First-line Temozolomide Research Articles

Outcome of grade 3 and 4 cytopenia in newly diagnosed glioblastoma multiforme (GBM) patients treated with temozolomide (TMZ).

2018 Background: Current standard treatment for GBM consists in radiotherapy (RT) plus concomitant and adjuvant (adj) TMZ. Myelosupression is the dose limiting toxicity of TMZ with grade 3 and 4 cytopenia occurring in ~16%. We describe the difference in outcome of newly diagnosed GBM patients treated with TMZ who developed grade 3 and 4 cytopenia. Methods: A 10-year retrospective analysis of newly diagnosed adult GBM patients (pts) treated with first-line TMZ. All pts received concurrent TMZ and RT with or without investigational drug. If the pt did not progress on magnetic resonance imaging (MRI) adj TMZ was given. Cytopenia events during TMZ therapy were graded using the National Cancer Institute Common Toxicity Criteria (v3). Survival distribution was estimated by the Kaplan-Meier method. Results: Of 191 pts, 23% developed grade 3 and 4 cytopenia. 74% pts were ≤ 65 years, 75% had 80-100% karnofsky performance status and 78% had surgical resection at diagnosis. 93% pts received 6 wks of concurrent RT 60 Gy and TMZ 75 mg/m2/d. The median dose of adj TMZ was 150-200 mg/m2/d1-d5 every 28d cycle. The median cycles was 4 (range, 0-24). The median progression free survival (PFS) was 6.7 months (mo). The 6 mo and 12 mo PFS for pts who had grade 3 and 4 cytopenia was 73% (95% confidence interval [CI], 57%-83%) and 33% (95% CI, 20%-47%); while in pts with no grade 3 and 4 cytopenia was 51% (95% CI, 43%-59%) and 24% (95% CI, 17.9%-31.8%). The unadjusted hazard ratio (HR) for death or disease progression of pts with grade 3 and 4 cytopenia, as compared to those without grade 3 and 4 cytopenia, was 0.58 [95% CI, 0.40 to 0.82; p< 0.003]. The HR for death or disease progression was 0.68 (95% CI, 0.47-0.98; p<0.045) among those with a methylated MGMT promoter. The total dose of TMZ was not different between both groups (p=0.284 by Wilcoxon rank sum test). Conclusions: Our study supports that newly diagnosed GBM pts who develop grade 3 and 4 cytopenia during TMZ therapy have improved PFS. Further clinical trials are required to validate grade 3 and 4 cytopenia as a potential biomarker for TMZ efficacy in an attempt to optimize and personalize GBM therapy.

First-line temozolomide chemotherapy in progressive low-grade astrocytomas after radiotherapy: molecular characteristics in relation to response

Only a few studies examined the effect of temozolomide (TMZ) in recurrent low-grade astrocytoma (LGA) after surgery, none of which included a homogeneous and sufficiently sized group of patients with progression after radiotherapy (RT). We evaluated a cohort of 58 patients treated with TMZ for progression after RT of a previous LGA and investigated the relation between outcome and mutations in the IDH1, IDH2, and TP53 genes, O⁶-methylguanine-methyltransferase (MGMT) promoter methylation, trisomy of chromosome 7, and loss of chromosomes 1p and 19q. All patients received first-line TMZ 200 mg/m²/day on days 1-5 every 4 weeks for a progressive LGA with a contrast-enhancing lesion on MRI after RT. Six months progression-free survival (PFS) was 67%, and the median overall survival was 14 months. An objective response was obtained in 54%. TP53 mutations and loss of chromosome 19q showed a borderline association with PFS, but none of the other molecular characteristics were correlated with the outcome to TMZ. Both a methylated MGMT promoter gene and IDH1 mutations were found in 86% of the tumor samples. A correlation was found between IDH1 mutations and MGMT promoter methylation (P < .001). Neither MGMT promoter methylation nor IDH1 mutations correlated with PFS, but the interval between the very first symptom of the LGA and the start of the TMZ was significantly longer in the patients with IDH1 mutations (P = .01) and a methylated MGMT promoter (P = .02). We conclude that MGMT promoter methylation and IDH1 mutations seem to predict survival from the time of diagnosis, but not PFS to TMZ.

Phase II study of ifosfamide, carboplatin, and etoposide in patients with a first recurrence of glioblastoma multiforme.

e12512 Background: The prognosis of recurrent glioblastoma multiforme (GBM) remains unsatisfactory. The authors conducted a phase II study of ifosfamide, carboplatin, and etoposide (ICE) for a first recurrence of GBM to determine whether it prolonged a patient's good quality life. Methods: This trial was an open-label, single-center phase II study. Forty-two patients with a first GBM relapse after surgery followed by standard radiotherapy (60 Gy) and first-line temozolomide- or nimustine-based chemotherapy were eligible to participate. The primary end point was progression-free survival at 6 months after the ICE treatment (PFS-6), and secondary end points were response rate, toxicity, and overall survival. Chemotherapy consisted of ifosfamide (1,000 mg/m2 on Days 1, 2, and 3), carboplatin (110 mg/m2 on Day 1), etoposide (100 mg/m2 on Days 1, 2, and 3), every 6 weeks. Results: Progression-free survival at 6 months after ICE treatment was 35% (95% CI 22%–50%). The median duration of PFS was 17 weeks (95% CI 10–24 weeks). The response rate was 25% (95% CI 9%–34%). Adverse events were generally mild and consisted mainly of alopecia. Conclusions: This regimen was well tolerated and has some activity and could be one of the options for patients with recurrent GBM. No significant financial relationships to disclose.

Predictive and prognostic potential of angiogenic serum factors and circulating endothelial cells in metastatic melanoma patients receiving temozolamide plus bevacizumab (SAKK 50/07).

8585 Background: First line chemotherapy/bevacizumab has shown a positive effect in melanoma in two phase II trials. However, there is a need for biomarkers to allow selection of patients who are more likely to benefit from this therapy. Methods: We investigated the predictive and prognostic potential of vascular endothelial growth factor- A (VEGF-A), stromal cell-derived factor-1alpha (SDF-1alpha), hematopoietic stem cells (CD34+), a subpopulation containing endothelial progenitor cells (CD34+, CD133+ [EPC]) and mature circulating endothelial cells (CECs) in 60 patients with metastatic melanoma treated with first-line temozolomide (days 1 to 7 of each cycle) and bevacizumab (day 1 of each cycle), each cycle lasting 2 weeks,from the trial SAKK 50/07, collected on day 1 (baseline) and 14 (follow-up). Results: There was a significant decrease of VEGF levels and EPC numbers from baseline to follow-up with a boarder-line significant association between VEGF levels and EPCs numbers at baseline (p = 0.068) and between change of VEGF levels and change of EPC numbers from baseline to follow-up (p = 0.092). Neither EPC nor CEC numbers at baseline or at follow-up (nor absolute changes) had a prognostic or a predictive potential, whereas VEGF-A levels below median baseline value (1,140 pg/mL) were associated with better overall survival (13.4 vs. 8.3 months; p = 0.018). This was also true for median follow-up VEGF levels (500 pg/mL) (13.7 vs. 8.4 months, p = 0.038). SDF1alpha levels above median baseline value (5,906 pg/mL) were associated with better median progression free survival (5.3 vs. 4.0; p = 0.029). Conclusions: Optimal inhibition of VEGF was associated with a better prognosis in this clinical setting. Interestingly, SDF1alpha was upregulated through the treatment. Their baseline levels were unexpectedly associated with a better prognosis. Changes of EPCs or CECs through treatment were not of prognostic value. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca, Essex Pharma, Novartis, Roche Essex Pharma, Roche AstraZeneca, Novartis

Continuous temozolomide (TMZ) monotherapy as first-line treatment in patients with metastatic melanoma (MM).

e19030 Background: TMZ is a promising treatment option in MM. Phase I-II studies of first-line TMZ monotherapy have shown median overall survival (OS) of up to 13.1 months and progression-free survival (PFS) up to 1.9 months. We present the results of first- line continuous TMZ monotherapy in patients with MM. Methods: Retrospective analysis of patients with cutaneous MM and measurable lesions treated from 2000–2009. Patients could have previously received adjuvant interferon (IFN) or surgery as primary treatment. Exclusion criteria included any previous chemotherapy and ocular melanoma. Brain metastases were allowed. TMZ was administered under compassionate use at 200 mg/m2 days 1-5 every 28 days until progression or unacceptable toxicity. Outcomes included response as primary endpoint and, OS, PFS and toxicity as secondary endpoints. Results: A total of 36 patients were included: mean age 54 years (range 24-81); 95% ECOG performance status 0- 1; 17 patients had previous adjuvant high-dose IFN therapy. Prior to TMZ therapy the median number of metastases was 2.3 (range 1-5) and 6 patients had brain metastases. The mean number of TMZ cycles administered was 8.8 (range 1-53). Efficacy was not evaluated in 2 patients due to early death. The objective response rate was 19%, the complete response rate was 8% and stable disease was achieved in an additional 17% of patients. New brain metastases were observed in only 3 patients. Mean OS was 20.2 months (range 0.8-110.8) and median OS 9.3 months (95% CI 5.1- 13.5). Median PFS was 4.6 months (20 weeks 95% CI 14.4-25.0). At time of analysis, 6 patients were alive and 3 were disease-free; of these 2 continue to receive TMZ. TMZ had an acceptable toxicity profile; the most common toxicity was hematological (17% grade 1-2 and 22% grade 3- 4). Conclusions: First-line continuous TMZ monotherapy in patients with MM resulted in a median OS consistent with previous trials and a median PFS somewhat higher than previously seen. The toxicity profile was acceptable. The low number of patients developing brain metastases reflects the protective effect of TMZ against this type of disease progression. No significant financial relationships to disclose.

Dose-intensified rechallenge with temozolomide: One week on/one week off versus 3 weeks on/one week off in patients with progressive or recurrent glioblastoma.

TPS154 Background: No standard of care has been defined for patients with glioblastoma who relapse or progress on or after standard temozolomide (TMZ)-based radiochemotherapy. Rechallenge with TMZ using various dose-intensified regimens is a common approach for recurrent glioblastoma. O6-methylguanylmethyltransferase (MGMT) promoter methylation is a strong prognostic marker in newly diagnosed glioblastoma. However, in recurrent glioblastoma, the prognostic value of the MGMT status has remained unclear. Methods: The DIRECTOR trial will investigate whether dose-intensified regimens of TMZ can overcome MGMT-mediated chemoresistance and which TMZ rechallenge regimen is most effective and tolerable in recurrent glioblastoma. Results: DIRECTOR is a prospective, randomized, open-label phase II trial which assesses the efficacy of 2 regimens of dose-intensified TMZ, 1 week on/1 week off (120 mg/m2) versus 3 weeks on/1 week off (80 mg/m2), in patients with glioblastoma who progress or relapse after standard first-line TMZ radiochemotherapy and at least 2 cycles of TMZ maintenance. To assess the MGMT promoter methylation status at recurrence, patients will have to undergo resection or biopsy at relapse. The primary endpoint is time-to-treatment failure (TTF) defined as progression, intolerability of study treatment, or death from any cause. Secondary endpoints are progression-free survival (PFS), overall survival (OS), response and MGMT correlations. 166 patients are needed to show a statistically significant difference in median TTF between arm A and B (HR 0.63) with 80% power. Efficacy is assessed every 2 months by MRI using MacDonald criteria. Quality-of-life will be evaluated utilizing QLQ-C30 and QLQ-BN20 EORTC scores. Dose adjustments for TMZ will be implemented according to protocol. Patients will be followed up until treatment failure (last study visit) and the centers are encouraged to further document the course of disease in 3-monthly intervals. Conclusions: The trial is performed in 13 sites in Austria, Germany, and Switzerland. Six of 166 patients have been enrolled. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Merck, Merck Serono, Roche, Schering-Plough Merck, Merck Serono, Roche, Schering-Plough, Wyeth Lilly, Merck Serono, Schering-Plough

Long-term adjuvant administration of temozolomide in patients with glioblastoma multiforme: experience of a single institution

Long-term administration of adjuvant temozolomide is common practice in many institutions, especially when treatment is well tolerated and stable disease is achieved. In this study, we evaluate the feasibility and efficacy of long-term temozolomide in patients with glioblastoma multiforme treated at a single institution. One hundred and fourteen patients with newly diagnosed glioblastoma were followed for the course of their disease. Treatment consisted of surgery [gross total resection (GTR) subtotal resection (STR) or biopsy] followed by radiotherapy and concomitant temozolomide. Adjuvant temozolomide was administered until evidence for progressive disease or serious side effects occurred. Follow-up was routinely performed every 3months. One hundred and fourteen patients with glioblastoma multiforme received a median of 6cycles of adjuvant first-line temozolomide (range 1-57). For patients with less than 6cycles, chemotherapy was stopped in 60% for reasons other than progression, while only in 17% of patients receiving 6 or more (P<0.0001). Median TTP was 7months (95% CI: 6-10months). PFS after 6months was 53%. Median OS in all patients was 15months (95% CI: 13-18months). TTP and OS directly correlate with the amount of chemotherapy cycles (each P<0.0001). No significant influence of the extent of surgical treatment on PFS (P=0.2141) and OS (P=0.4308) could be detected. This data set suggests that long-term administration of temozolomide is safe and efficacious. Side effects occur more frequently in the early phase of drug administration (<6cycles). There is a strong correlation of long-term temozolomide on PFS and OS regardless of the extent of surgery and other factors.

A phase II trial of primary temozolomide in patients with grade III oligodendroglial brain tumors

Glial tumors with oligodendroglial components are considered chemo-responsive. Forty newly diagnosed patients (11 anaplastic oligodendrogliomas [OD] and 29 anaplastic oligoastrocytomas [OA]) were enrolled into this multicenter, open-label, single-arm Phase II trial of first-line temozolomide (200 mg/m(2) on days 1-5 every 4 weeks for 6 cycles). The primary endpoint was 6-month progression-free survival (PFS) with response rate (RR), median PFS, and median overall survival (OS) as secondary endpoints. Of 39 evaluable patients at the 6-month time point (median follow-up, 34 months), 6-month PFS was 77% (95% confidence interval [CI], 74.5%-79.3%). There were 15 complete responses (CRs, 38%), 6 partial responses (PRs, 15%), and 9 disease stabilization (23%). The median PFS was 21 months (95% CI, 3-39 months), and the median OS was 43 months (95% CI, 20-66 months). Chromosome 1p/19q codeletions were seen in 47% (18 of 38) of the patients, and O-6-methylguanine-DNA-methyltransferase (MGMT) methylation was seen in 48% (10 of 21) of the patients. All patients with OD showed MGMT methylation and most (71%) had chromosome 1p/19q codeletions. Conversely, fewer patients with OA showed MGMT methylation (23%) or had chromosome 1p/19q codeletions (31%). The presence of either 1p/19q codeletion or MGMT methylation was associated with increased RR at 6 months but not with improved PFS or OS. Only 18% of the patients (7 of 40) experienced treatment-related grade 3/4 toxicities. This regimen was active and well tolerated. These data add to the growing body of data showing that primary chemotherapy may be an acceptable alternative to radiotherapy for patients with gliomas containing oligodendroglial histology.

Phase II study of ifosfamide, carboplatin, and etoposide in patients with a first recurrence of glioblastoma multiforme

The prognosis of recurrent glioblastoma multiforme (GBM) remains unsatisfactory. The authors conducted a Phase II study of ifosfamide, carboplatin, and etoposide (ICE) for a first recurrence of GBM to determine whether it prolonged a patient's good-quality life. This trial was an open-label, single-center Phase II study. Forty-two patients with a first GBM relapse after surgery followed by standard radiotherapy (60 Gy) and first-line temozolomide- or nimustine-based chemotherapy were eligible to participate. The primary end point was progression-free survival at 6 months after the ICE treatment (PFS-6), and secondary end points were response rate, toxicity, and overall survival. Chemotherapy consisted of ifosfamide (1000 mg/m(2) on Days 1, 2, and 3), carboplatin (110 mg/m(2) on Day 1), etoposide (100 mg/m(2) on Days 1, 2, and 3), every 6 weeks. Progression-free survival at 6 months after ICE treatment was 35% (95% CI 22-50%). The median duration of PFS was 17 weeks (95% CI 10-24 weeks). The response rate was 25% (95% CI 9-34%). Adverse events were generally mild and consisted mainly of alopecia. This regimen was well tolerated and has some activity and could be one of the options for patients with recurrent GBM.

First-line temozolomide therapy and MGMT status in elderly patients with primary CNS lymphoma

Objective: This series explores temozolomide monotherapy in elderly patients with primary CNS lymphoma (PCNSL) and severe comorbidities.

Re-challenge with temozolomide (TMZ) at recurrence in high-grade gliomas (HGG)

2034 Background: TMZ is standard therapy for patients (pts) with HGG. Recent data suggest potentially enhanced efficacy of alternative schedules of TMZ administration based on optimizing depletion of MGMT. However, no prospective data have been published on the efficacy of TMZ regimens after failure of first-line TMZ (FL-TMZ). We therefore assessed the outcome of rechallenge with TMZ in pts with HGG. Methods: A retrospective review of pt with recurrent HGG who were rechallenged with TMZ between Jan 2000 and Oct 2006 was conducted. Standard criteria for rechallenge were as follows: if pts relapsed=8 wks after discontinuation of FL-TMZ, they were treated with the same or an alternative regimen of TMZ; however, if they progressed while still receiving TMZ, they were treated with an alternative regimen. Results: Of a total 81 pts identified, 54 intra-institutional pts were evaluable, 23 glioblastoma (GBM), 22 anaplastic glioma (AG). Median age was 44 yr with median KPS of 80. The response rate (RR) to FL-TMZ was 65% in GBM and 95% in AG using Macdonald criteria. At rechallenge, pts received one of four TMZ regimens: 150–200 mg/m2/d for 5/28 days (n=35), 150 mg/m2/d for 7/14 days (n=7), 75 mg/m2/d for 21/28 days (n=4), or continuous 50 mg/m2/d (n=7). All pts had progressed during FL-TMZ or after initial discontinuation of TMZ. Discontinuation during rechallenge TMZ was due to progressive disease in 36 pts and patient request in 6 pts. None of the pts discontinued due to toxicity. The response rates were 66% and 70% in GBM and AG, respectively. 8/12 non-responders to FL-TMZ responded to alternate regimens of TMZ. Median time to progression (TTP) was 20 weeks and 22 weeks, respectively. Six-month progression-free survival was 41% in GBM and 43% in AG. Conclusions: TMZ was well tolerated without major toxicities and had a good RR in pts who had previously failed TMZ. Durable responses were observed in patients who had not initially responded to front-line TMZ. These data suggest that rechallenge with TMZ in previous responders and non-responders warrants further investigation in a prospective study. No significant financial relationships to disclose.

Safety and feasibility of long-term temozolomide treatment in patients with high-grade glioma

We surveyed neuro-oncologists regarding patients treated with temozolomide for at least 12 cycles or 12 months. Patients receiving first-line temozolomide for a median 13 cycles had a median progression-free survival (PFS) of 14 months. Patients with recurrent disease receiving a median 14 cycles had a median PFS of 15.5 months. A small percentage of patients experienced grade III to IV toxicity. These results suggest that long-term treatment with temozolomide is feasible and well tolerated.

Re-challenge with temozolomide at recurrence in high-grade gliomas

Background: Temozolomide (TMZ) is standard therapy for patients (pts) with high-grade gliomas (HGG). Recent data suggest potentially enhanced efficacy of alternative schedules of TMZ administration based on optimizing depletion of MGMT. However, no prospective data have been published on the efficacy of TMZ regimens after failure of first-line TMZ (FL-TMZ). We therefore assessed the outcome of rechallenge with TMZ in pts with HGG.

A phase II study of first-line temozolomide and second-line PCV in recurrent/progressive malignant gliomas

1574 Background: There is an increasing tendency to use TMZ as first-line treatment in recurrent malignant gliomas, reserving nitrosourea-based regimens as a salvage option, but few data are available in the literature regarding the results of this strategy. The objective of this study was to investigate the efficacy and toxicity of first-line temozolomide (TMZ) and second-line PCV in patients with recurrent/progressive malignant gliomas after surgery and conventional radiotherapy. Methods: The inclusion criteria of the study were as follows: age ≥ 18 yrs; biopsy-proven glioblastoma or anaplastic astrocytoma; tumor progression after standard conformal radiation therapy; Karnofsky Performance Status ≥ 60. TMZ was administered at 200 mg/m2 for 5 days in cycles of 28 days up to tumor progression or unacceptable toxicity; PCV was administered in the standard schedule every 6 weeks. Tumor response was evaluated according to the conventional criteria of MacDonald et al, 1990. Results: Fifty-four patients were evaluable. A median of 5 cycles of TMZ (range 1–18) were administered. Responses to TMZ were as follows: CR 2/54 (4%), PR 9/54 (16%), SD 22/54 (41%), PD 21/54 (39%). Median TTP was 5 months, with a PFS at 6 and 12 months of 30% and 13%. Responding patients (CR+PR) had a TTP of 12 months with a PFS at 6 and 12 months of 65% and 45%. Grade 3–4 toxicity after TMZ included thrombocytopenia (17%) and neutropenia (6%). Responses to second-line PCV (at tumor progression after TMZ) were as follows: CR 1/54 (2%), PR 3/54 (5%), SD 9/54 (17%), PD 41/54 (76%). Median TTP after PCV was 2.6 months, with a PFS at 6 and 12 months of 25% and 10%. Responding (CR+PR) patients had a TTP ranging from 9.2 to 38 months. Grade 3–4 toxicity after PCV included thrombocytopenia (15%), neutropenia (13%), neuropathy (11%) and skin rashes (6%). Median survival after first-line TMZ and second-line PCV was 14 months. Conclusions: TMZ is active as first-line treatment for recurrent malignant gliomas, with an overall response rate of 20% and mild toxicity. Some patients may benefit from second-line PCV, even if unresponsive to previous TMZ. Toxicity after second-line PCV is acceptable. No significant financial relationships to disclose.

A phase II study of first-line temozolomide and second-line PCV in recurrent/progressive malignant gliomas

1574 Background: There is an increasing tendency to use TMZ as first-line treatment in recurrent malignant gliomas, reserving nitrosourea-based regimens as a salvage option, but few data are available in the literature regarding the results of this strategy. The objective of this study was to investigate the efficacy and toxicity of first-line temozolomide (TMZ) and second-line PCV in patients with recurrent/progressive malignant gliomas after surgery and conventional radiotherapy. Methods: The inclusion criteria of the study were as follows: age ≥ 18 yrs; biopsy-proven glioblastoma or anaplastic astrocytoma; tumor progression after standard conformal radiation therapy; Karnofsky Performance Status ≥ 60. TMZ was administered at 200 mg/m2 for 5 days in cycles of 28 days up to tumor progression or unacceptable toxicity; PCV was administered in the standard schedule every 6 weeks. Tumor response was evaluated according to the conventional criteria of MacDonald et al, 1990. Results: Fifty-four patients were evaluable. A median of 5 cycles of TMZ (range 1–18) were administered. Responses to TMZ were as follows: CR 2/54 (4%), PR 9/54 (16%), SD 22/54 (41%), PD 21/54 (39%). Median TTP was 5 months, with a PFS at 6 and 12 months of 30% and 13%. Responding patients (CR+PR) had a TTP of 12 months with a PFS at 6 and 12 months of 65% and 45%. Grade 3–4 toxicity after TMZ included thrombocytopenia (17%) and neutropenia (6%). Responses to second-line PCV (at tumor progression after TMZ) were as follows: CR 1/54 (2%), PR 3/54 (5%), SD 9/54 (17%), PD 41/54 (76%). Median TTP after PCV was 2.6 months, with a PFS at 6 and 12 months of 25% and 10%. Responding (CR+PR) patients had a TTP ranging from 9.2 to 38 months. Grade 3–4 toxicity after PCV included thrombocytopenia (15%), neutropenia (13%), neuropathy (11%) and skin rashes (6%). Median survival after first-line TMZ and second-line PCV was 14 months. Conclusions: TMZ is active as first-line treatment for recurrent malignant gliomas, with an overall response rate of 20% and mild toxicity. Some patients may benefit from second-line PCV, even if unresponsive to previous TMZ. Toxicity after second-line PCV is acceptable. No significant financial relationships to disclose.