among all patients, the 1-year, 2-year and 3-year OS rates were 80%, 56.7% and 40%, respectively. In Fig. 1B, the median OS₂ (calculated from recurrence to death or end of follow-up) was 19.57 ± 1.51m(95% CI, 16.62 ± 22.52m). 6-month, 12-month, 18-month, 24-month OS rates were 88.0%, 66.7%, 60.0% and 36.7%, respectively. In Fig. 1C, the median OS3 (calculated from recurrence to death or end of follow-up) was 17.87 ± 4.29 m(95%CI: 9.46-26.28m). 1-year, 1.5 year, 2-year OS rates were 60.0%, 46.7% and 36.7%, respectively. In Fig. 1D, the median PFS(from the treatment of Anlotinib and TMZ to the endpoint) was 7.83 ± 0.82m(95%CI, 6.22-9.44m). 6-month, 1-year PFS rates were 63.3% and 36.7%, respectively.

When we analyzed female and male patients, there was no significant difference in median OS (female vs male: 18.70 ± 1.59m vs. 12.43 ± 2.17m, p = 0.501) and mPFS(female vs male: 7.33 ± 5.68m vs. 7.83 ± 0.67m, p = 0.539). (Fig. 2 AB).

We use the median age 55-year as the cut-off age. It seemed that patients ≤ 55 had a longer mOS than those patients > 55 years old(19.90 ± 6.29m vs. 10.53 ± 1.68m), but failed to reach statistical difference(p = 0.106). Nevertheless patients ≤ 55 had a longer mPFS compared with those > 55 years old(12.97 ± 1.71m vs. 7.33 ± 1.95m. p = 0.010.) (Fig. 2 CD).

We found that patients with different WHO grade glioma had different mOS(WHO Ⅲ vs. WHO Ⅳ: 28.47 ± 8.13m vs. 15.80 ± 7.73m, P = 0.036). Further pairwise analysis revealed that patients of WHO Ⅱ group had a longer mOS compared with those of WHO Ⅲ and Ⅳ group(Ⅱ vs. Ⅲ: χ² = 5.539, p = 0.019; Ⅱ vs. Ⅳ, χ² = 6.112, p = 0.013). There was no significant difference between WHO Ⅲ and Ⅳ group(χ² = 0.0303, p = 0.582). The median PFS showed significant difference between the 3 WHO grade groups(Ⅱ vs. Ⅲ vs. Ⅳ: --m vs. 11.17 ± 5.23m vs 7.20 ± 0.59m, P = 0.035). Further pairwise analysis revealed that patients of WHO Ⅱ group had a longer mPFS than that of WHO Ⅲ and Ⅳ(Ⅱ vs. Ⅲ: χ2 = 4.16, p = 0.041; Ⅱ vs. Ⅳ: χ2 = 6.15, p = 0.013). When we analyzed patients with WHO grade Ⅲ and grade Ⅳ gliomas, no significant difference was found(χ2 = 0.623, p = 0.430).(Fig. 2 EF).

In 1p/19q mutant related groups analysis, no significant differences were observed in mOS(17.87 ± 3.24m vs. 28.47 ± 7.14m vs. 12.43 ± 6.26m, p = 0.478) and mPFS(7.33 ± 1.88m vs. 12.97 ± 6.37m vs. 8.4 ± 0.82m, P = 0.514m) among 1p/19q negative, positive, unknown groups.(Fig. 2 GH).

In IDH mutant related groups analysis, although patients of IDH positive seemed to have longer mOS than that of IDH negative or IDH unknown, no significant differences were observed among the three groups(IDH negative vs. IDH negative vs. IDH unknown: 13.30 ± 3.70m vs. -m vs 12.43 ± 5.37m, p = 0.175). Furthermore, there were no significant difference among patients with IDH negative, positive or unknown(7.33 ± 1.87m vs. 12.97 ± 11.18m vs. 8.40 ± 0.49m, p = 0.804.) (Fig. 2 IJ).

Multivariate analysis

Multivariate Cox regression analysis was performed including age, grade and IDH mutant as covariates of OS, age and grade of PFS(Table 2). Univariate analysis revealed that none of the covariates above had significant effect on OS or PFS.(Table 2).

Table 2

Multivariate analysis of predictors for overall and progression-free survival in 30 glioblastoma
OS	Adjusted odds ratio	95% CI	p
Age	1.380	0.527–3.615	0.512
Grade	3.497	0.961–5.347	0.061
IDH	0.315	0.498–1.472	0.575
PFS	Adjusted odds ratio	95% CI	p
Age	2.091	0.847–5.160	0.110
Grade	1.878	0.934–3.774	0.077
CI: confidence interval; IDH: isocitrate dehydrogenase; OS: overall survival; PFS: progression-free survival.

Adverse Events

AEs for patients are summarized in Table 3. The toxicity profiles that occurred in patients included the following: hand-foot syndrome 43.3% (13/30), leukopenia 40% (12/30), transaminase elevation 40.0% (12/30), hypertension 30.0% (9/30), thrombocytopenia 30.0% (9/30), albuminuria 26.7% (8/30), hyperbilirubin 26.7% (8/30), anemia 23.3% (7/30), neutropenia 26.7% (8/30), and gastrointestinal reaction 30.0% (9/30). Grade 3 AE included hand-foot syndrome 6.7% (2/30), thrombocytopenia 6.7% (2/30), and hyperbilirubin 3.3% (1/30). These AEs were quickly reduced and recovered after a dose reduction or intermission. Therefore, detecting the drug's toxicity and adjusting the dosage from 12mg to 10mg and then from 10mg to 8mg were important. 4 patients received a dose adjustment. No treatment-related death occurred.

Table 3

Adverse Events in the Combination Therapy of Anlotinib and Temozolomide
Adverse Events	Grade Ⅰ (n,%)	Grade Ⅱ (n,%)	Grade Ⅲ (n,%)	Total (n,%)
Hand-foot syndrome	9	2	2	43.3%
Transaminase Elevation	9	3	0	40.0%
Leukopenia	7	5	0	40.0%
Hypertension	7	2	0	30.0%
Thrombocytopenia	5	2	2	30.0%
Hyperbilirubin	5	2	1	26.7%
Abuminuria	8	0	0	26.7%
Anemia	5	2	0	23.3%
Neutropenia	5	3	0	26.7%
Gastrointestinal Reaction	6	3	0	30.0%

The prognosis of patients with recurrent MG is quite poor. According to the NCCN guidelines, bevacizumab is the preferred drug for recurrent gliomas. Bevacizumab, a monoclonal antibody primarily inhibiting VEGF, has been used in patients with GBM as a later-line treatment since its approval in the USA for recurrent MG in 2009. Since then, it has become the standard treatment for patients with recurrent MG in the NCCN guidelines ^[14]. Another recommended regimen is bevacizumab plus chemotherapy (carmustine or lomustine, TMZ, or carboplatin). A meta-analysis showed that the combination of bevacizumab and chemotherapy in the treatment of recurrent MG significantly improved the progression-free survival and objective response rate but failed to extend the OS compared to single-agent bevacizumab ^[15]. Consequently, there is still no effective treatment regimen for rMG. Molecular-targeted drugs have become the focus of research on rMG ^[16]. The present study is a retrospective research that investigated the safety and efficacy of Anlotinib combined with TMZ for patients with rMG. Our data demonstrated that Anlotinib in combination with TMZ was effective in terms of PFS and OS. It was also well-tolerated in the evaluated patients’ population.

Anlotinib is a multitarget tyrosine kinase inhibitor and an oral small molecule inhibitor. The drug was originally designed to inhibit VEGFR2/3, FGFR1–4, PDGFRα/β, and c-Kit; thus, it has broad inhibitory effects on tumor angiogenesis and growth ^[11]. It was reported that Anlotinib is a suitable and promising treatment for GBM with FGFR3-TACC3 fusion after treatment failure with bevacizumab ^[12]. It may provide a new option for patients with recurrent GBM after TMZ or bevacizumab treatment.

In our retrospective study, the median OS was 17.87 months. 1-year, 1.5 year, 2-year OS rates were 60.0%, 46.7% and 36.7%, respectively. The median PFS with the treatment of Anlotinib and TMZ was 7.83 months. 6-month, 1-year PFS rates were 63.3%, 36.7%, respectively. In a previous study on dose-dense regimens of TMZ alone for rGBM, the patients had ORR of 11.1%, DCR of 30%, mPFS of 4.3 months, and mOS of 6.9 months ^[17]. However, studies using bevacizumab alone reported ORR of 38%, mPFS of 3 months, and mOS of 8 months^[18]. Apatinib combined with dose-dense TMZ showed ORR of 45%, DCR of 90%, mPFS of 6 months, and mOS of 9 months in an uncontrolled, open-label study on rGBM^[19]. Our result is also better in mOS but slightly inferior in mPFS compared with one previous study by Sun^[20], in which 26 newly diagnosed or recurrent high-grade gliomas received oral anlotinib during concurrent postoperative chemoradiotherapy or after recurrence. The median OS after oral anlotinib was 12 months, and the OS at 12 months was 42.6%. The median PFS after oral anlotinib was 8.9 months, and the PFS at 6 months was 72.5%. In another retrospective study^[21], 31 recurrent high-grade gliomas patients were treated with anlotinib or anlotinib and TMZ, the median OS was 7.7 months, and the OS at 12 months was 27.9%, the median PFS was 4.5 months, the PFS at 6 months was 40.2%. In Liu`s study^[22] on an anlotinib dose density regimen combined with temozolomide for recurrent glioblastoma, the 1-year overall survival (OS) rate was 47.7%. The 6-month progression-free survival (PFS) rate was 55%. The result difference among the studies may due to different enrollment criteria. Our study had the longest follow-up time period, whose median follow-up time reached 28.1 ± 5.07 months(95% CI:18.20-38.06). Our study also had the longest median OS of 17.9 months, which is the most important indicator of prognostic evaluation. This demonstrates that anlotinib combined with TMZ could reach better oncologic outcome and relatively satisfactory results in treating recurrent gliomas.

In our study, adverse reactions related to anlotinib in the treatment of recurrent glioma were favorablely tolerate. Because most were grade 1–2 side effects. Treatment-related grade 3 adverse effects included hand-foot syndrome 6.7% (2/30), thrombocytopenia 6.7% (2/30), and hyperbilirubin 3.3% (1/30). Dose reduction occurred in 4 patients(two from 12mg to 10mg, the other two from 12mg to 10mg and then to 8mg). And the side effects were relieved after dose adjustment. The results were similar with previous studies^[20–22], which demonstrate the favorable safety and tolerance profile of anlotinib combined with/without TMZ.

Although some basic and clinical progress has been made in antiangiogenic therapy of glioma, the clinical effect in real world is far from expectation. Multitarget antiangiogenic drugs such Anlotinib have some prospects. This study has some limitations that should be mentioned. First, this was a retrospective study with a limited number of patients that performed at a single institute. Second, genetic status and molecular markers were not fully evaluated due to some unknown genetic status. Nevertheless, the present study is another one that reported on the efficacy and safety of Anlotinib with TMZ for rMG with relatively large sample and the longest follow-up period.

Acknowledgements

Not applicable.

Disclosure

The abstract of this paper was presented at the 2021 ESMO Conference name 'Anlotinib plus Temozolomide for Recurrent Glioma: A Single-Center, Retrospective Study of 30 cases' as a poster with interim findings. The poster's abstract was published in 'Poster Abstracts' in Annals of Oncology (2021) 32 (suppl_5): S516-S529, The hyperlink is 'https://oncologypro.esmo.org/meeting-resources/esmo-congress-2021/anlotinib-plus-temozolomide-for-recurrent-glioma-a-single-center-retrospective-study-of-30-cases'.

Funding

The study was supported by the Huai`an City Natural Science Foundation projects ( grant no. HAB202251) and National Natural Science Foundation of China(grant no. 82003235).

Availability of data and materials

The analyzed data generated during the study are available from the corresponding author upon reasonable request.

Authors' contributions

YDC and JP conceived and designed the experiments. LPX, DDY, YYL and XFD performed the experiments and data analysis. LPX, DDY and XFD wrote the manuscript and it was revised for important intellectual content by YDC and JP. YDC and JP confirmed the authenticity of all the raw data. All authors read and approved the final manuscript.

Ethics approval and consent to participate

The study was carried out in accordance with the declaration of Helsinki and Good Clinical Practice guidelines. All patients provided written informed consent. This study was approved by the Institutional Research Ethics Committee of the First Affiliated Hospital of Nanjing Medical University(NO:2021-SR-193).

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Use of artificial intelligence tools

No AI tools have been used.

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No competing interests reported.

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Anlotinib plus Temozolomide for Recurrent Glioma: A Single-Center, Retrospective Study of 30 cases

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