Recurrent gliomas

Abstract

Background: Primary brain tumors have always been associated with high morbidity and mortality. Glioma is the most common type of malignant brain tumors,with a high probability of recurrence after surgical excision and with poor prognosis.The purpose of this study was to compare the therapeutic efficacy of computed tomography (CT)-guided interstitial ¹²⁵I seed implantation with traditional radiochemotherapy for treatment of recurrent gliomas.

Results: The response rate at 1, 3, 6 and 12 months after ¹²⁵I seed implantation was 68.6, 74.3, 77.1 and 62.8% respectively, which was significantly higher than the group treated with the conventional chemoradiation protocol (p < 0.05). Patients exposed to ¹²⁵I seed implantation had a median survival of 29.0 months, whereas the median survival of those treated with traditional radiochemotherapy was 19.0 months. The difference observed between the two groups was significant. There were no severe complications or mortality associated with either treatment, except for one case of intracerebral hemorrhage around the tumor area in the ¹²⁵I seed implants group.

Methods: From November 2002 to May 2010, 73 consecutive patients with recurrent gliomas were treated with CT-guided ¹²⁵I seed implantation (35 cases) or traditional radiochemotherapy (38 cases). Patients were followed up after treatment and the therapeutic effect was evaluated by comparing the response and survival rates of the two groups. In particular, patients treated with ¹²⁵I seed implantation were monitored for adverse side effects.

Conclusions: CT-guided ¹²⁵I seed implantation is safe and well-tolerated and more importantly, shows superior efficacy compared with conventional radiochemotherapy. This suggests that CT-guided ¹²⁵I seed implantation could be an alternative approach for recurrent gliomas.

Keywords: :

• ¹²⁵I
• brachytherapy
• computed tomography (CT)-guided implantation
• glioma
• radiochemotherapy

Introduction

Malignant gliomas, which typically arise in the lobar white matter or in the deep gray matter of the brain, are characterized by a diffusely infiltrating spread and are the most common and aggressive primary brain tumors in adults.¹ The duration of survival of patients with malignant gliomas has remained essentially the same in the last three to four decades, despite striking progress achieved in medical and surgical technology and in the understanding of the biological basis as well as the molecular genetics of glioma cells.^2,3

The current standard therapy for newly diagnosed malignant gliomas consists of surgery, preferably a gross total resection of contrast-enhanced areas, subsequent fractionated external-beam radiotherapy, adjuvant chemotherapy in some cases, or combinations of these three approaches.^4,5 Despite optimal treatment with surgery, radiotherapy and temozolomide, and subsequent beneficial outcomes, tumor recurrences is frequently observed. Treatment of recurrent malignant gliomas is challenging, because tumor infiltration and the potentiation of neurologic toxicity often makes repeated surgery unfeasible. Facing limited treatment options, patients are usually enrolled into chemotherapy trials. As a result, an increasing number of studies have been focused on developing effective approaches for the treatment of recurrent malignant gliomas.

Interstitial brachytherapy is a form of radiotherapy in which radioactive seeds or sources are placed in or near local tumor sites. One of the advantages of brachytherapy compared with regular radiation therapy is that it delivers a high dose of radiation to the tumor but reduced radiation exposure to the surrounding healthy tissue.⁶ Radioactive iodine-125 (¹²⁵I) and palladium-103 (¹⁰³Pd) are two commonly used seeds and have been applied in different circumstances. ¹²⁵I is a low-energy radioisotope with a relatively long half-life (59.6 d). It emits gamma-rays with maximum energies of 35 keV, which causes DNA double-strand breaks in tumor cells and eventually suppresses cell proliferation or leads to cell death.⁷ Brachytherapy with ¹²⁵I seeds has been used as a first-line choice for early prostate cancer.⁸ In addition, it provides an alternative approach for the treatment of various other cancers, including colon, cervical, prostate, breast, liver and skin cancers.^9-13

Despite its wide range of application and beneficial outcomes in various types of cancer therapy, the application of brachytherapy in central nervous system (CNS) tumors, such as recurrent malignant gliomas, has been greatly debated.¹⁴ In the current study, we used CT (CT)-guided precise interstitial ¹²⁵I implants in the treatment of recurrent gliomas. Unlike previous studies, we used skull drilling instead of skull opening for the ¹²⁵I seed implantation so as to reduce cerebral damage. A parallel treatment group received traditional chemoradiation therapy. The therapeutic efficacy was assessed and compared between the two treatment options. In addition, patients were followed up and complications due to treatment were monitored. The study found that characterized CT-guided ¹²⁵I seed implantation was more effective and better tolerated compared with conventional chemoradiation therapy. Therefore this report reveals its potential in the treatment of recurrent gliomas.

Results

Response rate comparison

To evaluate the therapeutic effectiveness of the ¹²⁵I seed implantation, we begun by comparing the patients’ responses at different time-points after the ¹²⁵I seed implantation with those of the patients given conventional chemoradiation therapy (Table 2). At 1, 3, 6 or 12 mo after ¹²⁵I seed implantation, 20.0%, 22.9%, 20.0% and 17.1% of patients respectively showed CR and 48.6%, 51.4%, 57.1%, 45.7% of patients partially responded. By comparison, the RRs(which reflect overall therapeutic efficacy)of the patients in the chemoradiation group at these time points were significantly lower, RRs at 1, 3, 6 and 12 mo after ¹²⁵I seed implantation was 68.6%, 74.3%, 77.1% and 62.8% respectively, which was significantly higher than the group treated with conventional chemoradiation (p < 0.05).

These data together support the superior efficacy of ¹²⁵I seed implantation relative to the conventional treatment options for patients with recurrent gliomas,and indicate optimal efficacy of ¹²⁵I seed implantation treatment in recurrent gliomas.(Figs. 1 and 2)

Figure 1. A 54-y-old female patient with recurrent gliomas. (A) CT images before 125I seed implantation treatment showed that brain tumor of left posterior parietal region was 30 mm × 40 mm × 50 mm. (B) outlined the planning target volume (PTV) with computerized treatment planning system (TPS) before 125I seed implantation to determine the needle insertion and dose distributions. (C) needle insertion during 125I seed implantation operation. (D) seed distribution after 125I seed implantation treatment. E: verification of TPS immediately after 125I seed implantation treatment. (F) dose volume histogram of PTV of pre-operation TPS. (G) dose volume histogram of PTV of post-operation TPS verification.

Figure 2. A 68-y-old male patient with recurrent gliomas. (A) CT images before 125I seed implantation treatment showed that brain tumor of left anterior parietal region was 25 mm × 30 mm × 40 mm. (B) needle insertion during 125I seed implantation operation. C:two months after 125I seed implantation treatment. (D) one year after 125I seed implantation treatment.

Survival rate comparison

The survival of the patients following each treatment were compared (Table 3). Consistent with the RR, the median survival of patients treated with ¹²⁵I seed implantation was significantly longer that those exposed to chemoradiation therapy. Two-year survival after brachytherapy was 77.1%, which was significantly higher than that of patients treated with chemoradiation therapy (52.6%). Although the one-year survival was also greater for the brachytherapy group, the difference was not statistically significant (Fig. 3).These data together demonstrate that CT-guided ¹²⁵I seed implantation has the curative advantage compared with the conventional approach.

Figure 3. Kaplan-Meier curve shows overall survival rates for patients who received 125I implantation (A) and for those who underwent conventional chemoradiation therapy (B).

Safety and tolerance

To evaluate CT-guided ¹²⁵I seed implantation more fully as an alternative approach for the treatment of recurrent glioma, after the implantation patients were monitored for adverse side effects and associated complications. During the follow-up period, no hemorrhagic inflammation, cerebrospinal fluid fistula, or radiation encephalopathy was detected in any patient treated with implantation, except one case of intracerebral hemorrhage around the tumor area. The patient recovered from the bleeding after emergency cerebral surgery. No treatment-related death occurred in either the ¹²⁵I seed implanted or chemoradiation-treated groups.Side effects due to chemoradiation therapy included bone marrow suppression, gastrointestinal reactions and alopecia.

Discussion

Implantation of radioactive ¹²⁵I seeds has long been recognized for its superiority to other radiotherapies. As low-energy radioactive seed interstitial implantation results in positive clinical treatment of many tumors previously resistant to high doses of radiation. The advantages of internal implantation are, first, due to the shorter distance to local tumor sites, thereby enabling a higher cumulative dose, up to 160 Gy, to the tumor.¹⁵ Second, with the substantial attenuation of radiation potency over short distance, implantation of radioactive seeds within or near the tumor avoids the serious complications caused by radiation exposure to non-target tissues, which frequently occur with traditional radiotherapy. Third, the inhomogeneous radiation absorption observed in traditional radiotherapy, results in attenuated therapeutic potency, which is not the case in internal radiation. In addition, previous study has shown that external radiotherapy is only effective in cells at certain phases of the cell cycle while ¹²⁵I seeds can kill tumor cells at any time by causing them to stay in the resting period and by inducing apoptosis in tumor stem cells. Finally, it is also noted that the implantation of low-energy radioactive seeds is able to suppress tumor metastasis by changing the immunophenotype of tumor cells.¹⁶

Given all these advantages, it is of no surprise that high expectations have also been placed on the efficacy of internal implantation to improve the outcome for patients with CNS tumors. However, various studies have shown conflicting results,^17-20 with some reports of no significant survival advantage. This has raised a question about the potential of applying brachytherapy in the treatment of CNS tumors, including malignant gliomas.²¹ In the present study, the question was addressed by comparing ¹²⁵I implantation and conventional chemoradiation in the treatment of recurrent gliomas. Our data indicate that brachytherapy is a more effective and better tolerated alternative to traditional chemoradiation. We speculate that differences in implants, optimal dose rate, target volume, timing of brachytherapy and patient selection might account for the controversial outcomes reported so far. Our data could provide guidance on using brachytherapy in the treatment of CNS tumors. Pseudo-progression: has been known to be relevant to treatment of high-grade gliomas. However, we did not observe the incidence of radiation-induced brain edema or early pseudo-progression.²² The reasons might be: 1) low dose rate radiation we applied causes mild side-effects and the brain edema did not last long²³; 2) by the time of assesment, which is usually 4–6 weeks following implantation, the paitents likely have recovered from acute edema caused by surgery²⁴; 3) the intratumoral ¹²⁵I implantation indeed caused very mild affect on the normal tissue regions and thereofore the radiation-induced edema was less servere compared with external radiation,^25,26

Several prognostic factors, such as age, histology and extent of surgery have been established for patients newly diagnosed with malignant gliomas. However, the prognostic factors for patients with recurrent malignant gliomas remain unclear. A previous study of 375 patients from eight phase-II trials which examined outcomes and prognostic factors associated with recurrent gliomas, indicated that histology was a dominant factor in determining outcome in this group of patients.²⁷ A more recent phase-II study of 51 adults with recurrent malignant gliomas suggested that histology, myelotoxicity and prior chemotherapy were significantly correlated with both time to tumor progression and survival.²⁸ All these factors should be considered when designing future trials for recurrent gliomas.

While many studies have focused on demonstrating the therapeutic effect of radioactive seed interstitial implantation, few have concentrated on delineating the molecular mechanisms that underlie outcome differences in traditional radiotherapy vs. interstitial implanted radiation. Fundamental research leading to a better understanding of the biological mechanisms may allow therapeutic modifications in radiotherapies, including brachytherapy, which could be evaluated in future clinical studies. Given the fact that most patients enrolled in this study had recurrent cancer following chemotherapy, the standard VM-26 (teniposide 200 mg/m²) regimen was replaced with elemene or temozolomide for patients in severe conditions, such as those with grade III + IV tumors or even worse. Elemene is an antitumor composite derived from the traditional Chinese Medicines, which was characterized by the ability to pass the blood-brain barrier and minor toxicity . In spite of such modification in regimen, the clinical outcome of our study was in agreement with the previous reports.^29,30

In spite of the small number of cases reviewed in the current study, the data strongly suggest that for treatment of recurrent gliomas CT-guided precise ¹²⁵I interstitial implantation holds advantages over conventional options. These advantages include precision of radiation location, less cerebral damage, and fewer complications. The use of CT-guided precise ¹²⁵I interstitial implantation should therefore be considered a viable alternative for the treatment of recurrent gliomas.

Patients and Methods

Patients

This study was approved by the local ethics committee and Institutional Review Board (Cancer Centre of Sun Yat-Sen University and Pingyi branch of Qilu Hospital). From November 2002 to May 2010, 73 consecutive patients with diagnosed recurrent brain gliomas were enrolled. Patients were informed of the potential risks, and written consent was obtained from the patients or their guardians before beginning the study. The enrolled patients were admitted to either of two independent hospitals that were working collaboratively. All the patients met the following inclusion criteria: the presence of post-surgical recurrences of glioma confirmed by pathological diagnosis, tumor diameter below 3 cm, tumor with clear borders on CT imaging, no metastasis observed in other organs, and suitable for the treatment approaches used in this study, i.e., the level of blood platelets was not less than 10 × 10¹⁰, coagulation time was less than 4 sec, and no intracranial vascular malformations, intracranial hemorrhage or thrombotic disorders detected. In the cases where tumor borders were hard to identify, the critical functional regions, such as those around brainstem, temporal lobe and optic nerve, were avoided during implantation. The patients enrolled in this study were divided into two groups. The detailed information of each group is presented in Table 1. No significant difference (p > 0.05) was observed between the two groups.

Table 1. Characteristics of 73 patients treated with recurrent gliomas

Characteristic	^125I Implantation	Radiochemotherapy
No. of patients	35	38
Female/male patients	10/25	12/26
Mean age (y)	44.9 (28–65)	46.3 (31–68)
Lesion diameter (cm)
< 3	16	18
≥ 3	19	20
Mean	3.42 (1.5–6.5)	3.36 (2.0–6.0)
Position of lesion
Frontal lobe	5	9
Temporal lobe	6	7
Occipital lobe	6	5
Parietal lobe	8	6
Cerebellum	4	5
Thalamus	3	4
Mesencephalon	3	2
Pathological grade
I + II	15	21
III + IV	20	17
Table 2. Comparison of the response rate of patients treated with ^125I implantation with conventional radiochemotherapy
Group	No. of Patients	Date (m)	Local control efficacy (%)
			CR** PR** NC** PD** RR
^125I implantation	35	1 3 6 12	7(20.0) 17(48.6)* 6(17.1) 5(14.3) 24(68.6)* 8(22.9) 18(51.4)* 4(11.4) 5(14.3) 26(74.3) * 7(20.0) 20(57.1)* 3(8.6) 5(14.3) 27(77.1) * 6(17.1) 16(45.7)* 4(11.4) 9(25.8) 22(62.8) *
Radiochemotherapy	38	1 3 6 12	7 (18.4) 14(36.9) 10(26.3) 7(18.4) 21(55.3) 10 (26.3) 13(34.2) 7(18.4) 8(21.1) 23(60.5) 9 (23.7) 16(42.1) 6(15.8) 7(18.4) 25(65.8) 8 (21.1) 12(31.5) 6(15.8) 12(31.6) 20(52.6)
Note: Data in parentheses are percentages. **CR = complete response; PR = partial response; NC = no change; PD = progressive disease. RR = indicates the percentage of patients with response, i.e., RR = PR+CR. *p < 0.05 vs. chemoradiation group.
Table 3. Comparison of survival of patients treated with ^125I implantation with conventional radiochemotherapy
	^125I implantation	Radiochemotherapy	p value
Median survival (mo)	29.3 ± 2.1	19.7 ± 1.4	p < 0.05
Overall Survival
1-y (%)	90.4	85.2	p > 0.05
2-y (%)	77.1	42.5	p < 0.05

Instruments

A High Speed Advantage Genesis CT scanner (GE Healthcare) was used. A treatment planning system was developed by Beijing University of Aeronautics and Astronautics. Instruments for seed implantation included 18-G implantation needles and a turntable implantation gun. ¹²⁵I seeds were obtained from Jun’an Pharmaceuticals Co. Ltd. The diameter and length of each seed was 0.8 mm and 4.5 mm respectively. The thickness of the wall of the titanium capsule was 0.05 mm. ¹²⁵I emits gamma rays (5% of 35 keV, 95% of 28 keV) with a half life of 59.6 d, a half value thickness of 0.025 mm of lead, penetration of 17 mm and incipient rate of 7 cGy/h.

Treatment planning system

A computerized treatment planning system was used to determine the dose distributions so as to maximize tumor control and minimize complications in normal tissue. Treatment planning and applied radiation dosages were based on three-dimensional (3D) models representing patient anatomy and tumor targets. Detailed information about the targeted tumor, including tumor size, status and location, as well as tumor connected vessels was collected using images and histological information provided by CT, magnetic resonance imaging and 3D models. Based on this information, decisions regarding the insertion site, path and direction of needles were decided and an isodose curve distribution was plotted.

Seeds were implanted 0.5–1 cm apart. For patients undergoing radiation treatment for the first time, the matched peripheral dose (MPD) was 90–110 Gy while that for patients who had been exposed to radiation therapy before the MPD was 80–90 Gy. The planning target volume margin was 0.5 cm greater than the clinical target volume. Dosage delivered to affected organs and tumors was measured using a dose-volume histogram. ¹²⁵I treatment plan is not based on tumor grade, but it is based on the size of tumor volume to obtain effective treatment dose. The specific effect of ¹²⁵I radiation on tumor cells can emits gamma-rays with maximum energies of 35 keV, which causes DNA double-strand breaks in tumor cells and eventually suppresses cell proliferation or leads to cell death, which have been reflected in a broad range of literature. CT scanning was performed immediately after seed implantation to confirm that the treatment plan was being followed and modification was made in case of inaccuracy (Figs. 1 and 2).

¹²⁵I seeds implantation

Implantation was guided by CT according to our treatment planning system. The volume and shape of each tumor was assessed with CT scanning and used to calculate the MPD and to determine the position and number of seeds needed by simulating the approximation of dose distribution in any given tumor (Figs. 1 and 2). The patients had their heads shaved and they were treated with diazepam the day before the surgery. General anesthesia was applied during the surgery. The drilling holes in the skull were located closest to the tumor foci and avoided critical cerebral areas, such as the major vessels and cerebral venous sinus. Needle insertion followed a fan-shaped path so as to minimize cerebral damage. In the fan-shaped area, the needle was gradually retrieved after reaching the furthest point. ¹²⁵I seeds were implanted into the cancerous embolus 5–10 mm apart along the length and diameter of the tumor. CT scanning was performed immediately after implantation to monitor potential complications, in particular, cerebral hemorrhage. The needle was inserted and retrieved with minor adjustment of angles as needed and this process was repeated two to five times to achieve the correct implant location. After the procedure, the puncture site was bandaged and compressed for homeostasis.

Treatment

In the conventional chemoradiation treated group, all the patients were irradiated 30–35 times at a dose of 60–70 Gy in a cycle of 40–60 d. The dosages were set prior to treatment according to the maximum accumulative dosages in different brain regions. The brainstem cumulative dose could not exceed 54 Gy, while those for regions close to temporal lobe, spinal cord, optic nerve and crystalline lens were below 60 Gy, 45Gy, 50 Gy and 9 Gy respectively, which is suitable for both external radiation and internal implantation. However, the low-energy photon ¹²⁵I applied in this study has been know to lose over 80% genery at a distance of 2 cm from the source center and practically all seeds were all implanted in the non-functional area in this case. It might not be necesseary to concider the dosage contraits.^25,26 Simultaneously, VM-26 (teniposide, 200 mg/m²) was given for three consecutive days followed by a two-week break in each cycle. The cycle was repeated four times. For patients with more severe conditions, such as those with grade III + IV tumors or larger, additional treatments with elemene injection (600 mg/day for 14 consecutive days each cycle) or temozolomide (250 mg/day for seven consecutive days each cycle) were included.

Evaluation of therapeutic effect

The assessment of therapeutic effect followed the Response Evaluation Criteria in Solid Tumors guidelines published by the World Health Organization. Tumor volume was examined by CT scanning. Two-dimensional (2D) tumor measurements (the product of the longest diameter and the longest perpendicular diameter for each tumor) were performed. The assessment criteria were: complete response (CR), tumor disappeared; partial response (PR), at least 50% decrease in values obtained in the 2D tumor measurements; no change (NC), no more than 50% decrease and less than 25% increase in the product of the two largest diameters; progressive disease (PD), more than 25% increase in the product of the longest diameter and its longest perpendicular diameter or appearance of a new tumor. The response rate (RR) was calculated as the sum of the CR and PR.²⁴

Statistical analyses

Data were represented as mean ± SD. Statistical analyses were performed using SPSS 11.5 software (SPSS Inc. Chicago, IL, USA). Cumulative survival curves were constructed using the Kaplan-Meier method and compared with the log-rank test. Results were considered significant at p < 0.05.

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Notes

† These authors contributed equally to this work.