|Year : 2017 | Volume
| Issue : 5 | Page : 785-789
Efficacy and safety of temozolomide plus whole-brain radiotherapy in the treatment of intracranial metastases
Hai-Peng Liu, Ke-Bin Zheng, Ji-Wei Wang
Department of Neurosurgery, Affiliated Hospital of Hebei University, Baoding, Hebei Province, PR China
|Date of Web Publication||13-Dec-2017|
No. 212, Yuhua East Road, Baoding 071000, Hebei Province
Source of Support: None, Conflict of Interest: None
Objective: This study aimed to explore the clinical efficacy and safety of temozolomide (TMZ) plus whole-brain radiotherapy (WBRT) in the treatment of intracranial metastases.
Subjects and Methods: A total of 72 patients with intracranial metastases were randomly divided into observation group and control group (each n = 36). The patients of observation group received WBRT plus TMZ, while the patients of control group received WBRT. The observation index of both groups included the short- and long-term clinical efficacies, improvement of symptoms and signs, quality of life (QOL), and adverse responses.
Results: After treatment, the objective remission rate in observation group (77.78%, 28/36) was evidently higher than that of in control group (47.22%, 17/36), with significant difference (P = 0.0074). However, the disease control rate in observation group (94.44%, 34/36) was only slightly higher than that of in control group (86.11%, 31/36) (P = 0.4263). Moreover, after treatment, compared to control group, observation group showed markedly better improvement in symptoms and signs, as well as QOL (P < 0.001), with significantly longer overall survival and progression-free survival (P < 0.001).
Conclusion: TMZ concomitant with WBRT can increase the local control, prolong the survival time and improve the QOL of patients with intracranial metastases.
Keywords: Intracranial metastases, quality of life, survival analysis, temozolomide, whole-brain radiotherapy
|How to cite this article:|
Liu HP, Zheng KB, Wang JW. Efficacy and safety of temozolomide plus whole-brain radiotherapy in the treatment of intracranial metastases. J Can Res Ther 2017;13:785-9
|How to cite this URL:|
Liu HP, Zheng KB, Wang JW. Efficacy and safety of temozolomide plus whole-brain radiotherapy in the treatment of intracranial metastases. J Can Res Ther [serial online] 2017 [cited 2019 Nov 14];13:785-9. Available from: http://www.cancerjournal.net/text.asp?2017/13/5/785/220470
| > Introduction|| |
Intracranial metastases are resulted from primary malignant tumors outside central nervous system (CNS), involving brain parenchyma, cerebrospinal fluid (CSF), cranial nerves, and intracranial vessels. Brain parenchyma metastasis has been the most common type of intracranial metastases, which is often followed by meningeal metastasis. According to the epidemiological investigation, the morbidity of intracranial metastases was much higher than that of primary intracranial tumors and approximately 20%–40% of malignant tumor patients presented with intracranial metastases during disease. The probability of intracranial metastasis in malignant tumor patients mainly depended on the pathological patterns of the primary tumors, including breast cancer, lung cancer, and head and neck squamous cell carcinoma.,, Among them, breast cancer has been the leading cause of intracranial metastases and accounted for about 32% of all cancers with intracranial metastases.
The clinical symptoms of intracranial metastases were similar to those of other intracranial space-occupying lesions, which were indicated by headache, local weakness, emotional disturbance, and sudden disturbance of consciousness. These severe neurological symptoms would be observed when intracranial metastases occurred, thus leading to poor prognosis, short survival time, and low quality of life (QOL). At present, surgery and stereotactic radiotherapy are the optimal protocols for the palliative therapy of intracranial metastases, which are only advisable for intracranial single nidus. However, multiple nidi were observed in most of the patients with intracranial metastases, for which the whole-brain radiotherapy (WBRT) was still the generally applied therapeutic method. Researches have confirmed that the accurate implementation of WBRT could relieve the symptoms of neurological system, increase the QOL and prolong the survival time of patients with intracranial metastases.,
Positive treatment after WBRT has been a critical factor for improving the prognosis of patients with intracranial metastases. However, it was still controversial whether chemotherapy could provide benefits for those patients. The clinical efficacy of chemotherapeutic agents mainly depended on their sensitivity to the primary tumors and whether these agents could pass through the blood-brain barrier (BBB). Temozolomide (TMZ) is a new oral alkylating agent with both broad-spectrum anti-tumor activity and high bioavailability. It has been commonly applied in the treatment of glioblastoma, in which it could enter into CSF through BBB and maintain a relatively high concentration in CNS. To further explore the efficacy and safety of TMZ concomitant with WBRT in the treatment of intracranial metastases, this study analyzed the short- and long-term clinical efficacies and toxic responses of this treatment and compared these with single radiotherapy, hoping to provide reference basis for clinical practices.
| > Subjects and Methods|| |
This study was approved by the Ethnic Community of our hospital, and all informed consent forms were signed by the patients and/or their families. A total of 72 patients with intracranial metastases were included as study subjects, who were admitted to Affiliated Hospital of Hebei University from June 2009 to September 2013.
Inclusion criteria: (1) The primary nidi were pathologically diagnosed with the number of metastatic nidi ≥3, which were confirmed by cerebral computed tomography or magnetic resonance image (MRI); (2) age was >18 years; (3) before treatment, Karnofsky performance status (KPS) ≥60 scores and expected survival time was >3 months; (4) before treatment, white blood cell count was ≥4.0 × 109/L, haemoglobin was ≥70 g/L and platelet was ≥100 × 109/L; (5) hepatic and renal function was normal; and (6) no history of chemotherapy or toxic responses from previous chemotherapy was observed.
Exclusion criteria: (1) With a history of radiotherapy for intracranial metastatic nidi; (2) the interval from the previous chemotherapy was <3 weeks; (3) accompanied with primary cardiovascular, renal and hematopoietic diseases; and (4) with severe psychological diseases. Of all the individuals, there were 53 males and 19 females; aged between 19 and 72 years, with the median age of 59. For primary tumors, there were 24 patients with nonsmall cell lung cancer (NSCLC), 13 with small cell lung cancer (SCLC), 21 with breast cancer and 14 with other tumors. There were 21 patients accompanied with other organic metastasis; 43 patients with the maximum diameter of metastatic nidi ≤3 cm. KPS scores: 10 patients were 60–70 scores and 62 were >70 scores. There were 16 patients with a history of chemotherapy. The patients were randomly divided into observation group and control group according to Random Number Table, with 36 cases for each group. There was no significant difference in the general data (gender, age and KPS score) between two groups, which was comparable (P > 0.05).
Both groups received linear accelerator 6MV photonic wire continuous radiotherapy. The position of patients was fix with the pyrolytic plastic mask. The left-right opposed irradiation of routine-level irradiation fields was conducted for the WBRT. The single radiotherapeutic dose was 2.0 Gy, q.d., 5 times every week, with a total dose of 40 Gy. Local boost-dose radiotherapy was performed with irradiation, which was confirmed to the following doses: The single dose was 2.0 Gy, q.d., 5 times every week, with a total dose of 10–20 Gy.
On this basis, for observation group, TMZ was added (Schering-Plough Europe company, Finland; subpackaged with S-P Labo N.V.; registration No.: H20120420; specification: 20 mg × 10 pieces) during radiotherapy, 75 mg/m2/day, q.d. After radiotherapy, complementary chemotherapy was administrated: TMZ of 150–200 mg/m2/day, for continuously 5 days, with 28 days as a cycle, until the disease progression or drug withdrawal due to intolerable toxic responses.
During chemo- and radio-therapy, dehydration therapy was conducted with mannite and dexamethasone according to the patients' conditions, which was aimed to alleviate the edema of cerebral tissues due to WBRT. During chemotherapy, granulocyte colony-stimulating factor, antiemetics, and stomach-protective agents were administrated when necessary. Their administrative dosages were adjusted based on the variations of symptoms and signs during treatment.
After 4–6 weeks of treatment, all subjects were re-examined using various laboratory indicators, symptoms and signs, QOL and cerebral 3.0 T MRI scanning, so as to monitor the nidus states and compare with those of before treatment. And then, the patients were followed up once every 3 months until January 2015 or death of patients.
The symptoms and signs during treatment, QOL before and after treatment, treatment-associated adverse responses and outcomes after corresponding therapies were observed. Short- and long-term clinical efficacies were evaluated with objective remission rate (ORR), disease control rate (DCR), overall survival (OS), and progression-free survival (PFS).
Evaluation criteria for the short-term efficacy
According to response evaluation criteria in solid tumors 1.1, the clinical efficacy was classified into complete remission (CR), partial remission (PR), stable disease (SD), and progressive disease. ORR = (CR + PR)/total cases × 100%; DCR = (CR + PR + SD)/total cases × 100%.
Improvement of symptoms and signs
Symptom remission was indicated with the decreased dose or withdrawal of symptomatic treatments, otherwise, it indicated no significant remission or aggravation of the symptoms.
Evaluation criteria of quality of life
KPS score was applied to evaluate the objective variations of QOL. After the end of treatment, KPS increase of ≥10 scores reflected improved QOL; KPS decrease of ≥10 scores reflected decreased QOL; and KPS increase or decrease of <10 scores reflected stable QOL.
Evaluation criteria for clinical safety
Referring to the National Cancer Institute Common Toxicity Criteria 4.0, all adverse responses were classified into degree 0–4, and corresponding symptomatic therapies were performed.
All data analysis was performed by SAS 9.3 and SPSS 17.0 software package (IBM, Chicago, IL). Classified variables were calculated and analyzed with Chi-square test or continuous calibration Chi-square test, while rank classified variables were analyzed with likelihood ratio Chi-square test. Median OS and PFS were detected with Wilcoxon rank-sum test. Survival analysis was expressed with Kaplan–Meier survival curve and detected by Log-rank test. P < 0.05 was considered as statistically significant.
| > Results|| |
Comparison of short-term efficacy on cerebral nidi between two groups
The tumor progression could be effectively controlled with both single radiotherapy and TMZ concomitant with WBRT [Figure 1]. After treatment, the ORR in observation group was 77.78% (28/36), which was evidently higher than that of in control group (47.22%, 17/36), with significant difference (χ2 = 7.1704, P = 0.0074). However, the DCR in observation group was 94.44% (34/36), which was only slightly higher than that of in control group (86.11%, 31/36), without significant difference (χ2 = 0.6330, P = 0.4263) [Table 1] and [Figure 1].
|Figure 1: Magnetic resonance image images of re-examination in both Groups. (a) Observation group before treatment. (b) Observation group 6 weeks after the end of treatment. (c) Control group before treatment. (d) Control group 6 weeks after the end of treatment|
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Comparison of improvement of symptoms and signs and quality of life after treatment
The improvement rates of symptoms and signs during treatment and 4–6 weeks after treatment were 94.44% (34/36) in observation group and 63.89% (23/36) in control group, respectively, with significant difference (χ2 = 10.1895, P = 0.0014). The QOL scores were increased in 32 patients of observation group and 19 patients of control group, respectively, with significant difference (χ2 = 11.3613, P = 0.0007).
Comparison of long-term efficacy between two groups
The median OS and PFS in observation group were 8.5 and 5.0 months, which were significantly longer than that of in control group, which were 5.0 and 3.0 months (P < 0.001) [Figure 2]a and [Figure 2]b.
|Figure 2: Kaplan–Meier curves of (a) overall survival and (b) progression-free survival of control group and observation group|
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Evaluation of safety
The hematological and gastrointestinal responses were two common acute adverse responses in both groups, and these symptoms were relieved after symptomatic treatment. There was no significant difference in the rates of adverse responses between observation group and control group (P > 0.05). No liver-, kidney-, or heart-related adverse responses were observed in both groups. There was no decreased dosage of chemotherapeutic agents due to adverse responses in both groups. The patterns and degrees of adverse responses were shown [Table 2].
| > Discussion|| |
In this study, the clinical efficacies and safety were compared between TMZ concomitant with WBRT and single WBRT in patients with intracranial metastases. Our results showed that compared with single WBRT, TMZ concomitant with WBRT demonstrated better efficacy, which could significantly improve the symptoms and signs, increase the QOL and prolong the survival time without increasing the treatment-associated adverse responses.
TMZ is a derivative of imidazotetrazines, and can be transformed into active metabolite 5-(3-methyl triazene-1-base)imidazo-4-amide (MTIC) in the human body. MTIC is a highly active DNA methylating agent and demonstrated cytotoxic effects via methylating the guanine on DNA O6. After oral administration, TMZ would be widely distributed in the whole body without liver metabolism and could enter into CSF through BBB, thus leading to high drug concentration in CNS. A multi-center randomized clinical trial indicated that TMZ concomitant with radiotherapy was superior to single radiotherapy for glioma patients, from the aspects of tumor remission rate, median survival time, and 2-year survival rate.
Some scholars have explored the clinical efficacy of TMZ in the treatment of intracranial metastases. TMZ was high in bioavailability, facile in passing through BBB, mild in adverse responses and favorable in patients' compliance for being orally administrated. Addeo et al. applied WBRT (30 Gy) concomitant with TMZ (75 mg/m2/day, p.o.) in 59 patients with intracranial metastases, followed by maintenance chemotherapy with TMZ (150 mg/m2/day, p.o.). It showed significant improved QOL, with 13 months of median OS and favorable drug tolerance. However, this study has not performed the comparison between single WBRT and WBRT concomitant with TMZ. One Phase II randomized trial on TMZ and concurrent radiotherapy in patients with brain metastases showed that ORR could be significantly improved with TMZ and radiotherapy, compared to single radiotherapy. Another Phase II randomized trial showed that for patients with brain metastases, PFS would be significantly improved in TMZ with WBRT compared with WBRT alone, indicating that TMZ could improve local control of brain metastases. Another study was performed on human epidermal-growth-factor receptor 2-positive breast cancer patients with intracranial metastases who was treated with TMZ and lapatinib. It found that gastrointestinal toxicity was the major adverse response, while the median OS and PFS were 10.94 and 2.60 months, respectively. Furthermore, animal experiments also illustrated that TMZ could inhibit intracranial metastases in breast cancer patients, and the inhibiting rate was closely associated with the dosage and administrative approaches. However, some studies found that TMZ combined with concurrent WBRT could not improve the local control and survival time of breast cancer patients with intracranial metastases; in which the ORR, median OS and PFS of single radiotherapy were 36%, 11.1 and 7.4 months, while those of in combined treatment were 30%, 9.4 and 6.9 months, respectively.
There were still some limitations in this study. First, the primary tumors were heterogeneous, with 24 cases of NSCLC, 13 cases of SCLC, 21 cases of breast cancer and 14 cases of other tumors. Therefore, the efficacies and safety of TMZ concomitant with WBRT might be complex. For example, compared with WBRT alone, TMZ combined with WBRT could improve the ORR in intracranial metastases patients with NSCLC, but not for patients with breast cancer. Second, the sample size was small and the results were not robust enough. Further large cohort study can focus on intracranial metastases patients from one tumor and exclude the heterogeneity of study population. Third, TMZ showed toxicity in conventional schedule. Compared with WBRT alone, WBRT and TMZ combination therapy demonstrated a higher rate of toxicity in intracranial metastases patients. Therefore, TMZ should be combined with other cytotoxic drugs which could cross BBB.
| > Conclusion|| |
The combined treatment of WBRT and TMZ showed higher efficacy, which could significantly improve the symptoms and signs, increase the survival quality and prolong the survival time without increasing the treatment-associated adverse responses. Further stratified analysis is needed through deeper investigation on the clinical efficacy of TMZ concomitant with WBRT in the treatment of intracranial metastases patients with different primary nidi, as well as on the clinical efficacy influenced by patients' clinical pathological characteristics.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| > References|| |
Mendoza A, Hong SH, Osborne T, Khan MA, Campbell K, Briggs J, et al.
Modeling metastasis biology and therapy in real time in the mouse lung. J Clin Invest 2010;120:2979-88.
Custódio-Santos T, Videira M, Brito MA. Brain metastasization of breast cancer. Biochim Biophys Acta 2017;1868:132-47.
Zhao X, Zhu G, Chen H, Yang P, Li F, Du N, et al.
Efficacy of icotinib versus traditional chemotherapy as first-line treatment for preventing brain metastasis from advanced lung adenocarcinoma in patients with epidermal growth factor receptor-sensitive mutation. J Cancer Res Ther 2016;12:1127-31.
Ghosh-Laskar S, Agarwal JP, Yathiraj PH, Tanawade P, Panday R, Gupta T, et al.
Brain metastasis from nonnasopharyngeal head and neck squamous cell carcinoma: A case series and review of literature. J Cancer Res Ther 2016;12:1160-3.
Akhavan A, Binesh F, Heidari S. Survival of brain metastatic patients in Yazd, Iran. Asian Pac J Cancer Prev 2014;15:3571-4.
Demircioglu F, Demirci U, Akmansu M. Lymph node ratio assessment of brain metastasis in early breast cancer cases. Asian Pac J Cancer Prev 2013;14:1665-7.
Harada H, Asakura H, Ogawa H, Mori K, Takahashi T, Nakasu Y, et al.
Prognostic factors in patients with brain metastasis from non-small cell lung cancer treated with whole-brain radiotherapy. J Cancer Res Ther 2016;12:267-70.
Duan L, Zeng R, Yang KH, Tian JH, Wu XL, Dai Q, et al.
Whole brain radiotherapy combined with stereotactic radiotherapy versus stereotactic radiotherapy alone for brain metastases: A meta-analysis. Asian Pac J Cancer Prev 2014;15:911-5.
Lippitz B, Lindquist C, Paddick I, Peterson D, O'Neill K, Beaney R, et al.
Stereotactic radiosurgery in the treatment of brain metastases: The current evidence. Cancer Treat Rev 2014;40:48-59.
Nieder C, Marienhagen K, Dalhaug A, Aandahl G, Haukland E, Pawinski A, et al.
Impact of systemic treatment on survival after whole brain radiotherapy in patients with brain metastases. Med Oncol 2014;31:927.
Liu Y, Hao S, Yu L, Gao Z. Long-term temozolomide might be an optimal choice for patient with multifocal glioblastoma, especially with deep-seated structure involvement: A case report and literature review. World J Surg Oncol 2015;13:142.
Kirstein MN, Panetta JC, Gajjar A, Nair G, Iacono LC, Freeman BB 3rd
, et al.
Development of a pharmacokinetic limited sampling model for temozolomide and its active metabolite MTIC. Cancer Chemother Pharmacol 2005;55:433-8.
Diez BD, Statkevich P, Zhu Y, Abutarif MA, Xuan F, Kantesaria B, et al.
Evaluation of the exposure equivalence of oral versus intravenous temozolomide. Cancer Chemother Pharmacol 2010;65:727-34.
Athanassiou H, Synodinou M, Maragoudakis E, Paraskevaidis M, Verigos C, Misailidou D, et al.
Randomized phase II study of temozolomide and radiotherapy compared with radiotherapy alone in newly diagnosed glioblastoma multiforme. J Clin Oncol 2005;23:2372-7.
Addeo R, Caraglia M, Faiola V, Capasso E, Vincenzi B, Montella L, et al.
Concomitant treatment of brain metastasis with whole brain radiotherapy [WBRT] and temozolomide [TMZ] is active and improves quality of life. BMC Cancer 2007;7:18.
Antonadou D, Paraskevaidis M, Sarris G, Coliarakis N, Economou I, Karageorgis P, et al.
Phase II randomized trial of temozolomide and concurrent radiotherapy in patients with brain metastases. J Clin Oncol 2002;20:3644-50.
Verger E, Gil M, Yaya R, Viñolas N, Villà S, Pujol T, et al.
Temozolomide and concomitant whole brain radiotherapy in patients with brain metastases: A phase II randomized trial. Int J Radiat Oncol Biol Phys 2005;61:185-91.
de Azambuja E, Zardavas D, Lemort M, Rossari J, Moulin C, Buttice A, et al.
Phase I trial combining temozolomide plus lapatinib for the treatment of brain metastases in patients with HER2-positive metastatic breast cancer: The LAPTEM trial. Ann Oncol 2013;24:2985-9.
Palmieri D, Duchnowska R, Woditschka S, Hua E, Qian Y, Biernat W, et al.
Profound prevention of experimental brain metastases of breast cancer by temozolomide in an MGMT-dependent manner. Clin Cancer Res 2014;20:2727-39.
Cao KI, Lebas N, Gerber S, Levy C, Le Scodan R, Bourgier C, et al.
Phase II randomized study of whole-brain radiation therapy with or without concurrent temozolomide for brain metastases from breast cancer. Ann Oncol 2015;26:89-94.
Tian J, Luo Y, Xiang J, Tang J. Combined treatment for non-small cell lung cancer and breast cancer patients with brain metastases with whole brain radiotherapy and temozolomide: A systematic review and meta-analysis. J Neurooncol 2017;135:217-27.
Addeo R, Caraglia M. Combining temozolomide with other antitumor drugs and target-based agents in the treatment of brain metastases: An unending quest or chasing a chimera? Expert Opin Investig Drugs 2011;20:881-95.
[Figure 1], [Figure 2]
[Table 1], [Table 2]