A pilot study of metronomic temozolomide treatment in patients with recurrent temozolomide-refractory glioblastoma

Kong, Doo‐Sik; Lee, Jung-Il; Kim, Won Seog; Son, Myung Jin; Lim, Do Hoon; Kim, Sung Tae; Park, Kwan; Kim, Jong Hyun; Eoh, Whan; Nam, Do‐Hyun

doi:10.3892/or.16.5.1117

Cited by 39 publications

(34 citation statements)

References 20 publications

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“…Our results show that both monotherapies (TMZ alone and ZD6474 alone) efficaciously reduced tumor volume, corroborating with previous reports (7,8,13,(20)(21)(22), while a more marked tumor volume reduction (94%) was achieved with the combination treatment, due to the highly anti-angiogenic (64% reduction of MVD) and anti-proliferative (40% reduction) effects of the combined therapy. To further understand the mechanisms involved, future studies need to investigate the expression changes of angiogenic markers, such as VEGF and EGF.…”

Section: Discussionsupporting

confidence: 92%

“…Its small size allows it to easily pass the blood-brain barrier and is therefore widely used in the clinic for the treatment of tumors of the central nervous system and metastatic melanoma (14,15). Previous literature has reported that low dose, metronomic TMZ administration leads to lower resistance to the drug and even inhibits angiogenesis (7,13). The present study also applied the low dose, metronomic TMZ therapy and observed a 80% reduction in tumor volume even with the single agent treatment.…”

Section: Discussionmentioning

confidence: 99%

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Combined therapy of temozolomide and ZD6474 (vandetanib) effectively reduces glioblastoma tumor volume through anti-angiogenic and anti-proliferative mechanisms

Kim

et al. 2012

Mol Med Report

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Abstract. Currently, clinically available options for treating glioblastoma (GBM) are quite limited, and there is a clear need to develop novel treatment strategies that can more effectively manage tumors. Here, we present a combination treatment of temozolomide (TMZ), a blood-brain barrier penetrating DNA alkylating agent, and ZD6474 (vandetanib), a VEGFR2 and EGFR dual-targeting anti-angiogenic agent, as a novel treatment strategy for GBM. In a U-87MG orthotopic xenograft model, the combination treatment provided a marked 94% tumor volume reduction. This reduction was greater than that achieved by monotherapy of either agent, and was correlated with a statistically significant reduction in microvessel density (CD31 + cells) and proliferation (PCNA + cells). These results confirm the necessity to target angiogenesis in addition to utilizing cytotoxic approaches, and provide the rationale for application of TMZ + ZD6474 combination therapy for treating GBM patients in the clinical setting.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Combined therapy of temozolomide and ZD6474 (vandetanib) effectively reduces glioblastoma tumor volume through anti-angiogenic and anti-proliferative mechanisms

Kim

et al. 2012

Mol Med Report

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“…Table 3 Retrospective studies and clinical trials with temozolomide in recurrent GbM (temozolomide + nitrosourea combination studies are described in Table 2 Table 3 Retrospective studies and clinical trials with temozolomide in recurrent GbM (temozolomide + nitrosourea combination studies are described in Table 2 (133)(134)(135)(136)(137)(138)(139)(140)(141)(142)(143)(144)(145). The toxicity profile did not vary between the different schemes.…”

Section: Temozolomide Monotherapy and Combination Regimensmentioning

confidence: 99%

Current Standards of Care in Glioblastoma Therapy

et al. 2017

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Glioblastoma (GBM) is the most common primary malignant brain tumor in adults. Regardless of ideal multidisciplinary treatment, including maximal surgical resection, followed by radiotherapy plus concomitant and maintenance temozolomide (TMZ), almost all patients experience tumor progression with nearly universal mortality and a median survival of less than 15 months. The addition of bevacizumab to standard treatment with TMZ revealed no increase in overall survival (OS) but improved progression-free survival (PFS). In newly diagnosed GBM, methylation of the O6-methylguanine-DNA methyltransferase (MGMT) promoter has been shown to predict response to alkylating agents, as well asgnosis. Therefore, MGMT promoter status may have a crucial role in the choice of single modality treatment in fragile elderly population. No standard of care is established in recurrent or progressive GBM. Treatment alternatives may include supportive care, surgery, re-irradiation, systemic therapies, and combined modality therapy. Despite numerous clinical trials, the identification of effective therapies is complex because of the lack of appropriate control arms, selection bias, small sample sizes, and disease heterogeneity. Tumor-treating fields plus TMZ represent a major advance in the field of GBM therapy, and should be Standards of Care in Glioblastoma Therapy 198 considered for patients with newly diagnosed GBM with no contraindications. As a disease with such a poor prognosis, treatment of GBM should go beyond improving survival and aim at preserving and even improving the quality of life of both the patient and the caregiver.

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“…Many trials evaluating temozolomide in the recurrent setting have also included anaplastic glioma, which appears to be highly responsive to repeat temozolomide therapy 58 . 65,66,69 or to start with a 200 mg/ m 2 loading dose followed by a lower-dose regimen (for example, 90 mg/m 2 every 12 hours 68 ). With these various approaches, the estimated 6-month pfs rate has been reported to be 24%-44%.…”

Section: 61mentioning

confidence: 99%

Canadian Recommendations for the Treatment of Recurrent or Progressive Glioblastoma Multiforme

Easaw¹,

Mason²,

Perry³

et al. 2011

Current Oncology

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Recommendation 1: Multidisciplinary Approach: To optimize treatment outcomes, the management of patients with recurrent glioblastoma should be individualized and should involve a multidisciplinary team approach, including neurosurgery, neuropathology, radiation oncology, neuro-oncology, and allied health professions. Recommendation 2: Imaging: The standard imaging modality for assessment of recurrent glioblastoma is Gd-enhanced magnetic resonance imaging (MRI). Tumour recurrence should be assessed according to the criteria set out by the Response Assessment in Neuro-Oncology Working Group. The optimal timing and frequency of MRI after chemoradiation and adjunctive therapy have not been established. Recommendation 3: Pseudo-progression: Progression observed by MRI after chemoradiation can be pseudo-progression. Accordingly, treated patients should not be classified as having progressive disease by Gd-enhancing MRI within the first 12 weeks after the end of radiotherapy unless new enhancement is observed outside the radiotherapy field or viable tumour is confirmed by pathology at the time of a required re-operation. Adjuvant temozolomide should be continued and follow-up imaging obtained. Recommendation 4: Repeat Surgery: Surgery can play a role in providing symptom relief and confirming tumour recurrence, pseudo-progression, or radiation necrosis. However, before surgical intervention, it is essential to clearly define treatment goals and the expected impact on prognosis and the patient’s quality of life. In the absence of level 1 evidence, the decision to re-operate should be made according to individual circumstances, in consultation with the multidisciplinary team and the patient. Recommendation 5: Re-irradiation: Re-irradiation is seldom recommended, but can be considered in carefully selected cases of recurrent glioblastoma. Recommendation 6: Systemic Therapy: Clinical trials, when available, should be offered to all eligible patients. In the absence of a trial, systemic therapy, including temozolomide rechallenge or antiangiogenic therapy, may be considered. Combination therapy is still experimental; optimal drug combinations and sequencing have not been established.

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A pilot study of metronomic temozolomide treatment in patients with recurrent temozolomide-refractory glioblastoma

Cited by 39 publications

References 20 publications

Combined therapy of temozolomide and ZD6474 (vandetanib) effectively reduces glioblastoma tumor volume through anti-angiogenic and anti-proliferative mechanisms

Combined therapy of temozolomide and ZD6474 (vandetanib) effectively reduces glioblastoma tumor volume through anti-angiogenic and anti-proliferative mechanisms

Current Standards of Care in Glioblastoma Therapy

Canadian Recommendations for the Treatment of Recurrent or Progressive Glioblastoma Multiforme

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