Temozolomide for the Treatment of Brain Metastases Associated With Metastatic Melanoma: A Phase II Study

Agarwala, Sanjiv S.; Kirkwood, John M.; Gore, Martin; Dréno, Brigitte; Thatcher, Nicholas; Czarnetski, Beate; Atkins, Michael B.; Buzaid, Antônio C.; Skarlos, Dimosthenis; Rankin, Elaine M.

doi:10.1200/jco.2004.11.044

Cited by 324 publications

(177 citation statements)

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“…An important observation in this study is that the median survival from starting chemotherapy was 2 months, which emphasises the very poor prognosis of patients with brain metastases from melanoma, even with good performance status. This figure is similar to the median overall survival of 3.2 months reported in the largest clinical trial of patients (N ¼ 151) with brain metastases from melanoma reported to date (Agarwala et al, 2004). It could be argued that restaging patients after three cycles of treatment (as opposed to two cycles) in the study reported here may have underestimated the response rate, but this would be true only for very short-lived responses, which would be of questionable clinical significance.…”

Section: Discussionsupporting

confidence: 82%

“…The brain is a common site of metastasis in melanoma and the standard treatment for brain metastases is radiotherapy although surgery has a role in selected patients. Dacarbazine is generally ineffective at treating brain metastases from melanoma although a response rate of 7% with a further 29% of patients experiencing disease stabilisation has been reported with the related orally administered alkylating agent temozolomide as a single agent (Agarwala et al, 2004). Temozolomide is associated with a response rate of 13 -25% in the treatment of metastatic melanoma outside the brain and is generally well tolerated with myelosuppression the major toxicity (Bleehen et al, 1995;Middleton et al, 2000;Bafaloukos et al, 2005;Kaufmann et al, 2005).…”

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confidence: 99%

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A Phase I/II study of lomustine and temozolomide in patients with cerebral metastases from malignant melanoma

et al. 2006

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Temozolomide is an alkylating agent with activity in the treatment of melanoma metastatic to the brain. Lomustine is a nitrosurea that crosses the blood brain barrier and there is evidence to suggest that temozolomide may reverse resistance to lomustine. A multicentre phase I/II study was conducted to assess the maximum-tolerated dose (MTD), safety and efficacy of the combination of temozolomide and lomustine in melanoma metastatic to the brain. Increasing doses of temozolomide and lomustine were administered in phase I of the study to determine the MTD. Patients were treated at the MTD in phase II of the study to six cycles, disease progression or unacceptable toxicity. Twenty-six patients were enrolled in the study. In phase I of the study, the MTD was defined as temozolomide 150 mg m À2 days 1 -5 every 28 days and lomustine 60 mg m -2 on day 5 every 56 days. Dose-limiting neutropaenia and thrombocytopaenia were observed at higher doses. Twenty patients were treated at this dose in phase II of the study. No responses to therapy were observed. Median survival from starting chemotherapy was 2 months. The combination of temozolomide and lomustine in patients with brain metastases from melanoma does not demonstrate activity. The further evaluation of this combination therefore is not warranted.

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Section: Discussionsupporting

confidence: 82%

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confidence: 99%

A Phase I/II study of lomustine and temozolomide in patients with cerebral metastases from malignant melanoma

et al. 2006

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“…The observed response rate of 9% and the stabilization of !11% of brain metastases in the current study are in line with the treatment results from a Phase II trial of temozolomide for brain metastases from melanoma that, similar to the current study, did not require immediate irradiation and showed a response rate of 6% and a stabilization rate of 26%. 13 Patient-or disease-related characteristics that distinguished patients with control of neurologic disease from nonresponders could not be demonstrated in the current study. Therefore, stabilization or response of extracranial metastatic melanoma to temozolomide was the only predictor of control of neurologic disease.…”

Section: Toxicitymentioning

confidence: 57%

“…11 Temozolomide is an analogue of dacarbazine that has excellent oral bioavailability and relatively high central nervous system (CNS) penetration. A large Phase II study of temozolomide for patients with brain metastasis from melanoma 13 who did not require immediate RT showed that temozolomide was tolerated well and produced an overall objective response rate of 6% and a stable disease (SD) rate of 26%, which is comparable to the response in patients with visceral extracranial metastasis. In the current study, we assessed the response of brain metastasis in patients who showed a response to temozolomide of systemic metastatic disease, and we evaluated whether it is feasible to defer or possibly withhold cranial RT.…”

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confidence: 98%

Temozolomide in advanced malignant melanoma with small brain metastases

Boogerd

Gast

Dalesio

2007

Cancer

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BACKGROUND.The efficacy of radiotherapy (RT) in patients who have brain metastases from melanoma is limited. In this study, the authors evaluated the efficacy of treatment with temozolomide in patients with metastatic melanoma, including small brain metastases, who did not require immediate RT and investigated the feasibility of deferring RT.METHODS.Patients with brain metastasis were identified from 3 prospective studies of temozolomide (with or without immunotherapy) for metastatic melanoma. Patients with brain metastasis that measured >2 cm, extensive edema, and localization in the brain stem were excluded from the study. For the current analysis, patients with leptomeningeal metastasis and patients who received previous stereotactic RT were excluded. In patients who achieved a systemic response or stabilization to temozolomide, the response of brain metastasis and the necessity for palliative cranial RT were evaluated.RESULTS.Among 179 patients who received temozolomide for advanced melanoma, 52 patients with brain metastasis were evaluable. Stabilization of systemic metastasis was noted in 7 of 52 patients (13%), and there were 6 responses (5 partial responses and 1 complete response; 11%); thus, in those 13 patients, 6 had stabilization of brain metastasis (11%) and 5 had a response (2 partial responses and 3 complete responses; 9%). Immunotherapy did not influence the neurologic response. The median time to neurologic progression was 7 months (range 2–15, months). RT for cerebral recurrence was required in 2 patients. The median survival of patients with brain metastases was 5.6 months (95% confidence interval, 4.4–6.8 months). Intracranial hemorrhagic complications were not observed.CONCLUSIONS.The current results indicated that it is feasible to treat patients who have advanced melanoma and small brain metastasis with temozolomide as the single treatment. The small subset of patients with systemic response usually showed durable stabilization or a response of brain metastasis. With this approach, neurologic disease can be controlled, and cranial irradiation may be deferred and even withheld in most of patients. Cancer 2007. © 2006 American Cancer Society.

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“…Topoisomerase I (topotecan, irinotecan) and II (etoposide, teniposide) inhibitors as well as platinum-based agents (cisplatin, carboplatin) are used for the treatment of lung cancer brain metastases (8), alkylating drugs such as dacarbazine, TMZ or nitrosoureas are used against melanoma or breast cancer manifestations in the brain (9,10). Of note, there is no specific chemotherapeutic agent for the treatment of brain metastases.…”

Section: Introductionmentioning

confidence: 99%

Immunological effects of chemotherapy and radiotherapy against brain tumors

Weiss

Weller

2016

Expert Review of Anticancer Therapy

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INTRODUCTION The mainstays of brain tumor therapy are surgery, radiotherapy and chemotherapy. Cancer immunotherapy is explored as an additional treatment modality. However, emerging evidence indicates that also radio-and chemotherapy have immunological effects in addition to their cytotoxic and cytostatic activities. AREA COVERED We summarize the literature on radioand chemotherapy-mediated immunological effects in primary and secondary brain tumors and outline open questions within the field. To this end, a literature search was performed using the terms 'brain tumor', 'immune system', 'immunogenic cell death', 'vaccination', 'checkpoint inhibition', 'radiotherapy', 'chemotherapy' and derivations thereof. Each treatment modality can exert various effects that comprise both immunestimulatory and immunosuppressive mechanisms. A detailed knowledge of these mechanisms is indispensable for an optimal combination of conventional anti-tumor treatments and novel immunotherapeutic approaches.

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Temozolomide for the Treatment of Brain Metastases Associated With Metastatic Melanoma: A Phase II Study

Abstract: Temozolomide was well tolerated and demonstrated activity in the treatment of brain metastases from MM. Further evaluation of temozolomide combination therapy is warranted.

Cited by 324 publications

References 24 publications

A Phase I/II study of lomustine and temozolomide in patients with cerebral metastases from malignant melanoma

A Phase I/II study of lomustine and temozolomide in patients with cerebral metastases from malignant melanoma

Temozolomide in advanced malignant melanoma with small brain metastases

Immunological effects of chemotherapy and radiotherapy against brain tumors

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