Temozolomide-associated blepharoconjunctivitis: a case report.

BACKGROUND: Temozolomide (TMZ) is an effective oral alkylating agent used in treating glioblastoma multiforme (GBM) and high-grade gliomas. It works by introducing methyl groups into DNA, inhibiting cell division. A case of blepharoconjunctivitis linked to the administration of TMZ is detailed in this report. CASE PRESENTATION: We present a case of a 58-year-old African-American man diagnosed with GBM. Following adjuvant TMZ treatment, he developed blepharoconjunctivitis, characterized by eyelid and conjunctival inflammation. Symptoms included eyelid swelling, crusting, and conjunctival discharge, which were promptly resolved with topical steroid cream and eye drops. CONCLUSIONS: Reports specifically linking TMZ to blepharoconjunctivitis are limited. The exact mechanism remains unclear but may involve inflammation extending from blepharitis to the conjunctiva. Healthcare providers must recognize and manage ophthalmic complications promptly. This case report highlights blepharoconjunctivitis associated with TMZ use in a GBM patient. While TMZ is an effective treatment, ophthalmic side effects can occur.

Effect of Pneumocystis jirovecii pneumonia prophylaxis on hematologic toxicity in patients receiving chemoradiation for primary brain tumors.

PURPOSE: Diffuse gliomas are managed with radiation and temozolomide; however, this therapy often results in hematologic toxicities. Patients undergoing chemoradiation also risk contracting Pneumocystis jirovecii pneumonia (PJP), and frequently receive prophylaxis against PJP during treatment. Independent of chemoradiation, some PJP prophylaxis drugs have the potential to cause myelosuppression, which could require cessation of chemotherapy. Here, we evaluate differences in the frequency of hematologic toxicities during chemoradiation when patients receive PJP prophylaxis. METHODS: This retrospective chart review evaluated patients with primary brain tumors treated with radiation and concurrent temozolomide. Analyses were performed to assess the effect of the type of PJP prophylaxis on risk for neutropenia, lymphopenia, or thrombocytopenia and the severity of these adverse effects as defined using the Common Terminology Criteria for Adverse Events. RESULTS: Of the 217 patients included in this analysis, 144 received trimethoprim-sulfamethoxazole (TMP/SMX) and 69 received pentamidine. Of the patients who received TMP/SMX, 15.3% developed an absolute neutrophil count < 1500 cells/µL compared with 7.2% of patients receiving pentamidine (p = 0.10). Platelet count < 100,000/µL occurred in 18.1% of patients who received TMP/SMX and 20.3% of patients who received pentamidine (p = 0.70). No significant differences in lymphocyte counts between therapies were seen. Severity of hematologic toxicities were similar between PJP prophylaxis groups. CONCLUSION: These findings suggest that the type of PJP prophylaxis does not significantly affect the risk for hematologic toxicity in brain tumor patients receiving radiation and temozolomide. Additional studies are merited to evaluate the higher rate of neutropenia in patients on TMP/SMX observed in this study.

Efficacy and safety of temozolomide-based regimens in advanced pancreatic neuroendocrine tumors: a systematic review and meta-analysis.

BACKGROUND: Recent advances in the management of pancreatic neuroendocrine tumors (pNETs) highlight the potential benefits of temozolomide, an alkylating agent, for these patients. In this meta-analysis, we aimed to assess the outcome of temozolomide, alone or in combination with other anticancer medications in patients with advanced pNET. METHODS: Online databases of PubMed, Web of Science, Embase, the Cochrane Library, and ClinicalTrials.gov were searched systematically for clinical trials that reported the efficacy and safety of temozolomide in patients with advanced pNET. Random-effect model was utilized to estimate pooled rates of outcomes based on Response Evaluation Criteria in Solid Tumors criteria, biochemical response, and adverse events (AEs). RESULTS: A total of 14 studies, providing details of 441 individuals with advanced pNET, were included. The quantitative analyses showed a pooled objective response rate (ORR) of 41.2% (95% confidence interval, CI, of 32.4%-50.6%), disease control rate (DCR) of 85.3% (95% CI of 74.9%-91.9%), and a more than 50% decrease from baseline chromogranin A levels of 44.9% (95% CI of 31.6%-49.0%). Regarding safety, the results showed that the pooled rates of nonserious AEs and serious AEs were 93.8% (95% CI of 88.3%-96.8%) and 23.7% (95% CI of 12.0%-41.5%), respectively. The main severe AEs encompassed hematological toxicities. CONCLUSIONS: In conclusion, our meta-analysis suggests that treatment with temozolomide, either as a monotherapy or in combination with other anticancer treatments might be an effective and relatively safe option for patients with advanced locally unresectable and metastatic pNET. However, additional clinical trials are required to further strengthen these findings. This study has been registered in PROSPERO (CRD42023409280).

Disseminated Cryptococcus neoformans presenting with an isolated pleural effusion in a patient receiving temozolomide and long-term steroids.

Cryptococcus neoformans is a ubiquitous environmental organism found worldwide. Infection with this organism occurs predominantly in immunocompromised hosts, including persons living with HIV or those with impaired cellular immunity. Cryptococcal pleural effusions have been described in cases with extensive pulmonary involvement. Here we present the case of a woman receiving temozolomide and steroids for glioblastoma multiforme, who developed cough and dyspnoea and was found to have an uncomplicated pleural effusion. Pleural fluid culture grew Cryptococcus neoformans with negative culture on bronchoalveolar lavage. High serum cryptococcal antigen titre of 1:64 prompted lumbar puncture which demonstrated positive cerebrospinal fluid for Cryptococcus neoformans She was treated with liposomal amphotericin B and flucytosine, followed by consolidation and maintenance therapy with fluconazole. Pleural involvement in the absence of pulmonary involvement has rarely been reported. We review pulmonary and radiographic manifestations of cryptococcal infection, when to assess for disseminated infection, and management principles.

Comparative study of concurrent conventional chemoradiotherapy versus hypofractionated chemoradiotherapy in newly diagnosed glioblastoma multiforme postoperative patients.

Purpose: To assess the treatment response and toxicity profile among two groups of newly diagnosed glioblastoma multiforme (GBM) postoperative patients receiving conventional radiotherapy (RT) versus hypofractionated RT with concurrent temozolomide (TMZ) in both. Materials and Methods: A total of 50 patients randomly allotted into two arms (25 in each). Dose received 60 Gy (2 Gy/#) in conventional fractionation RT versus 50 Gy (2.5 Gy/#) in hypofractionated RT with concurrent TMZ 75 mg/m2 orally daily in both arms, respectively. Follow-up was done at 1, 3, 6, and 12 months after completion of treatment to evaluate toxicities, treatment response, and progression-free survival (PFS). Results: All patients were well tolerated with treatment; no major adverse effects were monitored in two arms. There was no statistical significant difference in treatment response, which was found 64% versus 60% in arm A and arm B, respectively, at 3 months of follow-up (P = 0.768). Toxicity profiles were also noted similar in both arms. The 6-month PFS was 84% and 80% in arm A and arm B, respectively (P = 0.71) and 12-month PFS was 60% and 52% in arm A and arm B, respectively (P = 0.69). Conclusion: Among the patients followed, this study showed that hypofractionated RT regimen was not inferior to conventional RT regimen.

Melatonin Prevents Depression but Not Anxiety-like Behavior Produced by the Chemotherapeutic Agent Temozolomide: Implication of Doublecortin Cells and Hilar Oligodendrocytes.

Melatonin is a hormone synthesized by the pineal gland with neuroprotective and neurodevelopmental effects. Also, melatonin acts as an antidepressant by modulating the generation of new neurons in the dentate gyrus of the hippocampus. The positive effects of melatonin on behavior and neural development may suggest it is used for reverting stress but also for the alterations produced by chemotherapeutic drugs influencing behavior and brain plasticity. In this sense, temozolomide, an alkylating/anti-proliferating agent used in treating brain cancer, is associated with decreased cognitive functions and depression. We hypothesized that melatonin might prevent the effects of temozolomide on depression- and anxiety-like behavior by modulating some aspects of the neurogenic process in adult Balb/C mice. Mice were treated with temozolomide (25 mg/kg) for three days of two weeks, followed by melatonin (8 mg/kg) for fourteen days. Temozolomide produced short- and long-term decrements in cell proliferation (Ki67-positive cells: 54.89% and 53.38%, respectively) and intermediate stages of the neurogenic process (doublecortin-positive cells: 68.23% and 50.08%, respectively). However, melatonin prevented the long-term effects of temozolomide with the increased number of doublecortin-positive cells (47.21%) and the immunoreactivity of 2' 3'-Cyclic-nucleotide-3 phosphodiesterase (CNPase: 82.66%), an enzyme expressed by mature oligodendrocytes, in the hilar portion of the dentate gyrus. The effects of melatonin in the temozolomide group occurred with decreased immobility in the forced swim test (45.55%) but not anxiety-like behavior. Thus, our results suggest that melatonin prevents the harmful effects of temozolomide by modulating doublecortin cells, hilar oligodendrocytes, and depression-like behavior tested in the forced swim test. Our study could point out melatonin's beneficial effects for counteracting temozolomide's side effects.

LncRNA-associated competing endogenous RNA network analysis uncovered key lncRNAs involved in temozolomide resistance and tumor recurrence of glioblastoma.

Temozolomide (TMZ) is a common alkylating chemotherapeutic agent used to treat brain tumors such as glioblastoma multiforme (GBM) and anaplastic astrocytoma. GBM patients develop resistance to this drug, which has an unclear and complicated molecular mechanism. The competing endogenous RNAs (ceRNAs) play critical roles in tumorigenesis, drug resistance, and tumor recurrence in cancers. This study aims to predict ceRNAs, their possible involvement, and underlying molecular mechanisms in TMZ resistance. Therefore, we analyzed coding and non-coding RNA expression levels in TMZ-resistant GBM samples compared to sensitive GBM samples and performed pathway analysis of mRNAs differentially expressed (DE) in TMZ-resistant samples. We next applied a mathematical model on 950 DE long non-coding RNAs (lncRNAs), 116 microRNAs (miRNAs), and 7977 mRNAs and obtained 10 lncRNA-associated ceRNAs that may be regulating potential target genes involved in cancer-related pathways by sponging 25 miRNAs in TMZ-resistant GBM. Among these, two lncRNAs named ARFRP1 and RUSC2 regulate five target genes (IRS1, FOXG1, GNG2, RUNX2, and CACNA1E) involved in AMPK, AKT, mTOR, and TGF-ß signaling pathways that activate or inhibit autophagy causing TMZ resistance. The novel lncRNA-associated ceRNA network predicted in GBM offers a fresh viewpoint on TMZ resistance, which might contribute to treating this malignancy.

Safety and Efficacy of Anlotinib Hydrochloride Plus Temozolomide in Patients with Recurrent Glioblastoma.

PURPOSE: Glioblastoma (GBM) is a highly vascularized tumor with few treatment options after disease recurrence. Here, we report the efficacy and safety of anlotinib hydrochloride plus temozolomide in patients with recurrent GBM. PATIENTS AND METHODS: Patients with first definite postsurgical progression of histologically confirmed GBM preceded by standard radiotherapy and temozolomide chemotherapy were eligible for inclusion. All patients received temozolomide (150-200 mg/m2, orally, every day (QD) d1-5/4 wk) and anlotinib (10 mg, orally, QD, d1-14/3 wk) until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed 6-month progression-free survival (PFS) rate by the Response Assessment in Neuro-Oncology (RANO) criteria. RESULTS: Twenty-one patients were enrolled between May 2020 and July 2021, with a median age of 55 (range 27-68) years old. According to the Response Assessment in Neuro-Oncology (RANO) criteria, tumor response occurred in 17 patients, of which 9 patients had a complete response, and the objective response rate was 81.0% [95% confidence interval (CI), 62.6-99.3]. The disease control rate was 95.2% (95% CI, 76.2-99.9), with three additional patients achieving a stable disease without tumor progression. The median PFS was 7.3 months (95% CI, 4.9-9.7), and the 6-month PFS rate was 61.9% (95% CI, 39.3-84.6). The median overall survival was 16.9 months (95% CI, 7.8-26.0). The most common adverse events were leukocytopenia (66.7%), thrombocytopenia (38.1%), and hypertriglyceridemia (38.1%). Five patients had nine grade 3 adverse events, with a 23.8% incidence rate. Two patients discontinued therapy due to ischemic stroke (grade 3) and wound dehiscence (grade 1), respectively. No grade 4 or treatment-related deaths occurred in this study. CONCLUSIONS: Anlotinib combined with temozolomide is efficacious and tolerated in patients with recurrent GBM.

Lymphoproliferative disorder during temozolomide therapy; a representative case of a formidable complication and management challenges.

BACKGROUND: Lymphoproliferative disorder represents a heterogeneous clinicopathological spectrum characterized by uncontrolled proliferation of lymphocytes. Immunodeficiency is a major trigger of its development. While induction of immunodeficiency is a well-known adverse effect of temozolomide therapy, development of lymphoproliferative disorder following temozolomide therapy has not previously been described. CASE PRESENTATION: A patient with brainstem glioma developed constitutional symptoms, pancytopenia, splenomegaly and generalized lymphadenopathy during the 2nd cycle of maintenance therapy following induction therapy with temozolomide. Epstein-Barr virus-infected lymphocytes were observed histopathologically and "other iatrogenic immunodeficiency-associated lymphoproliferative disorder" (OIIA-LPD) was diagnosed. Although discontinuation of temozolomide led to rapid remission, relapse was observed 4 months later. CHOP chemotherapy was induced, resulting in secondary remission. Vigilant follow-up for another 14 months showed radiologically stable brainstem glioma and no further recurrence of OIIA-LPD. CONCLUSIONS: This is the first report documenting OIIA-LPD during temozolomide administration. Timely diagnosis of the disease and discontinuation of the causative agent were considered to be the management of choice. Close monitoring for relapse should be continued. Finding a balance between glioma management and controlling the remission of OIIA-LPD remains to be clarified.

Exploring temozolomide encapsulated PEGylated liposomes and lyotropic liquid crystals for effective treatment of glioblastoma: in-vitro, cell line, and pharmacokinetic studies.

Temozolomide (TMZ) is one of the best choices for treating glioblastoma. However, due to the short plasma half-life, only 20-30 % brain bioavailability can be achieved using traditional formulations. In the present study, PEGylated liposomes and lyotropic liquid crystals (LLCs) were developed and investigated to prolong the plasma circulation time of TMZ. Industrially feasible membrane extrusion and modified hot melt emulsification techniques were utilized during the formulation. Liposomes and LLCs in the particle size range of 80-120 nm were obtained with up to 50 % entrapment efficiency. The nanocarriers were found to show a prolonged release of up to 72 h. The cytotoxicity studies in glioblastoma cell lines revealed a âˆ¼1.6-fold increased cytotoxicity compared to free TMZ. PEGylated liposomes and PEGylated LLCs were found to show a 3.47 and 3.18-fold less cell uptake in macrophage cell lines than uncoated liposomes and LLCs, respectively. A 1.25 and 2-fold increase in the plasma t1/2 was observed with PEGylated liposomes and PEGylated LLCs, respectively, compared to the TMZ when administered intravenously. Extending plasma circulation time of TMZ led to significant increase in brain bioavailability. Overall, the observed improved pharmacokinetics and biodistribution of TMZ revealed the potential of these PEGylated nanocarriers in the efficient treatment of glioblastoma.

Pilot Study of Recurrent Ewing's Sarcoma Management with Vigil/Temozolomide/Irinotecan and Assessment of Circulating Tumor (ct) DNA.

PURPOSE: Treatment options for recurrent or refractory Ewing's sarcoma (ES) are limited. Vigil is a novel autologous tumor cell therapy expressing bi-shRNA furin/GMCSF plasmid, which previously demonstrated monotherapy activity in advanced ES. Herein we report safety and evidence of benefit to Vigil for ES as potential treatment. PATIENTS AND METHODS: In this pilot trial, eligible patients with recurrent or refractory ES who failed initial standard-of-care therapy received treatment with temozolomide (TEM) 100 mg/m2/day oral and irinotecan (IRI) 50 mg/m2/day oral, Days 1 to 5, in combination with Vigil (1 × 106-107 cells/mL/day intradermal, Day 15), every 21 days (Vigil/TEM/IRI). Objective response rate (ORR) by RECIST v1.1, progression-free survival (PFS), and overall survival (OS) were assessed. Circulating tumor (ct) DNA analysis was done by patient-specific droplet digital PCR on baseline and serially collected on-treatment samples. RESULTS: Eight of 10 enrolled patients were evaluable for safety and efficacy (mean age 24.6; 12.6-46.1 years old); 2 did not receive Vigil. Seven of 8 patients previously received TEM/IRI. No Vigil-related adverse events were reported. Common ≥Grade 3 chemotherapy-related toxicity included neutropenia (50%) and thrombocytopenia (38%). We observed two partial response patients by RECIST; both showed histologic complete response without additional cancer therapy. Median PFS was 8.2 months (95% confidence interval, 4.3-NA). Five patients showed stable disease or better for ≥6 months. Patient-specific EWS/FLI1 ctDNA was detectable in all 8 evaluable patients at baseline. Changes in ctDNA levels corresponded to changes in disease burden. CONCLUSIONS: Results demonstrated safety of combination Vigil/TEM/IRI.

Lactobacillus salivarius CPU-01 Ameliorates Temozolomide-Induced Intestinal Mucositis by Modulating Gut Microbiota, Maintaining Intestinal Barrier, and Blocking Pro-inflammatory Cytokines.

Chemotherapy-induced intestinal mucositis is one of the major toxic side effects in the treatment of cancer patients. The purpose of this study is to screen lactic acid bacteria which could alleviate intestinal inflammation and damage induced by chemotherapeutic agents and explore the possible underlying mechanisms. Lactobacillus salivarius CPU-01 was selected from traditional Chinese fermented foods due to its protective effects on the toxicity of temozolomide in Caenorhabditis elegans. Eighteen ICR mice were randomly divided into 3 groups including control group, temozolomide-induced intestinal mucositis group, and temozolomide + L. salivarius CPU-01 group, and were used to investigate the effect of L. salivarius CPU-01 on chemotherapy-induced intestinal mucositis. It has been demonstrated that the administration of L. salivarius CPU-01 can prevent colon shortening and alleviate colon tissue damage caused by temozolomide-induced intestinal mucositis in mice. L. salivarius CPU-01 relieved the intestinal microbiota disorders caused by temozolomide and contributed to the growth of beneficial bacteria, such as Lactobacillus, Clostridia UCG - 014_norank, and Akkermansia. In vivo experiments also indicated that L. salivarius CPU-01 can suppress the level of temozolomide-induced pro-inflammatory cytokines in serum and mRNA expression in the small intestine tissues. It was also found that L. salivarius CPU-01 significantly increased the expressions of intestinal tight junction (TJ) proteins, ZO-1, and Occludin proteins in mice treated with temozolomide. These findings suggest that L. salivarius CPU-01 can ameliorate temozolomide-induced intestinal mucositis by modulating gut microbiota, blocking pro-inflammatory cytokines, and repairing the intestinal barrier. These findings suggest probiotics may serve as a potential alternative therapeutic strategy for the prevention of chemotherapy-induced intestinal mucositis in the future.

Efficacy and Safety of Lanreotide Autogel and Temozolomide Combination Therapy in Progressive Thoracic Neuroendocrine Tumors (Carcinoid): Results from the Phase 2 ATLANT Study.

INTRODUCTION: Lanreotide autogel (LAN) and temozolomide (TMZ) are guidelines-recommended monotherapies for thoracic neuroendocrine tumors (carcinoids; T-NETs), but prospective data for both combined and monotherapies are lacking. ATLANT (NCT02698410) evaluated efficacy and safety of LAN/TMZ in progressive T-NETs. METHODS: ATLANT was a 12-month, Italian, phase 2, single-arm, open-label, multicenter pilot study. Eligible patients had unresectable, locally advanced/metastatic, well-/moderately differentiated T-NETs with radiological progression. Patients received subcutaneous LAN 120 mg every 28 days and oral TMZ 250 mg/day for 5 consecutive days every 28-day cycle. Main endpoints are disease control rate (DCR) at 9 months (primary; investigator-assessed), median progression-free survival (PFS), biomarkers, and safety. RESULTS: The number of patients was 40; 60% were male. Primary tumor site was lung (90%) and thymus (10%). Carcinoid type was typical (20.0%) and atypical (52.5%). DCR at 9 months was 35.0% (95% confidence interval (CI) 20.63-51.68; nonacceptability threshold ≤10%, p < 0.0001; not significantly above clinically relevant threshold ≥30%, p = 0.2968). DCR between 7.5 and 10.5 months (sensitivity analysis) was 45.0% (95% CI: 29.26-61.51) and clinically relevant (p = 0.0320 at ≥30% threshold). Median PFS was 37.1 (95% CI: 24.1-52.9) weeks. No association was observed between biomarker variations (chromogranin A, neuron-specific enolase, somatostatin receptor type-2, Ki-67, 6-O-methylguanine-DNA-methyl-transferase) and DCR or PFS. Most patients (97.5%) had treatment-emergent adverse events (TEAEs); 72.5% had treatment-related TEAEs. TEAEs were mainly grade 1/2. No unanticipated TEAEs were reported. CONCLUSIONS: This study showed that the LAN/TMZ combination has promising efficacy in progressive T-NETs, and was well tolerated. Larger studies are warranted to support the clinical benefits of LAN/TMZ in patients with T-NETs.

Safety of temozolomide use in adult patients with renal dysfunction.

PURPOSE: Temozolomide (TMZ), a cytotoxic DNA alkylating agent, is the main chemotherapy used for the treatment of high grade astrocytomas. The active alkylator, methylhydrazine, is not recovered in urine and thus renal function is not expected to affect clearance. Prescribing information for TMZ states pharmacokinetics have not been studied in adults with poor renal function, eGFR < 36 mL/min/1.73 m2. We reviewed our clinical experience with TMZ in patients with impaired renal function to evaluate safety of administering full dose TMZ. METHODS: The primary endpoint was to characterize the incidence and severity of thrombocytopenia in patients with eGFR < 60 mL/min/1.73 m2 who received TMZ for treatment of high grade gliomas (HGG) or primary CNS lymphoma (PCNSL). Secondary endpoints included incidence and severity of neutropenia, lymphopenia hepatotoxicity, and number of TMZ cycles administered. Medical records of patients with HGG or PCNSL treated with TMZ from October 1, 2016-September 30, 2019 were accessed to identify cases for this study. RESULTS: Thirty-two patients were eligible for this study. Of the seven patients with eGFR < 36 mL/min/1.73m2, 38/39 cycles (97%) were completed without grade 3-4 thrombocytopenia. No patients experienced grade 3-4 neutropenia, and grade 3-4 lymphopenia occurred in 5 cycles (15%). One patient discontinued TMZ 7 days prior to completion of radiation due to thrombocytopenia. CONCLUSION: Hematologic toxicity in patients with severe renal dysfunction, eGFR < 36 mL/min/1.73m2, is similar to that of patients with normal renal function. Severe renal impairment does not preclude use of temozolomide, but cautious monitoring of blood counts is warranted.

Clinical features of glioma patients who develop pneumocystis pneumonia with temozolomide chemoradiotherapy.

INTRODUCTION: The treatment of glioma with temozolomide chemoradiotherapy predisposes patients to pneumocystis pneumonia (PCP). Because PCP is a rare outcome, very little is known about specific clinical risk factors for its development in patients with glioma. METHODS: We performed a population-based retrospective cohort study of glioma patients undergoing temozolomide chemoradiotherapy 2005 to 2019 in Ontario, Canada. We compared clinical features of patients who did not versus did develop PCP within one year of chemoradiotherapy. We examined the overall survival of patients by PCP status. RESULTS: There were 5130 patients with glioma treated with temozolomide chemoradiotherapy. Ultimately, 38 patients (0.74%) were diagnosed with PCP within 1 year of chemoradiotherapy. Most (71%) infections occurred between 0-90 days and 29% occurred between 91-365 days. Median survival was 12.3 months in patients who did not develop PCP and 8.6 months in those who did develop PCP (P < 0.001). Trough 90-day lymphocyte counts were lower in the PCP group. When the lymphocytes fell below 0.19 × 109/L (or 0.25 × 109/L among patients without PCP prophylaxis), the risk of PCP was > 3.5%. CONCLUSIONS: Pneumocystis pneumonia is rare in glioma patients who receive temozolomide chemoradiotherapy. Infection is associated with shorter survival and the development of lymphopenia. Reserving PCP prophylaxis for patients whose lymphocyte counts drop below 0.25 × 109/L may be a reasonable strategy.

Comparative efficacy and safety of therapeutics for elderly glioblastoma patients: A Bayesian network analysis.

Optimal management strategies for elderly glioblastoma (GBM) patients remain elusive. Overall survival (OS) and progression-free survival (PFS) in elderly newly diagnosed GBM (ndGBM) patients were analyzed with random-effects Bayesian network meta-analysis with the estimated hazard ratio (HR) with a 95% confidence interval (95% CrI). In addition, OS, PFS and adverse event (AE) data on ndGBM and recurrent GBM (rGBM) were assessed. Seventeen eligible trials with 12 on ndGBM and 5 on rGBM were identified. For the improvements it induced in the OS of elderly ndGBM patients, tumor treating field (TTF) + temozolomide (TMZ) (HR: 0.11, 95% CrI: 0.02-0.67 vs. supportive care (SPC)) ranked first, followed by TMZ + hyperfractionated radiotherapy (HFRT) (HR: 0.17, 95% CrI: 0.03-0.95 vs. SPC). For the improvements it induced in the PFS of elderly ndGBM patients, bevacizumab (BEV) + HFRT ranked first, followed by TMZ + HFRT. TMZ was observed to be more effective in O6-methylguanine-DNA-methyltransferase (MGMT) promoter-methylated ndGBM patients than HFRT and standard radiotherapy (STRT). For elderly rGBM patients, the treatments included were comparable. The rates of other neurological symptoms (16.1%) and lymphocytopenia (10.4%) were higher in ndGBM patients; lymphocytopenia (10.3%) and infection (8.1%) were higher in rGBM patients among the ≥ 3 grade AEs. TMZ-related AEs should be further considered. In conclusion, TTF + adjuvant TMZ and TMZ + HFRT are most likely to be recommended for elderly ndGBM patients. No best treatment for rGBM in elderly patients is illustrated. TMZ is identified to be more effective in elderly ndGBM patients with methylated MGMT status; however, AEs associated with TMZ-related therapy should be well considered and managed.

Association between microRNAs 10b/21/34a and acute toxicity in glioblastoma patients treated with radiotherapy and temozolomide.

A personalized approach to chemoradiation is important in reducing its potential side effects and identifying a group of patients prone to toxicity. MicroRNAs have been shown to have a predictive potential for radiotoxicity. The goal of the study was to test if levels of miRNA in peripheral blood mononuclear cells of glioblastoma patients are associated with toxicity and to identify the peak time point for toxicity. MicroRNA-10b/21/34a levels were measured in 43 patients with and without toxicity, at baseline, at the 15th, and at the 30th fraction by Real-Time quantitative Polymerase Chain Reaction. MicroRNA-10b/21 levels increased with toxicity grade (p = 0.014; p = 0.013); miR-21/34a levels were significantly different between patients with and without toxicity at the 15th fraction (p = 0.030; p = 0.045), while miR-34a levels significantly changed during treatment (p < 0.001). All three miRNAs showed a significantly high positive correlation with one another. MiR-34a might be considered as a predictive factor for toxicity due to its changes during treatment, and differences between the groups with and without toxicity; miR-10b might be used to predict toxicity; miR-10b/21 might be used for predicting the grade of toxicity in GB patients.

The efficacy of temozolomide combined with levetiracetam for glioblastoma (GBM) after surgery: a study protocol for a double-blinded and randomized controlled trial.

BACKGROUND: Temozolomide is applied as the standard chemotherapy agent in patients with glioblastoma (GBM) after surgery. However, the benefit of this treatment for patients is limited by the invasive growth of gliomas and drug resistance. There are indications from fundamental experimental and retrospective studies that levetiracetam has the potential to improve the survival rate of patients with GBM. However, it has yet to be determined whether the combination of temozolomide and levetiracetam is more effective than standard temozolomide chemotherapy. Therefore, we designed a randomized clinical trial to investigate the therapeutic effect of the new combined regime for treating GBM. METHODS/DESIGN: This is a double-blind and randomized clinical trial conducted in a single center. One hundred forty-two patients will be recruited and screened for the inclusion and exclusion criteria. Then, eligible participants will be randomly assigned to an experimental group or a control group in a 1:1 ratio. Based on the administration of radiation therapy (RT), participants in the experimental group will be prescribed levetiracetam plus temozolomide chemotherapy for 34 weeks while participants in the control group will receive placebo tablets plus temozolomide for the same duration. A 3-year follow-up will be conducted on all patients after intervention. Accordingly, the primary outcome will be progression-free survival (PFS). The secondary endpoints include overall survival (OS), the Karnofsky Performance Status (KPS), the objective response rate (ORR), and adverse event incidence. DISCUSSION: It is expected that the results of this trial will provide high-level evidence regarding the clinical benefits of levetiracetam and temozolomide combined in the treatment of GBM. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR2100049941 . Registered on 14 August 2021.

Sex-Dependent Analysis of Temozolomide-Induced Myelosuppression and Effects on Survival in a Large Real-life Cohort of Patients With Glioma.

BACKGROUND AND OBJECTIVE: To investigate the association of radiochemotherapy-induced cytopenia with sex and its potential effect on survival in patients with glioma. METHODS: We retrospectively analyzed cytopenia during temozolomide-based concomitant radiochemotherapy in 492 patients with glioma. Histologic grading, molecular pathology, surgical procedures, adjuvant chemotherapy subsequent to the radiochemotherapy phase, and overall survival (OS) were recorded. The extent of cytopenia was correlated with sex and outcome. RESULTS: Treatment-induced severe cytopenia (leukocytopenia, lymphocytopenia, neutropenia, and thrombocytopenia) was more frequent in women than men (44 vs 18%; p = 0.0002). In women with IDH-wt high-grade astrocytomas, there was a negative correlation of severe cytopenia in general and thrombocytopenia in particular during temozolomide radiochemotherapy with OS independent from other predictors (92 [77-111] vs 73 [21-127] weeks; p < 0.05). In men, there was also a trend for this unfavorable effect. In addition, severe cytopenia in all blood cell lineages correlated with reduced temozolomide dose exposure during radiochemotherapy (all p < 0.05 in the total cohort) and reduced dose exposure was independently associated with worse OS (hazard ratios for OS in complete vs reduced temozolomide dose in the total and female cohort 0.66 [0.47-0.92] and 0.4 [0.24-0.69], p < 0.05). DISCUSSION: Our analysis of treatment-induced cytopenia in a large cohort of patients with glioma confirms that women are at higher risk and demonstrates an association of cytopenia with shortened survival in women. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that women with glioma treated with temozolomide-based concomitant radiochemotherapy have more frequent treatment-induced severe cytopenia than men and that severe myelosuppression correlates with worse OS in women.