Months Of Temozolomide Research Articles

A combined analysis of two prospective randomised studies exploring the impact of extended post-radiation temozolomide on survival outcomes in newly diagnosed glioblastoma.

The optimal duration of post-radiation temozolomide in newly diagnosed glioblastoma remains unclear, with no published phase III randomised trials. Standard-of-care stipulates 6months. However, in routine care, it is often extended to 12months, despite lacking robust supporting data. GEINO14-01 (Spain) and EX-TEM (Australia) studies enrolled glioblastoma patients without progression at the end of 6months post-radiation temozolomide. Participants were randomised 1:1 to six additional months of temozolomide or observation. Primary endpoint was 6-month progression free survival from date of randomisation (6mPFS). Secondary endpoints included overall survival (OS) and toxicity. 204 patients were required to detect an improvement in 6mPFS from 50 to 60% (80% power). Neither study recruited sufficient patients. We performed a combined analysis of individual patient data. 205 patients were recruited: 159 in GEINO14-01 (2014-2018) and 46 in EX-TEM (2019-2022). Median follow-up was 20.0 and 14.5months. Baseline characteristics were balanced. There was no significant improvement in 6mPFS (57.2% vs 64.0%, OR0.75, p = 0.4), nor across any subgroups, including MGMT methylated; PFS (HR0.92, p = 0.59, median 7.8 vs 9.7months); or OS (HR1.03, p = 0.87, median 20.1 vs 19.4months). During treatment extension, 64% experienced any grade adverse event, mainly fatigue and gastrointestinal (both 54%). Only a minority required treatment changes: 4.5% dose delay, 7.5% dose reduction, 1.5% temozolomide discontinuation. For glioblastoma patients, extending post-radiation temozolomide from 6 to 12months is well tolerated but does not improve 6mPFS. We could not identify any subset that benefitted from extended treatment. Six months should remain standard-of-care.

NIMG-34. TEMPORAL MUSCLE THICKNESS AS A PROGNOSTIC MARKER IN A REAL-LIFE COHORT OF NEWLY DIAGNOSED MGMT PROMOTER METHYLATED GLIOBLASTOMA PATIENTS: A MULTICENTRIC IMAGING ANALYSIS

Abstract BACKGROUND In cranial MRI assessed temporal muscle thickness (TMT) correlates with lumbar skeletal muscle mass, which serves as surrogate marker of sarcopenia. Prior research has identified TMT as a prognostic marker in glioblastoma. However, incorporation into clinical practice is challenging due to the heterogeneity of previous studies and the absence of established cutoff values. To address this, we conducted a multicenter analysis to validate recently proposed sex-specific cutoff values in a homogeneous real-life cohort of newly diagnosed MGMT promoter-methylated glioblastoma patients uniformly treated with combined CCNU/temozolomide. We implemented a balanced control cohort for comparison. METHODS TMT was measured at baseline using preoperative or early postoperative MRI and in the disease course using the first MRI after completion of radiotherapy. Patients were TMT-based divided into “at risk of sarcopenia” or “normal muscle status”. Kaplan-Meier statistics and multivariable Cox regression analysis were used for correlation with survival. RESULTS In total, n = 126 patients were analyzed (n = 66 received CCNU/temozolomide; n = 60 received temozolomide). Patients with normal muscle mass at baseline (> 6,3 mm for men; > 5,2 mm for women) had significantly prolonged mOS (44.3 versus 16.7 months for CCNU/temozolomide; 29.5 versus 17.4 months for temozolomide) compared to those at risk of sarcopenia. In a multivariable Cox regression analysis, normal muscle mass (HR: 0.39, 95% CI: 0.23-0.66; p = 0.0003) and age at diagnosis of < 50 years (HR: 0.42, 95% CI: 0.22-0.79; p = 0.0067) were significant prognostic markers. Longitudinally, survival was best in patients with lack of TMT decline. CONCLUSIONS This analysis suggests TMT to serve as a prognostic marker in glioblastoma patients treated with CCNU/temozolomide or with temozolomide. However, for TMT assessment to be implemented in a generalizable manner, such as for patient selection for therapeutic measures, further validation in prospective controlled trials is necessary.

P01.15.A Longitudinal assessment of neurocognition and quality of life in low-grade glioma patients receiving first-line Temozolomide

Abstract Background While maximal safe resection is the first therapeutic option in patients with newly-diagnosed diffuse low-grade glioma (DLGG), the timing and choice of further treatments (chemotherapy, radiation therapy or combinations of both) remain controversial. Because the expected survival is long in these young patients, the oncological impact of treatments must be balanced with the possible side effects, in particular regarding neurocognitive functioning and quality of life (QoL). Temozolomide (TMZ), an alkylating agent, is widely used in this setting. Here we aimed at evaluating the feasibility of a longitudinal neurocognitive and QoL assessment in DLGG patients receiving TMZ. Material and Methods We conducted a prospective study including adult DLGG patients receiving TMZ as first-line treatment after surgical resection(s) or biopsy. Neurocognition and QoL were evaluated longitudinally until progression. The feasibility was evaluated in terms of participation and compliance of a complete neurocognitive and QoL assessment (defined as the completion of these assessments at baseline, 6 months and 12 months). Secondary objectives were the description of the proportion of patients with changes in neurocognitive or QoL scores on TMZ. Results Of 29 eligible patients, 26 accepted to enter the study (participation rate 86.7%): 57.7% men, median age 45y. Tumor type was distributed as follows: astrocytoma, IDH-mutant 13/26, astrocytoma, IDH wild-type 1/26 and oligodendroglioma, IDH mutant and 1p19q codeleted 12/26. The compliance rate was 95.6% (evaluable in 23 patients as 3 patients had tumor progression within the first 12 months of TMZ). After TMZ, 13.6% of patients experienced a decline of the MoCA score as compared to baseline (from normal to abnormal). Cognitive complaints according to the FACT-COG assessment were stable for 90.9%. The complete cognitive and QoL evaluations (baseline and after 12 months of TMZ) will be presented. Conclusion Our data shows that a longitudinal evaluation of cognition and QoL is feasible in low-grade glioma patients. It suggests that first-line TMZ does not negatively affect neurocognition and QoL. These results must be evaluated in the long-term setting (evaluations ongoing) and confirmed in a larger, multicenter cohort.

A randomized study of temozolomide or temozolomide and capecitabine in patients with advanced pancreatic neuroendocrine tumors: Final analysis of efficacy and evaluation of MGMT (ECOG-ACRIN E2211).

4004 Background: Patients with advanced pancreatic neuroendocrine tumors (NETs) have few treatment options that yield objective tumor response. Retrospective and small, prospective studies suggest that the combination of capecitabine and temozolomide is associated with high response rates (RR) and relative long progression-free survival (PFS). This trial was conducted to establish a role for the combination of capecitabine and temozolomide. Methods: E2211 was a multicenter, randomized, phase II trial comparing temozolomide (200 mg/m2 PO QD days 1-5) vs. capecitabine/temozolomide (capecitabine 750 mg/m2 PO BID days 1-14; temozolomide 200 mg/m2 PO QD days 10-14) in patients with advanced pancreatic NETs. Eligibility criteria included: metastatic or unresectable, low or intermediate grade pancreatic NETs, progression within preceding 12 months, and no prior temozolomide, DTIC, capecitabine or 5-fluorouracil. The primary endpoint was PFS; secondary endpoints were Overall Survival (OS), RR, safety, and MGMT as evaluated by immunohistochemistry (IHC) and promoter methylation. Allowing for 5% ineligibility, 145 randomized patients were required to obtain 138 eligible patients to detect a difference in median PFS of 9 versus 14 months (hazard ratio of 0.64) using a two-sided log-rank test at the overall 0.20 significance level with 81% power. Results: 144 patients were enrolled between 4/2013 to 3/2016 to temozolomide (n = 72) or capecitabine/temozolomide (n = 72); the efficacy analysis population included 133 eligible patients. At the scheduled interim analysis in January 2018, median PFS was 14.4 months for temozolomide vs. 22.7 months for capecitabine/temozolomide (HR = 0.58), which was sufficient to reject the null hypothesis for this final primary endpoint (stratified log rank p = 0.022. In the final analysis (5/2021), median OS was 53.8 months for temozolomide and 58.7 months for capecitabine/temozolomide (HR = 0.82, p = 0.42) and RR was 34% for temozolomide and 40% for capecitabine/temozolomide (p = 0.59). Capecitabine/temozolomide was associated with higher rates of grade 3-4 AEs (45% vs. 22%, p = 0.005). MGMT deficiency, defined as either low IHC or positive promoter methylation, was associated with greater odds of response (OR [95% CI] = 6.38 [2.19, 18.60] and 9.79 [1.09, 87.71], respectively). Conclusions: E2211 is the first prospective randomized trial of capecitabine/temozolomide and shows the longest PFS and highest RR reported for patients with pancreatic NETs in a prospective randomized study. MGMT deficiency was associated with greater odds of objective response. Clinical trial information: NCT01824875.

Temozolomide Alone or Combined with Capecitabine for the Treatment of Metastatic Neuroendocrine Neoplasia: A “Real-World” Data Analysis

Background: Neuroendocrine neoplasias (NENs) are a rare group of tumors with different prognosis and response to therapy. Their heterogeneity is dependent on the site of origin, morphology, and Ki67. Temozolomide (TEM) appears to be active in metastatic NENs (mNENs) but there is limited evidence about its efficacy in gastrointestinal NENs. We analyzed “real-world” data on the use of TEM alone or in association with capecitabine (CAPTEM) in patients with mNENs. Patients and Methods: One hundred consecutive patients with advanced NENs treated with TEM or CAPTEM between 2009 and 2019 were included. A pretreatment tumor growth rate (TGR₀) was calculated. Overall survival (OS), progression-free survival (PFS), tolerance, objective response rate (ORR), and disease control rate (DCR) were analyzed. A propensity score analysis and inverse probability of treatment weights for Cox regression models were used. Results: TEM-based therapy was administered to 95 patients (26.3% CAPTEM and 83.7% TEM) with a median age of 59 years (range 26–85) years. ECOG performance status was 0–2. Carcinoid syndrome was reported in 12 (12.6%) patients. Twenty (21.1%) patients with grade (G) 3 neuroendocrine carcinoma (NEC) and 9 (9.4%) with G3 neuroendocrine tumors (NETs) were included in the analysis. Median PFS of the entire group was 10.4 months (95% confidence interval [CI]: 6.0–11.5). In multivariate analysis, a higher risk of progression was observed for NEC G3 patients (hazard ratio [HR] 2.70, 95% CI: 1.25–5.84) and for a TGR ≥19.55 (HR: 2.53, 95% CI: 1.45–4.40). Median OS was 23.4 months (95% CI: 17.0–29.0) and was similar in both treatment groups (23.9 vs. 20.5 months for TEM and CAPTEM, respectively, p = 0.585). In multivariate analysis, TGR ≥19.55 was associated with a higher risk of death (HR: 2.18, 95% CI: 1.16–4.11) than TGR <19.55, as was NEC G3 (HR: 2.42, 95% CI: 1.04–5.59) with respect to NETs. No differences in terms of mPFS or mOS were seen in relation to the primary site of disease. In the 86 patients evaluable for response, ORR was 44.1% and the DCR was 70.9%. Mild adverse events (grade I–II) included anemia, neutropenia, and headache. Rare cases of G 3 neutropenia and thrombocytopenia were recorded. Conclusions: TEM-based regimens are associated with a high DCR and a relatively tolerable toxicity profile in NENs of pancreatic, intestinal, and lung origin. Further investigation of these specific NETs is warranted in prospective clinical trials.

524P - A study in recurrent small cell lung cancer patients, comparing weekly paclitaxel, irinotecan and temozolomide in second-line: A prospective study from a south Indian tertiary cancer hospital

BackgroundRecurrence is a rule after 1st line therapy in small cell lung cancer (SCLC). Patients who would not tolerate platinum or who recur within 6 months of 1st line therapy; choice of 2nd line is not well defined in them. MethodsSCLC patients, who progressed within 6 months after 1st line, or at anytime but who are not candidates for platinum, were non-randomly assigned to receive Paclitaxel 80mg/m2 weekly or Irinotecan 100mg/m2 weekly, till progression or for 12 cycles, or Temozolomide 75mg/m2 21days, every 4 weekly for 6 cycles in patients with brain metastasis. Response, toxicities, survival durations were noted. ResultsIn Irinotecan arm 1(12.5%) had PR, 2(25%) had SD and 3(37.5%) had PD (Response rate[RR]=37.5%). In the Taxane arm, 2(9.5%) had CR, 8(38.0%) had PR, 5(23.8%) had SD, and 6(28.5%) had PD (RR = 71.4%). 2(33.3%) had PR, 1(16.6%) had SD (RR = 50%) in the Temozolomade arm. Mean and median PFS after 2nd line after a min follow up of 18 months was 2.27 and 1.5 months for the whole cohort. Same for Taxane, Irinotecan and Temozolomide were (3.04 and 3 months), (0.81 and 0 months) and (1.5 and 0 months) respectively (p = 0.035). HR for progression for Taxane and Irinotecan were (0.565 p = 0.24, 95% CI [0.218-1.464]) and (1.358 p = 0.575, 95% CI [0.466-3.957]) respectively. Avg grade ¾ haematologic toxicities, febrile neutropenia, GI and hepatotoxicities were lowest for Taxane (0.81/patient p = 0.001, 0.48/patient p = 0.047, 1.14/patient p = 0.137 and 0.19/patient p = 0.08 respectively). Hypersensitivity (all grades) were more common for Irinotecan than taxane (0.62 vs 0.33/patient, p = 0.196). 3 patients died of causes attributed to therapy (2 out of 8 [25%] of Irinotecan arm, 1 out of 21 [4.7%] of Taxane arm). Median OS for the whole cohort was 11.5 months; highest for Taxane 12.5 months> 11 months for Temozolomide>9.5 months for Irinotecan, p = 0.185. HR for death for Taxane and Irinotecan were (0.643 p = 0.376, 95% CI [0.242-1.710]) and (1.383 p = 0.550, 95% CI [0.477-4.009]) respectively. ConclusionsWeekly Paclitaxel in 2nd line may have favourable toxicity profile and response rate comparable to Irinotecan or Temozolomide; may translate into better quality of life and OS. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Glioblastoma in the Canton of Zurich, Switzerland revisited: 2005 to 2009.

A population-based analysis of patients with glioma diagnosed between 1980 and 1994 in the Canton of Zurich in Switzerland confirmed the overall poor prognosis of glioblastoma. To explore changes in outcome, registry data were reevaluated for patients diagnosed between 2005 and 2009. Patients with glioblastoma who were diagnosed between 2005 and 2009 were identified by the Zurich and Zug Cancer Registry. The prognostic significance of epidemiological and clinical data, isocitrate dehydrogenase 1 (IDH1)(R132H) mutation status, and O6 methylguanine DNA methyltransferase (MGMT) promoter methylation status was analyzed using the Kaplan-Meier method and the Cox proportional hazards model. A total of 264 patients with glioblastoma were identified, for an annual incidence of 3.9 compared with the previous incidence of 3.7. The mean age of the patients at the time of diagnosis was 59.5 years in the current cohort compared with 61.3 years previously. The overall survival (OS) rate was 46.4% at 1 year, 22.5% at 2 years, and 14.4% at 3 years in the current study compared with 17.7% at 1 year, 3.3% at 2 years, and 1.2% at 3 years as reported previously. The median OS for all patients with glioblastoma was 11.5 months compared with 4.9 months in the former patient population. The median OS was 1.9 months for best supportive care, 6.2 months for radiotherapy alone, 6.7 months for temozolomide alone, and 17.0 months for radiotherapy plus temozolomide. Multivariate analysis revealed age, Karnofsky performance score, extent of tumor resection, first-line treatment, year of diagnosis, and MGMT promoter methylation status were associated with survival in patients with IDH1(R132H) -nonmutant glioblastoma. The OS of patients newly diagnosed with glioblastoma in the Canton of Zurich in Switzerland markedly improved from 1980 through 1994 to 2005 through 2009. Cancer 2016;122:2206-15. © 2016 American Cancer Society.

Glioblastoma multiforme: A bigger challenge in resource-limited countries

Glioblastoma multiform (GBM), the most common and the most aggressive brain tumor in older adults, once diagnosed kills majority of the patients within the first year despite aggressive surgical resection and high doses of radiation therapy (RT). Initially, nitrosureas such as lomustine were the main chemotherapeutic agents used although they only showed modest success.[1] Since Stupp et al. published their breakthrough findings in 2002, the accepted standard therapy worldwide for GBM has been concurrent fractionated RT (60 Gy, 2 Gy × 5 d/wk for 6 weeks) with temozolamide followed by maintenance therapy with temozolamide prolonged the survival with minimal toxicity.[2] Investigators later found that a higher initial Karnofsky performance Score and O6-methylguanine–DNA methyltransferase (MGMT) methylation were associated with better prognosis and longer survival.[3,4] In this issue of the Journal, Kumar et al. reported a series consisting of 439 patients with GBM over a period of nine years in their institution where healthcare was not equally accessible or affordable.[5] They divided the group into two groups: Those whose Karnofsky Performance Score was <70 and received RT dose of 30-35 Gy in 10-15 fractions and those with Karnofsky Performance Score ≥70 who received conventional RT dose of 60 Gy in 30 fractions once daily for five days a week with or without adjuvant chemotherapy with temozolamide or lomustine. The authors found that the two-year survival rates were 2.2% and 8.2% with median survivals of 6.3 and 7.9 months, respectively, (P = 0.0010). They also found that the main reason for not initiating or discontinuation of RT or adjuvant chemotherapy with either temozolamide or lomustine was secondary to cost and not due to toxicity. The study was limited by its retrospective nature and grouping of patients based solely on performance status with those in poor performance status plus larger tumor burden selectively receiving lower RT doses, thus faring worse. The challenges the authors faced as with many similar resource-limited countries was being unable to provide what is the known best standard of care for their patients. The authors urged that in patients with poor performance status, hypofractionated RT schedule may be considered. In a recent publication in Lancet Oncology by Malstrom et al. consisting of 291 patients with GBM, the investigators found that the standard fractionated RT (60 Gy administered in 2 Gy fractions over 6 weeks) was associated with poor outcomes, especially in patients older than 70 years. In their study, the median survival in the intent-to-treat population was 8.3 months for temozolomide, 7.5 months for hypofractionated radiation, and 6 months for standard radiation. The authors concluded that both temozolomide and hypofractionated radiotherapy as defined by (34 Gy administered in 3·4 Gy fractions over 2 weeks) should be considered as standard treatment options in elderly patients with glioblastoma.[6] Similarly, Lo et al. highlighted their findings during the 2011 American Society of Clinical Oncology annual meeting and concluded hypofractionated radiotherapy to be a safe and effective treatment for glioblastoma, especially in those patients who are elderly or have poor performance status.[7] In resource-limited countries with high patient volume, late disease presentation, and high treatment abandonment, we are far from being able to provide testing on MGMT promoter methylation status as a useful predictive marker for benefit from temozolomide or various other targeted anti-angiogenic therapies. Would it then be more desirable to consider hypofractionated RT as the standard therapy for those diagnosed with GBM? As Kumar et al. have revealed, hypofractionated RT is well-tolerated, and it can also reduce the overall treatment time without negative effects on survival compared with conventional fractionation.

Impact of temozolomide on gonadal function in patients with primary malignant brain tumors

Cumulative exposure to alkylating agents may produce impaired reproductive function. Temozolomide is an alkylating agent approved for treating malignant gliomas. A pilot study was undertaken to investigate the effects of temozolomide on semen integrity in men with newly diagnosed or recurrent malignant gliomas. Eligible patients had no known fertility problems or impotence. Comprehensive semen analysis and serum sex hormones were obtained at baseline and following 3 and at least 6 months of temozolomide. Thirteen men were recruited. Mean age was 42 years (28-58). Three had recurrent and 10 newly diagnosed malignant glioma. Four were unable to ejaculate or were azoospermic at baseline. Four provided samples at baseline and after at least 6 months of temozolomide. Five were unable to complete the study. Two of four patients with paired baseline and 6-month samples received 6 months of standard monthly temozolomide. Two patients received standard radiation and concurrent temozolomide followed by adjuvant temozolomide. At 6 months, three of these four patients demonstrated low sperm motility (two low at baseline); three had abnormally low percent normal forms (one abnormal at baseline); two developed abnormally low sperm density. Sex hormone values were normal in all four patients at all time points. Changes in semen analysis parameters following 6 months of temozolomide were observed. The small sample size precludes any firm conclusions regarding the importance and duration of these findings and their relation to temozolomide exposure. With validation in a larger study, these results may have important implications for counseling prior to initiation of temozolomide therapy in these patients.

Phase II trial of concomitant low dose temozolomide with external beam radiation (EBRT) followed by 12 months of temozolomide and irinotecan for newly diagnosed glioblastoma (GBM): Preliminary results of RTOG 04–20

1510 Background: Irinotecan and temozolomide compare favorably to regimens tested in recurrent GBM. RTOG 04–20 intensifies the Stupp R, et al. (N Engl J Med. 2005 Mar 10;352(10):987–96) adjuvant regimen, using irinotecan and temozolomide in place of temozolomide alone. Methods: Adult patients with newly diagnosed histologically confirmed, supratentorial GBM were eligible. Subjects began temozolomide 75mg/m2 daily the night before initiation of EBRT, and continued until the final day of RT. Pneumocystis prophylaxis was begun prior to RT and for 2 weeks following RT. Within 6 wks after EBRT, subjects with stable or improved MRI were scheduled to receive temozolomide 150mg/m2 on days 1–5, and irinotecan 200mg/m2 on days 1 and 15 of 28 day cycles × 12. Clinical assessments and post contrast MRI are required prior to EBRT, after RT, and after every 2 treatment cycles. Only nonenzyme inducing anticonvulsants were allowed. Results: Accrual of 170 patients was completed in September 2005 with 140 patients currently evaluable. Median age is 57yr, 80% were RPA class III or IV. Prior to cycle 1 of adjuvant therapy, 32 subjects withdrew (20 progressed, 4 toxicity). Of the first 25 subjects receiving irinotecan, 10 suffered grade 3–4 hematologic toxicities in the initial 3 cycles. The protocol was modified by dose reducing irinotecan to 100mg/m2 in cycle 1, escalating to 150 and 200mg/2 in subsequent cycles only if no dose limiting hematologic toxicity occured. No data is yet available on patients who started adjuvant therapy at the lower dose of irinotecan. Diarrhea and constitutional symptoms are the most common nonhematologic toxicies Conclusions: Irinotecan 200mg/m2 days 1 and 15 with temozolomide 150mg/m2 days 1–5 of 28 day cycles was well tolerated treating recurrent GBM, but this regimen was too myelosuppressive when given after concomitant low dose temozolomide and EBRT. Primary outcome data should be available in late 2006. [Table: see text]

An analysis of adjuvant temozolomide plus radiotherapy vs radiotherapy alone in a single academic institution

1575 Background: The NCIC CE.3/EORTC 22981/26981 was open during the time period of August 2000 to March 2002. When the study closed, there existed a gap in care that did not address the ongoing management of patients (pts) with glioblastoma multiforme (GBM) that had been surgically excised. As a result of this gap, it was decided that the adjuvant use of temozolomide (TMZ) was to become the standard of care at our centre due to its lack of perceived toxicities and early evidence for its activity. Methods: An analysis was performed of all pts with GBM that were seen at the centre from 1998 to the summer of 2005. In total, 240 pts were identified across multiple medical and radiation oncologists. 75 pts were treated with radiotherapy (RAD) alone post surgery, 86 pts were treated with RAD + TMZ post surgery, 18 pts only had surgery and the remaining pts were unresectable. Average age was 59.7 years for pts treated only with RAD, and 54.6 years for those treated with TMZ + RAD (p = 0.028). 59% of pts treated with RAD were male, while 62% treated with RAD + TMZ were male. Median follow-up was 11.3 months for RAD and 15.7 months for TMZ + RAD (p = 0.0001816). Preliminary survival analysis demonstrates a 56% reduction in the risk of death for pts treated with TMZ + RAD when compared to RAD (log rank p = 9.6 × 10−6). Median survival was 12.7 months for pts treated with RAD and 27 months for pts treated with TMZ + RAD (see table ). A further analysis including recursive partitioning analysis (RPA) and duration of therapy post RAD will be attempted to confirm the similarities between the two groups. Conclusion: Adjuvant TMZ + RAD has increased overall survival by 14.3 months in our institution. Further analysis is necessary to determine the impact on duration of therapy of TMZ. [Table: see text] [Table: see text]