The effect of temozolomide-based chemotherapy in patients with cerebral metastases from melanoma
D. BafaloukosDimosthenis TsoutsosGeorges FountzilasHelena LinardouChristos ChristodoulouHaralabos P. KalofonosE. BriassoulisP. PanagiotouH. HatzichristouHelen Gogas
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Abstract:
Cerebral metastases from melanoma are correlated with a poor prognosis. Temozolomide is an oral alkylating agent that can cross the blood–brain barrier and in phase II and III trials, patients with advanced metastatic melanoma achieved overall response rates of 13 to 21%. The present study evaluated the efficacy and toxicity of temozolomide-based chemotherapy in patients with cerebral metastases from melanoma. Twenty-five patients (median age 48 years) with histologically confirmed stage IV melanoma and cerebral metastases treated with temozolomide-based chemotherapy. 10 patients received temozolomide plus docetaxel, nine patients temozolomide plus cisplatin and six patients temozolomide as single agent. Six patients achieved an objective response (24%). All responses were partial. The disease was stable in five patients (20%) and 13 patients progressed (52%). The median response duration was 6.9 months (range 1.8 to 16 months). The median time to progression (TTP) for all patients was 2 months, compared with a median TTP of 3.9 months, among responders and a median TTP of 1.8 months, for patients who remained stable or progressed (P<0.0001). The median survival time for the entire patient population was 4.7 months. The median survival for responders was 5.5 months and for non-responders was 3.6 months. The difference was statistically significant (P<0.05). The toxicity was mild. The most frequently reported adverse event were myelotoxicity and nausea and vomiting. Four patients developed grade 3/4 leukopenia, two grade 4 neutropenia, and one patient developed grade 3 thrombocytopenia. There was no treatment discontinuation caused by toxicity. Temozolomide-based chemotherapy may have a role in patients with cerebral metastases from melanoma. Further exploration is required. Toxicity was manageable.Keywords:
Temozolomide
We evaluated the stability of temozolomide, an alkylating agent, in solutions after opening the capsule. First, we established an analytical method for determination of temozolomide concentration by HPLC. The calibration curve for temozolomide was linear between 0.5-20 μg/ml (r=0.999). We then evaluated the stability of temozolomide in each buffer solution (pH 2-9) for 30 min. Temozolomide was decomposed pH-dependently between pH 7 and 9, and completely decomposed at pH 9. Temozolomide in several drinking water samples and beverages was decomposed according to their pH values. We also examined the time-dependent degradation of temozolomide in different pH solutions. Temozolomide started to decompose at 5 min in alkaline and neutral solutions, whereas 90% of temozolomide remained intact in acidic solution at 60 min. These results indicate that the stability of temozolomide after opening the capsule is affected by pH of solvents, and temozolomide is almost stable in acidic solutions.
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Temozolomide is known to affect efficacy of immunotherapy due to effects on the tumor microenvironment and host immune cell function. The effects of temozolomide dosing on efficacy of immune checkpoint inhibition is unknown. HYPOTHESIS: Dose modification of temozolomide modulates host immunity to increase efficacy of immune checkpoint blockade in a murine syngeneic glioblastoma model. Experiments were performed utilizing GL261 tumor bearing mice treated with standard dose (SD) temozolomide (50mg/kg x 5 days), metronomic dose (MD) temozolomide (25mg/kg x 10 days) and/or anti-PD1 antibody. SD temozolomide treatment resulted in greater lymphopenia and a more immunosuppressive profile compared to MD temozolomide in GL261 tumor bearing mice. SD temozolomide caused an upregulation of Tim-3, Lag-3 and PD-1 on peripheral and splenic CD4 and CD8 T cells. MD temozolomide increased PD-1 expression without concomitant Tim-3 or Lag-3 expression on CD4 and CD8 T cells. SD temozolomide also resulted in an increase in myeloid derived suppressor cells which was not observed with MD temozolomide. Moreover, antigen specific CD8 T cells were less functional as measured by IFN-gamma secretion when treated with SD temozolomide as compared with MD temozolomide. Analysis of tumor infiltrating lymphocytes also demonstrated increased exhaustion when treated with SD temozolomide compared to MD temozolomide. Combination treatment with PD-1 blockade and either MD or SD temozolomide demonstrated higher expression of checkpoints and immune exhaustion profiles in the SD temozolomide group measured by RNA sequencing. Survival analysis revealed that PD-1 blockade resulted in survival benefit in tumor bearing animals. However, SD temozolomide abrogated this survival benefit when combined with PD-1 blockade. MD temozolomide preserved the survival advantage of PD-1 blockade. Dose modification of temozolomide impacts efficacy of immune checkpoint blockade by modulating immune effector cells. Strategies to reverse T cell exhaustion induced by SD temozolomide are underway.
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No standard treatment of recurrent malignant glioma is established. Moreover, it is unclear if rechallenge with Temozolomide is effective. We present here feasibility and first treatment results of a dose dense, individually dose adapted 21-day regimen with Temozolomide for recurrent malignant gliomas.
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The changes induced in host immunity and the tumor microenvironment by chemotherapy have been shown to impact immunotherapy response in both a positive and a negative fashion. Temozolomide is the most common chemotherapy used to treat glioblastoma (GBM) and has been shown to have variable effects on immune response to immunotherapy. Therefore, we aimed to determine the immune modulatory effects of temozolomide that would impact response to immune checkpoint inhibition in the treatment of experimental GBM.Immune function and antitumor efficacy of immune checkpoint inhibition were tested after treatment with metronomic dose (MD) temozolomide (25 mg/kg × 10 days) or standard dose (SD) temozolomide (50 mg/kg × 5 days) in the GL261 and KR158 murine glioma models.SD temozolomide treatment resulted in an upregulation of markers of T-cell exhaustion such as LAG-3 and TIM-3 in lymphocytes which was not seen with MD temozolomide. When temozolomide treatment was combined with programmed cell death 1 (PD-1) antibody therapy, the MD temozolomide/PD-1 antibody group demonstrated a decrease in exhaustion markers in tumor infiltrating lymphocytes that was not observed in the SD temozolomide/PD-1 antibody group. Also, the survival advantage of PD-1 antibody therapy in a murine syngeneic intracranial glioma model was abrogated by adding SD temozolomide to treatment. However, when MD temozolomide was added to PD-1 inhibition, it preserved the survival benefit that was seen by PD-1 antibody therapy alone.The peripheral and intratumoral immune microenvironments are distinctively affected by dose modulation of temozolomide.
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Purpose of review The discovery of temozolomide in the 1980s was expected to be an important advance in improving survival for patients with malignant brain tumors. Numerous clinical studies have demonstrated the activity of temozolomide against recurrent or refractory gliomas and noncentral nervous system malignancies. In the last 2 years, studies have focused on exploring strategies to optimize the efficacy of temozolomide, including evaluating different temozolomide dosing schedules and combining temozolomide with other antineoplastic agents, radiation therapy, or drug resistance-modifying agents. Recent findings A critical review of these studies suggests that temozolomide, as currently used, has limited efficacy in treating refractory malignant infiltrative brain tumors, and survival benefit is, at best, a few weeks longer than that with procarbazine. There is enthusiasm about the activity of temozolomide in the treatment of recurrent low-grade gliomas and advanced malignant melanomas. Temozolomide has activity and a favorable safety profile in all dosing schedules tested. Nevertheless, the trials evaluating the efficacy of temozolomide suffer from being uncontrolled, with short follow-up periods. Summary Despite the advantages of a favorable safety profile and oral administration, temozolomide has yet to realize its initial promise and full potential. Studies of temozolomide combined with novel drug resistance-modifying agents will likely improve disease control while minimizing toxicities, leading to improved survival benefit. Larger, randomized trials comparing temozolomide with standard therapy are needed to confirm the suggested benefit from temozolomide in malignant brain tumors. Temozolomide will continue to be attractive as an agent in the treatment of brain tumors because of its desirable features and safety.
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Temozolomide is the most commonly used chemotherapy drug in patients with glioblastoma, although about half of those treated are resistant to temozolomide, and some patients eventually fail. Due to the limited effectiveness of existing therapies, immunotherapy in patients with glioblastoma is under intense investigation. However, early attempts at immunotherapy in glioblastoma patients as monotherapy have had disappointing results. Therefore, combinatorial treatment strategies are being explored. Temozolomide has multiple effects on the immune system that depend on the route of administration and dosing strategy and may have unpredictable consequences for immunotherapy. Temozolomide has both direct antitumor activity and immunomodulatory properties. The timing and dose of temozolomide significantly alters its effects on immune cells and the tumor microenvironment. The effect of temozolomide on response to new treatments such as immune checkpoint inhibitors is currently unknown. The effects of temozolomide dosing and timing, as well as the inhibition of immune checkpoints, are the subject of constant attention. Combination strategies involving temozolomide and immunotherapy should be carefully considered to ensure optimal results.
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