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Temozolomide plus thalidomide in patients with brain metastases from melanoma
A Phase II study
Version of Record online: 28 APR 2005
Copyright © 2005 American Cancer Society
Volume 103, Issue 12, pages 2590–2597, 15 June 2005
How to Cite
Hwu, W.-J., Lis, E., Menell, J. H., Panageas, K. S., Lamb, L. A., Merrell, J., Williams, L. J., Krown, S. E., Chapman, P. B., Livingston, P. O., Wolchok, J. D. and Houghton, A. N. (2005), Temozolomide plus thalidomide in patients with brain metastases from melanoma. Cancer, 103: 2590–2597. doi: 10.1002/cncr.21081
- Issue online: 2 JUN 2005
- Version of Record online: 28 APR 2005
- Manuscript Accepted: 10 JAN 2005
- Manuscript Revised: 4 DEC 2004
- Manuscript Received: 27 SEP 2004
- Schering-Plough Corporation
- Celgene Corporation
- brain metastasis;
Temozolomide plus thalidomide is a promising oral combination regimen for the treatment of metastatic melanoma. The current Phase II study examined the efficacy and safety of this combination in chemotherapy-naive patients with brain metastases.
Patients with histologically confirmed metastatic melanoma and measurable brain metastases received temozolomide (75 mg/m2 per day for 6 weeks with a 2-week break between cycles) plus concomitant thalidomide (200 mg/day escalating to 400 mg/day for patients < 70 years or 100 mg/day escalating to 250 mg/day for patients ≥ 70 years). The primary end point was tumor response in the brain assessed every 8 weeks.
Twenty-six patients with a median age of 60 years were treated. All patients had progressive brain metastases: 16 were symptomatic and 25 had extensive extracranial metastases. Eight patients had received whole-brain radiotherapy, 4 had received stereotactic radiotherapy, and 8 had received craniotomy with resection of hemorrhagic lesions. Fifteen patients completed ≥ 1 cycle (median, 1 cycle; range, 0–4 cycles), and 11 discontinued treatment before completing 1 cycle (7 for intracranial hemorrhage, 2 for pulmonary embolism, 1 for deep vein thrombosis, and 1 for Grade 3 rash). Of 15 patients assessable for response, 3 had a complete or partial response (12% intent to treat) and 7 had minor response or stable disease in the brain. However, 5 of these 10 patients had disease progression at extracranial sites. The median survival period was 5 months for all 26 patients and 6 months for the 15 assessable patients.
Temozolomide plus thalidomide was an active oral regimen for patients with brain metastases from malignant melanoma. Cancer 2005. © 2005 American Cancer Society.
Once melanoma metastasizes beyond the regional lymph nodes, 5-year survival rates are only approximately 10% (range, 6.7–18.8%).1 Metastasis to the central nervous system (CNS) is a major cause of treatment failure. Melanoma is the third most common tumor to metastasize to the brain. Because of the extremely poor prognosis and lack of effective therapy for patients with brain metastases, such patients are often excluded from clinical trials. Although dacarbazine is the most active single chemotherapy agent for the treatment of metastatic melanoma, it is ineffective in the treatment of brain metastasis.
Temozolomide is a well tolerated, orally bioavailable alkylating agent with excellent CNS penetration.2, 3 Temozolomide has been shown to improve disease progression-free survival compared with dacarbazine alone in patients with metastatic melanoma,4 has the added benefit of penetration into the CNS,4 and may reduce the incidence of CNS progression in patients with metastatic melanoma.5, 6 Myelosuppression is the primary toxicity associated with temozolomide but is noncumulative and infrequently causes dose delays or discontinuation. Temozolomide is typically administered for 5 consecutive days every 28 days at a dose of 150–200 mg/m2 per day, but also can be safely administered on an extended daily schedule at a dose of 75 mg/m2 per day.7 This extended daily dosing regimen results in higher plasma concentrations of the active metabolite, (3-methyltriazenyl)imidazole-carboxyamide (MTIC), and may overcome drug resistance by depleting the DNA repair enzyme, O6-alkylguanine-DNA alkyltransferase.7–9
Thalidomide is also orally bioavailable, has several relevant biologic activities including antiangiogenic effects,10–12 and has demonstrated clinical activity against a range of solid tumors, including melanoma.13, 14 Melanoma is a highly vascularized tumor, suggesting a possible therapeutic role for an antiangiogenic agent.
Previous reports on this regimen from Phase I/II studies in patients with advanced melanoma without brain metastases have shown that daily dosing with temozolomide (75 mg/m2 per day for 6 weeks followed by a 2-week rest) can be safely combined with thalidomide at daily doses ≤ 400 mg.15, 16 A previous case report on the first patient with melanoma brain metastases who was treated with this regimen on a compassionate basis has also been published.17 The goal of this open-label, Phase II study was to further investigate the safety and efficacy of this regimen in patients with brain metastases from melanoma.
MATERIALS AND METHODS
Eligible patients had a histologic or cytologic diagnosis of metastatic melanoma, clinical evidence of brain metastasis, and measurable disease in the brain, defined as ≥ 1.0 cm in diameter by spiral computed tomography (CT) scan or magnetic resonance imaging (MRI) scan. Lesions within a previous field of radiotherapy had to have shown recent disease progression to be considered measurable. Eligible patients were required to be ≥ 18 years of age and have the following characteristics: a Karnofsky performance status score ≥ 70%, an absolute granulocyte count ≥ 1500 cells/mm3, a platelet count ≥ 150,000/mm3, a serum bilirubin and serum creatinine level ≤ 1.5 times the upper limit of laboratory normal, and serum alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase levels ≤ 3 times the upper limit of normal. Eligible patients must not have received previous chemotherapy, and no concurrent radiotherapy or biologic therapy was allowed. Previous treatment with biologic therapy or radiotherapy must have been completed ≥ 4 weeks before study treatment. Previous surgery must have been completed ≥ 2 weeks before study drug administration. All patients were required to use appropriate birth control methods. Informed written consent for the protocol approved by the Memorial Sloan-Kettering Cancer Center (MSKCC; New York, NY) institutional review board was obtained from all partcipants.
Patients were excluded if they were pregnant or lactating, had preexisting neuropathy ≥ Grade 2, had human immunodeficiency virus (HIV) infection or HIV-related illness, or had any medical condition that would interfere with the intake of oral medication (e.g., partial bowel obstruction) or otherwise make the patient unsuitable to participate in a clinical trial.
This was an open-label, Phase II study conducted at MSKCC as part of a larger Phase I/II protocol. Previously published cohorts from this protocol excluded patients with brain metastases.15, 16 Target accrual for this component of the study was 15 patients assessable for tumor response in the brain based on the completion of ≥ 1 cycle of therapy. Patients received treatment with temozolomide (75 mg/m2 per day × 6 weeks with a 2-week rest between cycles) plus concomitant thalidomide. For patients < 70 years, the starting dose of thalidomide was 200 mg per day, and the dose was escalated in 100-mg increments every 2 weeks to a maximum of 400 mg per day. For patients ≥ 70 years, the starting dose was 100 mg per day, and the dose was escalated in 50-mg increments every 2 weeks to a maximum of 250 mg per day. Treatment was continued until unacceptable toxicity or disease progression occurred. Prophylactic antibiotics were not administered.
The dose modification plan allowed the withholding of temozolomide in the event of Grade 4 hematologic toxicity or any Grade 3 or 4 nonhematologic toxicity (National Cancer Institute Common Toxicity Criteria) until toxicity resolved to ≤ Grade 1. Subsequently, temozolomide would be administered at a dose of 50 mg/m2 per day.
Dose modification guidelines for thalidomide allowed escalation of the dose as tolerated unless Grade 2 rash or Grade 3 or 4 nonhematologic toxicity developed. In the event of Grade 3 or 4 neurotoxicity, the thalidomide dose was held until the toxicity decreased to ≤ Grade 1 and was then restarted at the next lower dose level. Patients who were unable to tolerate the lowest dose level (50 mg per day) within 2 weeks were removed from study. If the lower dose was tolerated, attempts to reescalate the dose were made every 2 weeks.
Tumor response was assessed by physical examination, chest X-ray, CT scan, MRI scan, or other diagnostic tests as appropriate at the end of each 8-week cycle of therapy. Standard World Health Organization response criteria were used. A complete response (CR) was defined as the complete disappearance of all evidence of tumor and symptoms of disease for ≥ 4 weeks. A partial response (PR) was defined as a ≥ 50% decrease in the sum of the products of the greatest perpendicular diameters of all measured lesions persisting for ≥ 4 weeks. Nonmeasurable but assessable lesions must also have decreased by 50% (e.g., bone lesions). A minor response was defined as a ≥ 25% but < 50% decrease in the sum of all measured lesions. A mixed response was defined as a > 50% decrease in the sum of all measurable lesions and as disease progression in nonmeasurable (e.g., bone) lesions. Stable disease (SD) was defined as no change or as a < 25% decrease or increase in the sum of all measured lesions.
The primary efficacy end point was an objective tumor response in the brain, defined as a CR or PR. Patients who completed at least one cycle of study treatment were assessable for tumor response. With a sample size of 15 patients assessable for tumor response in the brain, the response rate could be estimated to within ± 25%. Secondary end points included extracranial response, safety, and survival. Survival time was defined as the time from initiation of treatment to the date of death or March 20, 2004, whichever came first. Survival distribution was estimated by the Kaplan-Meier method.18 All analyses were descriptive.
A post-hoc analysis of prognostic factors was also conducted. Prognostic factors for survival were defined by retrospective analysis of 355 patients with melanoma with brain metastases treated at MSKCC. (This retrospective study was also approved by the MSKCC institutional review board; unpublished data.) Medical records were reviewed for the following factors: age, gender, presence of extracranial metastases, hemorrhagic brain metastases, hydrocephalus, concomitant leptomeningeal metastases, number of brain lesions, neurologic symptoms at diagnosis and type of symptoms, presence of brain metastases at diagnosis of Stage IV disease (American Joint Committee on Cancer), number and type of previous therapies, previous surgery, previous stereotactic radiosurgery, previous whole-brain radiotherapy, and radiotherapy dose. These factors were analyzed for correlation with overall survival using univariate and multivariate Cox's regression analysis.
A total of 26 patients (14 males, 12 females) were treated from November 2000 to March 2003. Demographics and baseline disease characteristics are shown in Table 1. The median age of the patients was 60 years (range, 27–82 years) and the median Karnofsky performance status was 80. Seven patients were ≥ 70 years of age. Of the 26 patients, 18 had known primary cutaneous melanoma, 6 had unknown primary melanoma, and 2 had vulvar melanoma. All patients had brain metastases: 16 exhibited neurologic symptoms and 11 had extensive brain parenchymal lesions (> 5). The median number of brain metastases was 5 (range, 1–21 brain metastases). Notably, 25 of 26 patients had extensive extracranial disease. The median number of metastatic sites was 5 (range, 1–7 metastatic sites), and 62% of patients had lung metastases and 46% had liver metastases. In addition, 14 patients had elevated lactate dehydrogenase (LDH) levels. Before study entry, eight patients had received whole-brain radiotherapy, four had received stereotactic radiotherapy, and eight had undergone craniotomy with resection of symptomatic hemorrhagic lesions.
|Characteristics||No. of patients (%)|
|Median age (range)||60 (27–82 yrs)|
|Median Karnofsky performance status (range)||80 (70–90)|
|Median no. of metastatic sites (range)||5 (1–7)|
|Sites of metastasis|
|Lymph nodes (distant)||20 (77)|
|Soft tissue||17 (65)|
|Small intestine||4 (15)|
Patients completed a median of 1 cycle of therapy with temozolomide plus thalidomide (range, 0–4 cycles). Eleven patients were removed from the study before they completed the first cycle after a median of 24 days (range, 11–32 days), and 10 patients completed only 1 cycle (Table 2). Reasons for not completing the first cycle included intracranial hemorrhage (n = 7), deep vein thrombosis (DVT) with pulmonary embolism (n = 2), DVT (n = 1), and Grade 3 rash (n = 1).
|Treatment cycles||No. of patients (%)|
Fifteen patients completed at least one cycle of treatment and were assessable for response. An objective response in the brain was observed in three assessable patients (two had CRs and one had a PR). An additional 7 patients had a minor response (n = 1) or SD (n = 6) (Table 3). None of these responders (including those with a minor response or SD) received steroid therapy, except for one patient who had achieved a CR in the brain and subsequently received steroids for multiple compression fractures of the vertebral spine due to bone metastases. The overall response (intent to treat) rate was 12%. The overall median duration of response or SD in the brain was 4 months (range, 2–40+ months). However, 5 of these 10 patients had disease progression at extracranial sites of disease and were removed from the study after receipt of 1 cycle. No objective responses were observed in extracranial metastases. However, four patients had a minor response as their best clinical response at extracranial sites before study treatment was discontinued.
|Response||No. of patients|
For the 3 patients with an objective response in the brain, the response durations in the brain were 3 months for the patient with a PR and 4 and 5 months, respectively, for the 2 patients with CRs. The patient with a PR in the brain also had a minor response in the lung but was removed from the study after only one cycle because of progression of cutaneous and subcutaneous metastases. This patient died of progression of extracranial disease 6 months after study entry. One patient with a CR in the brain had a mixed response in extracranial metastases (resolution of pleural effusion and ascites and stable liver metastases but progression of an adrenal mass) and was removed from the study after one cycle. This patient also died of progression of extracranial disease 6 months after study entry. The other patient with a CR in the brain had a PR in the lung and liver after two cycles of therapy, but was removed from the study after the third cycle because of disease progression in bone. This patient subsequently died with vertebral spine compression fractures 7 months after study entry. In addition to these three patients with confirmed objective responses in the brain, one additional patient achieved a CR in the brain after two cycles, but this was counted as SD because it was based on a noncontrast CT scan compared with a pretreatment CT scan with contrast. This patient had a minor response in pelvic masses and multiple intransit metastases in the leg but was removed from the study after the second cycle because of an asymptomatic pulmonary embolus, which was incidentally discovered on the restaging CT scan. This patient died of recurrent brain metastases 14 months after study entry.
The median overall survival for all patients was 5 months (95% confidence interval, 3–7 months) and was 6 months for the 15 patients who completed ≥ 1 cycle of therapy. Figure 1 shows the Kaplan-Meier estimate of overall survival for all patients. Of the 26 patients enrolled, 25 died of disease progression, and 1 patient remains alive at ≥ 40 months after study entry. This patient, who had received no previous radiotherapy for brain metastases, had received four cycles of treatment and achieved SD in the brain and a minor response for lung and mesentery metastases. After the patient stopped treatment, both intracranial and extracranial disease continued to regress without further therapy, and a CR in all sites of metastases was achieved 1 year later.
In a separate univariate regression analysis of prognostic factors for survival based on 355 patients with melanoma with brain metastases treated at MSKCC between 1991 and 2001 (unpublished data), 6 factors significantly associated with poorer survival prognosis were identified. These included age (> 65 years), presence of extracranial metastases, presence of neurologic symptoms, > 1 parenchymal brain lesion, hydrocephalus, and leptomeningeal metastases. Of these, age, extracranial metastases, neurologic symptoms, and the number of parenchymal lesions were significant prognostic factors for survival in a multivariate analysis. Among the 26 patients in the current Phase II study, all but 1 had extracranial metastases, 10 were > 65 years, 16 had neurologic symptoms (most commonly seizures, headache, and weakness), 11 had > 5 parenchymal lesions, 4 had leptomeningeal metastases, and 2 had hydrocephalus. Overall, every patient had at least two adverse prognostic factors, and six patients had at least four (Table 4). In addition, 13 patients had elevated LDH levels, a known negative prognostic factor for patients with metastatic melanoma.1 Therefore, this group of patients had a poor prognosis, and the median survival was shorter in patients with more of these adverse prognostic factors.
|No. of adverse prognostic factors||No. of patients||Median survival, mos (range)|
|Elevated LDH level||13||3.0 (0.5–7.5)|
The most common nonhematologic adverse events (≥ Grade 2) were fatigue, constipation, dizziness, and CNS hemorrhage (Table 5). The majority of Grade 3 and 4 adverse events were disease-related complications or neurologic symptoms. Seven patients had Grade 4 CNS hemorrhage, and 3 patients had Grade 4 pulmonary embolisms resulting in study discontinuation. Four of the seven patients with CNS hemorrhage had a history of intracranial hemorrhage and required craniotomy to relieve neurologic symptoms before study entry. There was no Grade 3 or 4 drowsiness or somnolence, and only 4 (15%) patients reported Grade 2 drowsiness. The most common hematologic and laboratory abnormalities (≥ Grade 2) are shown in Table 6. Nine patients (35%) developed Grade 3 lymphopenia, and 6 patients (23%) had moderate hypoalbuminemia, 5 of whom had mild hypoalbuminemia before study entry. No patient discontinued treatment because of hematologic toxicity, and there were no opportunistic infections. Moreover, there was no Grade 3 or 4 thrombocytopenia, anemia, or neutropenia.
|Toxicity||No. of patients (%)|
|Grade 2||Grade 3||Grade 4|
|Fatigue||9 (35)||2 (8)||—|
|Constipation||8 (31)||1 (4)||—|
|Dizziness||5 (19)||1 (4)||—|
|CNS hemorrhage||—||—||7 (27)|
|Ataxia||1 (4)||4 (15)||—|
|Neurosensory||3 (12)||2 (8)||—|
|Thrombosis||—||1 (4)||3 (12)|
|Anxiety||3 (12)||1 (4)||—|
|Emesis||3 (12)||1 (4)||—|
|Rash||2 (8)||1 (4)||—|
|Nausea||1 (4)||2 (8)||—|
|Depression||2 (8)||1 (4)||—|
|Bone pain||3 (12)||—||—|
|Toxicity||No. of patients (%)|
|Grade 2||Grade 3||Grade 4|
|Leukopenia||2 (8)||1 (4)||—|
Although many patients were unable to complete the first cycle of therapy, the current study suggests that the combination of a low-dose daily schedule of temozolomide plus thalidomide has activity against brain metastases from melanoma. Three (12%) patients had an objective response in the brain, including 2 patients with CRs, and 7 additional patients had a minor response or SD in the brain. The median duration of response or SD was 4 months (range, 2–40+ months). In addition, 1 patient who had achieved SD in the brain and a minor response in lung and mesentery metastases after 4 cycles of treatment remains free of metastatic disease after > 3 years. However, the majority of patients progressed rapidly in extracranial disease, thus highlighting the need to concurrently control both cranial and extracranial disease if clinical outcome is to be further improved. In our previous experience treating 17 patients with melanoma with more favorable prognostic factors and less extracranial disease with this regimen on a compassionate basis, we have observed 7 objective responses in the brain, including 4 CRs, and the median duration of response was 8 months (range, 4–27+ months) (unpublished data). Therefore, durable responses in the brain are achievable by this regimen. The current study, along with our previous clinical experience, indicates that this regimen is active against melanoma brain metastases and provides a solid rationale for further investigation.
The median survival of 5 months (range, 0.5–40+ months) observed in the current study is not unexpected for a group of patients with such extensive brain metastases and extracranial disease, especially considering that nearly one-half of the patients did not complete the first cycle of therapy. Indeed, an analysis of prognostic factors for survival (defined by regression analysis of survival outcomes in 355 patients with melanoma with brain metastases treated at MSKCC) suggested that this was a poor-prognosis group of patients. Of 26 patients, 6 had ≥ 4 adverse prognostic factors, and these patients had an estimated median survival ≤ 3 months. Others have reported median survivals of 2.75–4.1 months after diagnosis of melanoma brain metastases,19–22 and analyses of prognostic factors for survival have identified the presence of active extracranial metastases, multiple brain metastases or higher cranial tumor volume, poor performance status, older age, and elevated serum LDH levels as significant adverse factors.19–21, 23, 24 Patients with a limited number of brain lesions who are candidates for surgery or radiosurgery also have a better prognosis than patients with more extensive intracranial disease.19, 22, 25
This regimen of concomitant daily temozolomide plus thalidomide was generally well tolerated by all patients, including the elderly patients in this trial (7 patients were ≥ 70 years). The majority of patients were able to tolerate the planned escalation of the thalidomide dose. Thalidomide-associated rash and neurologic symptoms were generally mild to moderate in severity and manageable in the majority of patients. Neurologic symptoms consisted mainly of Grade 2 drowsiness and neurosensory dysfunction. However, Grade 3 rash led to 1 early discontinuation, and 3 additional patients discontinued therapy because of pulmonary embolism. Hematologic toxicity associated with temozolomide (mainly Grade 3 lymphopenia) was not dose limiting, and there were no infectious complications, albeit the duration of therapy was relatively short. The incidence of Grade 3 lymphopenia observed in the current trial was consistent with that previously reported in patients receiving extended daily temozolomide.7 Recently, it was reported that prolonged daily administration of temozolomide was associated with CD4+ lymphopenia in the majority of patients, and there were documented opportunistic infections.26 In that report, 2 patients had severe lymphopenia and pancytopenia after prolonged daily administration of temozolomide for 6 and 14 months without a break. One patient treated with nonstop temozolomide developed Aspergillus pneumonia, and the other developed Pneumocystis pneumonia. These findings suggest that a break in treatment is important to allow recovery of T lymphocytes. Prophylactic antibiotics are appropriate for patients who develop severe lymphopenia or are receiving concomitant steroid therapy.
This combination regimen has a number of potential advantages over existing treatments for metastatic melanoma. First, it is a convenient oral regimen. Second, it may enhance antitumor activity compared with standard-dose temozolomide.16 Third, in contrast to dacarbazine and other standard agents such as cisplatin and interleukin-2, temozolomide appears to have superior activity in the CNS and produces an objective response in the brain. Agarwala et al.27 recently reported the results of a large Phase II study of single-agent temozolomide (150–200 mg/m2 per day × 5 days every 28 days) in 151 patients with melanoma with brain metastases. Eight (5%) patients achieved an objective response (1 patient had a CR and 7 patients had PRs), and 34 (29%) had SD in the brain. However, the median overall survival period was only 3.5 months. That study represents the largest clinical experience with standard 5-day dosing of temozolomide in patients with melanoma with brain metastases and demonstrated the antitumor activity of temozolomide in the brain. These studies provide a compelling rationale for the further exploration of temozolomide for the treatment of melanoma, particularly in patients with brain metastases. The combination of temozolomide with thalidomide may have additional advantages given the immunomodulatory and antiangiogenic activity of thalidomide.10–12 Because melanoma is a highly vascularized tumor, combination of a cytotoxic agent with an antiangiogenic agent may improve antitumor activity. However, caution should be exercised because of the increased risk of toxicity, particularly thrombotic complications. Thrombotic complications have been reported in patients with multiple myeloma receiving thalidomide and chemotherapy or steroids.28 In our study, the three patients removed from study for thrombotic complications before completion of one cycle of therapy (two had pulmonary embolisms and one had DVT) were all receiving steroid therapy for intracranial metastases.
Temozolomide has also been combined with other agents that have activity against melanoma. The combination of temozolomide plus docetaxel is noteworthy, based on the results of a Hellenic Cooperative Oncology Group study demonstrating a 27% overall response rate (5 patients with CRs and 12 patients with PRs) in patients with melanoma and a PR in 3 of 8 (38%) patients with brain metastases.29 A recent randomized Phase II study comparing temozolomide (200 mg/m2 every 8 hours × 5 doses per week) alone versus temozolomide (200 mg/m2 per day × 5 days every 28 days) plus interferon-alfa (IFN-α; 5 million International Units subcutaneously 3 times per week) or low-dose thalidomide (100 mg/day) in metastatic melanoma demonstrated that combination therapy yielded higher response and survival rates compared with temozolomide alone, although these results did not reach statistical significance in this small randomized trial.30 Twenty-one (12%) patients were known to have brain metastases. Only one CNS response was observed in a patient who received temozolomide plus thalidomide. Two-year survivals rates were 7%, 9%, and 17% for temozolomide alone, temozolomide/IFN-α, and temozolomide/thalidomide, respectively.
In summary, the combination of continuous daily oral temozolomide plus thalidomide appears to be a promising oral regimen for the treatment of metastatic melanoma, particularly in patients with brain metastases. Early use of this regimen may improve clinical outcomes. An ongoing study being conducted by the Cancer and Leukemia Group B (CALGB 500102) will further define the clinical benefit of this regimen in patients with metastatic melanoma in the brain. In addition, a large international Phase III trial was recently started to investigate a cyclic regimen of temozolomide (150 mg/m2 per day every other week) versus standard dacarbazine in previously untreated patients with metastatic melanoma. It is believed that the current study will provide further evidence of the clinical benefit of alternating weekly dosing with temozolomide. This cyclic regimen increases drug exposure by 3-fold compared with the standard 5-day temozolomide regimen.9 The hypothesis that continuous daily dosing is more effective than the standard temozolomide regimen, perhaps because of improved depletion of alkyltransferase, has also led to testing novel strategies such as combining temozolomide with O6-benzylguanine. The results of these trials will continue to guide the development of more effective treatment strategies for advanced metastatic melanoma.
- 2Pharmacokinetic study of temozolomide penetration into CSF in a patient with dural melanoma [abstract]. Ann Oncol. 1998; 9: 138., , , et al.
- 3Cerebrospinal fluid levels of temozolomide as a surrogate marker for brain penetration [abstract]. Proc Am Soc Clin Oncol. 2001; 20: 59a., , , , , .
- 8Protracted daily administration of temozolomide is feasible: a phase I and pharmacokinetic-pharmacodynamic study [abstract]. Proc Am Soc Clin Oncol. 2000; 19: 202a., , , et al.