Involved-field Radiotherapy Combined With Concurrent Intrathecal-MTX Versus Intrathecal-Ara-C for Leptomeningeal Metastases From Solid Tumor: A Randomized Phase II Clinical Trial
Phase: PHASE2
Conditions: Leptomeningeal Metastasis
Sponsor: The First Hospital of Jilin University

 
 
Involved-field Radiotherapy Combined With 
Concurrent Intrathecal-MTX Versus Intrathecal-Ara-C 
for Leptomeningeal Metastases From Solid Tumor: A 
Randomized Phase II Clinical Trial 
 
NCT number: NCT03082144 
 
IRB approval date: February 1, 2017 
 
 
 
 
 
 
 
 
 
 
 
 

 
Study Protocol 
 
Objective:  
This study was designed to investigate the efficacy and safety of 
concurrent involved-field radiotherapy and intrathecal chemotherapy for 
patients with leptomeningeal metastases from solid tumors. Furthermore, 
another purpose of the study is to compare the two intrathecal chemotherapy 
drugs in the concomitant therapeutic modality. 
 
Design: 
It is a prospective, randomized controlled, parallel group, and phase II 
clinical trial. The study participants were newly diagnosis patients with 
leptomeningeal metastases from solid tumors. Patient with hematological 
malignancy (e.g., leukemia and lymphoma) or primary brain tumor was 
excluded. 
In our previous study [1], it has been proved that concurrent radiotherapy 
and intrathecal methotrexate (MTX) for leptomeningeal metastases (LM) from 
solid tumors with adverse prognostic factors showed great effectiveness and 
safety. This treatment regimen improved the prognosis of LM patients from 
solid tumors with adverse prognostic factors for the first time. The findings 
suggest that the concomitant regimen could be an optimal treatment option for 
LM. MTX and cytarabine (ara-C) are conventional cytotoxic drugs，which are 
the most frequently used agents for intrathecal chemotherapy. The common 
regimen of intrathecal dose of MTX and ara-C was 15mg and 50mg, 
respectively. 
This study was approved by the Ethic Committee of The First Hospital of 
Jilin University on February 1, 2017. All procedures were compliant with the 
Declaration of Helsinki. The study plan and regimen schema is provided in 

Figure 1,2. The patients were randomly divided into two groups, who will 
accept the treatment of involved-field radiotherapy (RT) combined with 
concurrent intrathecal-MTX or intrathecal-ara-C, respectively. Concomitant 
regimen consisted of intrathecal chemotherapy (via lumbar puncture, MTX 15 
mg, plus dexamethasone 5 mg, or ara-C 50mg, plus dexamethasone 5 mg, 
once per week, 4 weeks in total) and RT. RT consisted of fractionated, 
conformal radiation given at a daily dose of 2 Gy. The planning volume 
consisted of sites of symptomatic disease, bulky disease observed on MRI, 
including the whole brain and basis cranii received 40 Gy in 20 fractions and/or 
segment of spinal canal received 40-50 Gy(the first lumbar vertebra and the 
above segments were given 40 Gy in 20 fractions; the first lumbar vertebra and 
the inferior segments were given 40/50 Gy in 20 fractions). Patients with 
Karnofsky performance status score (KPS) of ≤ 40 and irradiation intolerance 
were required to receive induction intrathecal chemotherapy (MTX 15 mg, or 
ara-C 50mg, plus dexamethasone 5 mg, twice per week). Then these patients 
were allowed to receive concomitant therapy upon neurologic improvement 
and radiotherapy tolerance. 
The primary endpoint was clinical response rate (CRR). The secondary 
endpoints were safety and overall survival (OS). 
 
Methods: 
We adopted the criteria of evaluation for clinical response established in 
our previous study based on improvement of neurologic symptoms/signs and 
changes of KPS [1]. The criteria have been proved associated with the 
prognosis of LM patients and suitable for clinical application. The clinical 
response was evaluated by at least two experienced neuro-oncologists. The 
evaluation consists of 5 layers, including complete response (CR), obvious 
response (OR), partial response (PR), stable disease (SD) and progressive 
disease (PD) (Table 1). Clinical evaluation was performed once per week from 
the beginning of LM-related therapy, till 2 weeks later after salvage therapy. 

Clinical response was defined as continuous presence of CR, OR or PR within 
an interval of at least 1 week. SD and PD were defined as ineffective. Adverse 
events (AEs) were evaluated according to the Common Terminology Criteria 
for Adverse Events (CTCAE, version 3.0). Events of grade 3~5 was defined as 
moderate and severe adverse events. Survival time was measured from the 
enrollment of the study until death or the last follow-up.  
 
Statistical Analysis Plan 
SPSS 17.0 software was used for data analysis. Survival analysis was 
performed using the Kaplan-Meier method. Log-Rank test was used to 
compare the survival time of patients. Univariate and multivariate Cox 
regression analysis were carried out to determine the risk factors of OS. Chi 
square test and Fisher exact test were used to evaluate the difference of 
clinical response rate and OS between patients with various features. P<0.05 
demonstrated significant difference. 
 
References: 
[1] Pan Z, Yang G, He H, et al. Concurrent radiotherapy and intrathecal 
methotrexate for treating leptomeningeal metastasis from solid tumors with 
adverse prognostic factors: A prospective and single-arm study. Int J 
Cancer. 2016;139(8):1864-72. 
 
 
 
 
 
 

Figure 1 
 
 
 
 
 
 
 
 

Figure 2 
 
 
 
 
 
 
 
 
 
 

Table 1   Criteria of clinical response evaluation 
 
Neurological symptoms and signs 
KPS score 
Complete 
response 
Almost normal neurological examination. Mild cranial 
nerve symptoms including tinnitus or blurred vision may 
exist. GCS score of 15. 
≥90  
Obvious 
response 
Significant 
neurologic 
improvement. 
No 
severe 
symptoms/signs, such as severe headache, somnolence, 
mental status. Dizziness, confusion, mild headache, 
cranial nerve paralysis, or radiculitis may exist. GCS≥12. 
≥ 70, or elevation of 
≥ 30 compared with 
the baseline level. 
Partial 
response 
Partial neurological improvement. Still with headache, or 
other mild/moderate symptoms/signs. GCS≥9. 
50-70, or elevation 
of 10-20 compared 
with the baseline 
level.  
Stable 
disease 
No visible neurological improvement.  
Elevation of ≤ 10 
compared with the 
baseline level. 
Progressive 
disease  
Deteriorative neurological symptoms and signs. 
Decrease 
of 
KPS 
compared 
to 
the 
baseline level. 
Two conditions both of neurological symptoms/signs and KPS must be satisfied synchronously. 
KPS, Karnofsky performance status score; GCS, Glasgow Coma Scale. 
The clinical response was evaluated by at least two experienced neuro-oncologists. Clinical 
evaluation was performed twice per week from the beginning of LM-related therapy, till 2 weeks 
later after salvage therapy. Clinical response was defined as continuous presence of complete 
response (CR), obvious response (OR), partial response (PR) within an interval of at least 1 week. 
Stable disease (SD) and progressive disease (PD) were defined as ineffective.