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ORIGINAL ARTICLE
Year : 2018  |  Volume : 14  |  Issue : 1  |  Page : 78-83

Enhanced antitumor effects of radiotherapy combined local nimustine delivery rendezvousing with oral temozolomide chemotherapy in glioblastoma patients


1 Department of Neurosurgery, Zhengzhou University People's Hospital, Zhengzhou, China
2 Department of Pathology, Zhengzhou University People's Hospital, Zhengzhou, China
3 Department of Radiotherapy, Zhengzhou University People's Hospital, Zhengzhou, China

Date of Web Publication8-Mar-2018

Correspondence Address:
Dr. Xing-Yao Bu
Department of Neurosurgery, Zhengzhou University People's Hospital, Zhengzhou 450008
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_844_17

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 > Abstract 

Background: Glioblastoma (GBM) is one of the worst cancers with bad prognosis despite systemic chemotherapy and radiotherapy after surgery.
Methods: In this study, 71 patients with GBM were enrolled and randomly assigned to two groups: Receiving radiotherapy with concomitant and adjuvant temozolomide (TMZ) (TMZ, standard therapy) after surgery, or receiving radiotherapy with concomitant and adjuvant local delivery of nimustine (ACNU) rendezvousing with oral TMZ (rendezvous therapy). In the follow-up of all patients and the progression-free survival (PFS), overall survival (OS), Karnofsky performance score (KPS) and toxicities were recorded.
Results: For the whole cohort, the median OS was 18.0 months, and the median PFS was 7.8 months. A significantly longer OS was observed in patients received rendezvous therapy than those who receiving standard therapy (18.5 months vs. 16.0 months; P = 0.014), as well as PFS (8.8 months vs. 7.0 months; P = 0.008). The KPS ≥70 rates were 81.8%, 40.9%, 20.5% in 1, 2, and 3 years for the rendezvous therapy group, significantly superior to standard therapy group. The most common toxicities were tolerable gastrointestinal reaction, liver dysfunction, and hematological toxicities, which were relieved with symptomatic treatment. Grade 3 or 4 toxicity was documented in 8 (18.3%) patients in rendezvous therapy group, while it was observed in 6 (22.2%) patients in standard therapy group during whole treatment process.
Conclusions: Compared to standard therapy, the antitumor effects of rendezvous therapy were more effective in GBM patients without increasing the toxicities.

Keywords: Antitumor effects, glioblastoma standard therapy, rendezvous therapy


How to cite this article:
Yang DY, Bu XY, Zhou ZL, Yan ZY, Ma CX, Qu MQ, Zhao YW, Kong LF, Wang YW, Luo JC. Enhanced antitumor effects of radiotherapy combined local nimustine delivery rendezvousing with oral temozolomide chemotherapy in glioblastoma patients. J Can Res Ther 2018;14:78-83

How to cite this URL:
Yang DY, Bu XY, Zhou ZL, Yan ZY, Ma CX, Qu MQ, Zhao YW, Kong LF, Wang YW, Luo JC. Enhanced antitumor effects of radiotherapy combined local nimustine delivery rendezvousing with oral temozolomide chemotherapy in glioblastoma patients. J Can Res Ther [serial online] 2018 [cited 2021 Oct 26];14:78-83. Available from: https://www.cancerjournal.net/text.asp?2018/14/1/78/226767


 > Introduction Top


Glioblastoma (GBM) is one of the most malignant cancers for bad prognosis even with multimodal therapy. The current standard therapy for GBM included surgery and followed by radiotherapy concomitant with temozolomide (TMZ) and adjuvant TMZ.[1] Although the standard therapy improved the survival time of patients with GBM, median overall survival (OS) time has been still <15 months, and further, exploration is needed to increase the efficacy in the treatment of GBM. Thus, treatments that included the combination of TMZ with other drugs were explored and studied.[2],[3],[4] Methylguanine DNA methyltransferase (MGMT) promoter CpG island methylation was closely correlated to MGMT protein expression and sensitivity of cells to alkylating agents (ACNU, TMZ) in GBM,[5],[6],[7] individualized and multimodal approach were advocated in current studies in the treatment of GBM.

ACNU has been a standard chemotherapeutic agent against gliomas since 1980.[8] Recently, several recent studies have investigated the convection-enhanced delivery (CED) of ACNU as a new strategy to treat GBM effectively.[9],[10],[11] The delivery of local drug to tumor tissue would bypass the blood–brain barrier (BBB). Thus, prolonged and higher levels of intracerebral chemotherapeutic agents could be obtained compared to that of with systemic administration.[12] MGMT removed methylation damage induced by nitrosourea from the O'6-position of DNA guanines before cell injury, and this enzyme was detectable in 76% of glioma tissues.[10] MGMT in glioma cells is the primary defense against nitrosourea, but the cellular methyltransferase activity of MGMT would be exhausted after ACNU taking effects. In our study, local administration of ACNU was applied based on standard therapy. ACNU was administered by puncturing OR, which was connected to a silicone tube with a multiperforated basket placed in the tumor resection cavity. A high concentration of drugs would be delivered across the BBB into the central nervous system. The device provided wider distribution of agents within the target site and minimized systemic exposure. Importantly, the whole process has been easy to manipulate.

To validate the concomitant administration of ACNU in the standard therapy, we compared the results from two prospective patient groups: One treated with radiotherapy alone followed by adjuvant TMZ (standard therapy), and the other treated with radiotherapy with concomitant and adjuvant local ACNU delivery rendezvousing with oral TMZ chemotherapy (rendezvous therapy).


 > Methods Top


Patient eligibility criteria and grouping

Eligible patients who had been confirmed GBM (WHO Class IV) histologically underwent full-resection by microsurgery, were aged 18–65 years, with a good performance status (Karnofsky performance score [KPS] ≥70), postoperated 2 weeks. Blood chemistry, and hepatic and renal function were as follows: WBC count ≥4 × 109/L, hemoglobin level ≥100 g/L, platelets count ≥100 × 109/L, aspartate transaminase level ≤40 IU/L, alanine transaminase level ≤40 IU/L, serum creatinine level ≤140 umol/L. MGMT protein, MGMT methylation states, and isocitrate dehydrogenase 1 (IDH1) gene sequences were detected. Baseline medication was recorded in all patients. Patients with multiple or disseminated tumors were excluded from the study. In addition, we excluded patients who were pregnant, insulin injection, myocardial infarction, or unstable angina pectoris within the last 2 months, mental disorders, a history of pulmonary fibrosis or interstitial pneumonia, or other forms of cancer occurring within 5 years of treatment. All patients provided informed consent regarding the collection of tumor specimens and conduct of molecular evaluation. The study was approved by the Research Ethics Board of ZhengZhou University.

Treatment

Standard therapy

All the patients received standard radiotherapy after incision healing and hematologic function examination. Radiotherapy was planned with dedicated computer tomography and three-dimensional planning systems. Radiotherapy consisted of fractionated focal irradiation at dose of 1.8–2.0 Gy per fraction given once daily over a period of 6 weeks, which reduced under a total dose of 60.0–61.2 Gy to the gross tumor volume, with a 2.0–3.0 cm margin for the clinical target volume. Patients received the radiotherapy concomitant with TMZ at a dose of 75 mg/m 2/day for 6 consecutive weeks followed by 6 cycles of adjuvant TMZ (150–200 mg/m 2) for 5 days every 28 days.

Rendezvous therapy

OR was designed to provide percutaneous access to the tumor cavities through a silicone elastomer port connected to a catheter. All patients underwent the implantation of OR and intracapsular injection. First, 20% mannitol 125 ml with 2.5 mg dexamethasone was applied to increase permeability of the BBB and reduce the reaction of the local delivery of chemotherapeutic agents. Then, 2.5 mg/ml of chemotherapeutic agents (ACNU) was administrated through puncturing OR through 25-gauge noncoring needle. Patients received the ACNU interstitial chemotherapy (2.5 mg/day, 3 days/week, intracapsular injection) rendezvousing with TMZ chemotherapy (75 mg/[m 2•day], 7 days/week) for 6 consecutive weeks during radiotherapy, followed by 6 cycles of adjuvant ACNU interstitial chemotherapy (2.5 mg/day for 3 days during each 28 days cycle) and TMZ chemotherapy (150-200 mg/[m 2•day] for 5 days each 28 days cycle).

Evaluations and follow-up

KPS scores were applied to evaluate the quality of life (QOL). The blood and serum laboratory examinations were also performed to evaluate the next treatment and the adverse effects associated with chemoradiotherapy. The examinations were performed before each cycle of adjuvant chemotherapy at a frequency of nearly every 4 weeks. The magnetic resonance imaging (MRI) scan was performed every 4–8 weeks. After the completion of the treatment protocol, patients were assessed every 3 months. Adverse effects were graded with the National Cancer Institute Common Toxicity Criteria, version 3.0. Tumor progression on MRI was defined according to Response Evaluation Criteria in Solid Tumors, version 1.0. Progression of disease was defined as a 20% increase in tumor size, as shown by contrast-enhanced imaging, or the development of new lesions, neurologic deterioration, or death by any cause. Further, treatment at recurrence or progression was discretionary with records. In the treatment process, specific to patients with suspected local reaction, the patients were observed based on the current treatment options until the next review. Patients with 20% or greater increase in tumor size or under worse condition were treated as disease progression. If MRI showed that the local reaction reduced gradually, then it would be determined as pseudoprogression.

Statistical analysis

The primary endpoint was OS while the secondary end-point was progression-free survival (PFS). OS was calculated from the date of random assignment to the date of death from any cause and censored at the last follow-up for event-free patients. PFS was calculated from the date of randomization to the date of progression or death from any cause and censored at the last verifiable progression-free date for event-free patients. The selection bias when grouping patients into 2 clinical studies were evaluated and baseline characteristics of the two groups were compared with Chi-square tests, Fisher exact tests, and Student's t-tests. Patients who remained alive were censored at the date of their last visit. Survival rates and curves were estimated with the Kaplan–Meier method, and comparisons of prognostic subgroups were performed with the log-rank test. To account for the effects from prognostic factors on OS and PFS, multiple regression analyses were performed with a Cox proportional hazards model. In this study, P < 0.05 indicated statistical significance.


 > Results Top


Study population

Seventy-one patients were enrolled between February 2010 and December 2012 and randomly assigned into two groups. Considering the economic situation and the wishes of the patients, some of them could chose the treatment alternatively. A total of 27 patients were randomly assigned to receive standard therapy and 44 patients received rendezvous therapy. The median duration of follow-up after randomization for patients who were alive without a study event was 2.1 years (ranged 20 days to 4.6 years; see the Supplementary Appendix for details). Patients from the two groups were comparable in terms of clinical and molecular factors [Table 1]. At the end of follow-up, 25 (92.6%) patients died in the standard therapy group and 37 (84.1%) patients died in the rendezvous therapy group.
Table 1: Study population

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Survival studies

The PFS and OS curves of two groups were shown [Figure 1] and [Table 2]. The median PFS was 7.8 months (95% confidence interval [CI], 7.11–9.77) for the whole patient series. In the rendezvous therapy group, the median PFS was 8.8 months (95% CI: 8.42–11.07), which was significantly longer than that of in standard therapy group (7.0 months, 95% CI: 6.24–8.38) (P = 0.008). In standard therapy group, PFS rate was 70.4% at 6 months, 25.9% at 9 months, 11.1% at 12 months. While the PFS rate in rendezvous therapy group was 81.8%, 50.0%, and 22.7%, respectively. The median OS was 18.0 months (95% CI: 16.51–22.58) for the overall patient series. The median survival of rendezvous therapy group was significantly longer than standard therapy group (P = 0.014). OS rate was 74.1% at 12 months, 29.6% at 18 months, 7.4% at 24 months in standard therapy group, and it was 86.4%, 65.9%, and 25.0%, respectively, in rendezvous therapy group [Figure 2].
Figure 1: Kaplan–Meier estimates of progression-free survival (a) and overall survival (b) for the two treatment groups

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Table 2: Overall survival and progression-free survival in each study cohort

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Figure 2: Time distribution of the progression-free survival (a) and overall survival (b) junctures in standard therapy group and rendezvous therapy group

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In a multivariate Cox model that was adjusted for sex, dominant or nondominant side of tumor, MGMT promoter status, MGMT protein level, and IDH1 gene state, patients who received rendezvous therapy showed a significantly longer median PFS (Hazard ratio [HR] =0.496; 95% CI: 0.29–0.840) (P = 0.009) and median OS (HR = 0.453; 95% CI: 0.254–0.809) (P = 0.007) compared with those receiving standard therapy. Besides, patients with methylated MGMT promoter experienced significantly longer PFS (HR = 0.545; 95% CI: 0.326–0.911) (P = 0.021) and OS (HR = 0.540; 95% CI: 0.306–0.953) (P = 0.033) compared with those who had unmethylated MGMT promoter. Longer OS was observed in patients with low level of MGMT (HR = 0.574; 95% CI: 0.336–0.980) (P = 0.042), compared with patients with high level of MGMT protein [Table 3].
Table 3: Multivariate analysis of factors associated with survival

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Quality of life analysis

The KPS ≥70 rates of two groups in 1st month were 92.6% (25/27) and 93.2% (41/44). There was no significant difference between the two groups. The KPS ≥70 rates of 1, 2, and 3 years after surgery were 70.4% (19/27), 29.6% (8/27), and 14.8% (4/27) in standard therapy group, while the rates were 81.8% (36/44), 40.9% (18/44), and 20.5% (9/44) in rendezvous therapy group. However, despite of obvious improvement, there was no statistical difference between the two groups.

Adverse effects

All adverse effects that occurred during treatment were summarized [Table 4]. The most common adverse events were tolerable gastrointestinal reaction, hematological toxicities (expressed as neutropenia, thrombocytopenia, and anemia), liver dysfunction, etc. Most of them were relieved by giving symptomatic treatment. The follow-up regular blood and serum laboratory examinations showed that there was no significant damage of pulmonary, renal, and hepatic function, except different degree of hematological toxicities during the treatment process. The incidence rate of III/IV Grade of adverse events was 22.2% (6/27) and 18.3% (8/44) in standard therapy group and rendezvous therapy group, respectively. No patient died of adverse events in either group. All the other adverse effects were self-limited and resolved soon after the cessation of treatment before beginning the subsequent treatment.
Table 4: Adverse effects

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 > Discussion Top


The present study demonstrated the outcome of adding local interstitial delivery of ACNU to the standard treatment for GBM. Preferable prognosis could be obtained when patients were treated with radiotherapy with concomitant and adjuvant local ACNU delivery rendezvousing with oral TMZ chemotherapy after initial surgery.

Advances in medical and surgical treatments have resulted in quantum leaps in the OS of GBM while survival of patients with GBM has only been moderately improved.[13],[14] Current studies suggested that multimodal approach with local interstitial delivery ACNU with irradiation or systemic administration of TMZ was a promising strategy for treating GBM and other malignant tumors.[10],[15],[16] One rationale for the resection of GBM was that survival might be prolonged with surgery through a cytoreductive effect, immediately reducing tumor burden and removing cells that could be resistant to chemotherapy or other therapeutic modalities. However, the dormant tumor cells were activated rapidly in breeding period because of the resection. A positive response to initial radiation therapy for GBM has been reported to be more likely in patients who have undergone more extensive initial resection.[17] The resection of GBM was the initial and base of the multimodal approach to the subsequent treatment. TMZ a novel oral imidazotetrazinone methylating agent, which demonstrated a schedule-dependent antitumor activity in GBM.[18] Systemic administration of TMZ would make concurrently synergistic effects with concomitant radiotherapy. The cerebral penetration of some chemotherapeutic agents would be improved by radiation-induced opening of the BBB [19],[20] as well as the survival.[21] In addition, TMZ derivative was rapidly degraded and finally excreted by the kidney.

In the application of systemic chemotherapy to intracranial malignancies, poor penetration of most anticancer drugs across the BBB into the central nervous system remained a major obstacle.[12],[22] Sugiyama et al.[10] proposed a new concept of multimodal approach using CED of ACNU with radiotherapy or systemic chemotherapy of TMZ for the treatment of GBM and yielded impressive effects and offered a potentially effective method for treating GBM. However, the encapsulated ACNU in nanoparticles may lead to exceptional high or low dose of ACNU to be released through CED. Besides, the short-tissue retention time of ACNU was another limiting factor of the antitumor efficacy. In our clinical practices, local interstitial therapeutic drugs would be delivered through implanted OR during operation circumvent the BBB. High-drug concentrations reached the site of injection, which were widely distributed within the target site.[10] Bodell et al.[23] studies demonstrated that injection of BCNU into human GBM tumors up to 2.5 cm from the site of injection in the tumor produced high concentrations of BCNU obtained with systemic delivery. Steinbok et al. study showed synergistic effect of BCNU and irradiation in animal in vivo. X-ray-mediated increase of BCNU-induced DNA cross-linking was considered as the mechanism. It was resulted from increased cell apoptosis by combined treatment with such agents. The results of our study coincided exactly with above results.

Local interstitial delivery of ACNU was sensitive to BBB circumvented tumor cells, and reached high drug concentrations within the target site. Remaining tumor cells were killed in the way of “point to surface. “Local ACNU rendezvous with systemic administration of TMZ killed remaining tumor cells in a way of “surface to point.” Irradiation has increased ACNU-induced DNA cross-linking to kill cells. In addition, it also promoted antitumor efficacy by changing the integrity of the BBB to increase dose intensity of TMZ. With local application of ACNU into the brain parenchyma, transient opening of the BBB was induced to increase concentrations of TMZ. The abundant O'6-alkylguanine produced by continuous administration of TMZ might deplete MGMT and enhance the efficacy of ACNU. The combined effects of rendezvous therapy would kill uttermost remaining tumor cells. Therefore, the median PFS and median OS of rendezvous therapy group would be significantly longer than standard therapy group.

According to the results of multiple regression analysis, the factors affecting the survival of patients, in addition to the therapeutic regimen, MGMT methylation status and level of MGMT expression have been strong and independent prognostic factors for survival in GBM patients. Mutations in IDH1 or IDH2 were observed in a subset of gliomas. There were many phenotypic differences between mutant and wild-type IDH1/2 gliomas, the most critical one was that IDH1/2 mutant glioma patients demonstrated markedly improved survival, compared to IDH1/2 wild-type glioma patients.[24] Because mutations in the IDH2 gene was at a much lower frequency, only IDH1 gene was analyzed in patients. However, may be due to the relatively small sample size, patients with IDH1 gene mutation did not present a significant survival advantage in PFS nor OS. In the process of clinical observation, a few patients receiving local delivery of ACNU experienced ear pain occasionally, which could be endured. A small number of patients experienced mild discomfort of head, which could be relieved with the therapy.


 > Conclusions Top


Radiotherapy with concomitant and adjuvant local ACNU delivery rendezvousing with oral TMZ chemotherapy (rendezvous therapy) was a crucial step in the standard treatment for postoperative GBM patients. Compared with standard therapy, the antitumor effects of rendezvous therapy is more effective in GBM patients, resulting in better survival, higher QOL, without increasing the adverse effects.

Financial support and sponsorship

This work was supported by the Key Programs of Science and Technique Foundation of Henan Province (152102310136) and the Medical Science and Technique Foundation of Henan Province (201601016).

Conflicts of interest

There are no conflicts of interest.

 
 > References Top

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