The added value of concurrently administered temozolomide versus adjuvant temozolomide alone in newly diagnosed glioblastoma

Purpose Temozolomide (TMZ), given concurrently with radiotherapy (RT) and as adjuvant monotherapy afterwards, has led to improved survival in glioblastoma multiforme (GBM). However, it is unclear whether its primary mechanism of action is through enhancement of radiation response, independent cytotoxicity, or both. We sought to determine the relative contribution of concomitant temozolomide in patients treated by concurrent and adjuvant TMZ versus adjuvant TMZ alone in the setting of newly diagnosed GBM. Methods and Materials We identified patients diagnosed with GBM and treated with surgery, involved-field radiotherapy, and chemotherapy at MGH between 2002 and 2004. Eligible patients received either adjuvant temozolomide alone (group 1) or temozolomide concurrently with RT followed by adjuvant TMZ (group 2). The primary endpoint of this retrospective analysis was overall survival (OS). Results Forty-three patients (group 1, n = 21; group 2, n = 22) were included in this study. The median follow-up was 33.7 months for surviving patients. There were no significant differences in baseline characteristics between these two groups. On univariate analysis, patients who received concurrent and adjuvant temozolomide experienced a 2-year OS of 51% and median survival of 25.5 months, compared with a 2-year OS of 36% and median survival of 15.6 months for group 1 patients (P < 0.05). On multivariable analysis, the hazard ratio (HR) favoring concurrent TMZ trended towards significance (HR = 0.51, P = 0.08) despite modest patient numbers. Conclusions Concurrent and adjuvant TMZ was associated with improved survival compared to adjuvant TMZ alone, highlighting the potentiation of radiation effect by temozolomide in the clinical setting. Statement of originality: This work is completely original and has not been published or presented elsewhere. John W. Henson and Bindu Avutu contributed equally to this publication.     

Tonsillar pseudotumor: complications of chronically-administered temozolomide

The current standard of care for patients with Glioblastoma multiforme (GBM) is surgery, followed by radiation in combination with Temozolomide (TMZ), followed by adjuvant TMZ. The most appropriate length of treatment of adjuvant TMZ after the completion of radiation is unclear. We present the case of a 45 year old female with GBM who received adjuvant TMZ on an experimental study for 24 1-month cycles (150 mg/M² 7 days on/7 days off continuously-a higher TMZ dose than standard). After 24 months on study she was stable without GBM regrowth, but presented with a right tonsil and pharynx mass consistent with a new primary malignancy. Tonsillar biopsy was positive for Epstein–Barr virus, Cytomegalovirus and Herpes Simplex Virus, but no tumor. This case highlights the risks and possible complications of immunosuppression associated with long term TMZ use.     

The efficacy and safety of extended adjuvant temozolomide following concurrent radio-chemotherapy among Egyptian patients with newly diagnosed glioblastoma multiforme

Although concurrent radio-chemotherapy and adjuvant temozolomide (TMZ) treatment for 6 cycles has been established as a standard of care for newly diagnosed glioblastoma multiforme (GBM) patients, the recommended duration of adjuvant TMZ remains a matter of debate. Hereby, we aimed to report for the first time our experience from Upper Egypt through comparing survival and toxicity profile between two treatment modalities of adjuvant TMZ (> six cycles versus six cycles) and delineating factors of prognostic significance in Egyptian patients with newly diagnosed GBM treated by radiation therapy with concomitant and adjuvant TMZ. Between June 2016 and February 2018, the medical records of 121 patients were eligible to be retrospectively reviewed to extract the study relevant data. All patients received concurrent radio-chemotherapy, followed by TMZ for 6 cycles in 29 patients (Group 1) and for >6 cycles in 26 patients (Group 2). Patients in Group 1 had a median PFS of 15 months (95% CI: 10.215-19.785), while those in Group 2 had a median PFS of 18 months (95% CI: 16.611-19.389). After a median follow up duration of 20 months (range: 12-41), the median OS was 18 months (95% CI: 13.420-22.580) in Group 1 and 22 months (95% CI: 18.777-25.223) in Group 2. There was no statistically significant correlation between the number of chemotherapy cycles and PFS (P=0.513) or OS (P=0.867). The extent of surgical resection was the only independent prognostic factor for both PFS (P=0.015) and OS (P=0.028) by multivariate analysis. Three grade ≥3 hematologic toxicity were encountered in 3 patients. One in the six-cycle group (neutropenia), and two in the extended cycles group (one had neutropenia and the other one developed thrombocytopenia). No statistically significant difference in the toxicity profile between both groups. The results of our study suggest that extended TMZ therapy is safe and tolerable, however it did not significantly improve PFS or OS as compared to the standard six-cycle course. Larger randomized studies are required to shed more light on this issue.     

Extended adjuvant temozolomide for treatment of newly diagnosed glioblastoma multiforme

The standard of care for newly diagnosed glioblastoma multiforme (GBM) is temozolomide (TMZ) chemotherapy given concurrently with radiation for 6 weeks followed by 6 months of adjuvant TMZ. Originally, patients in Alberta were treated with only six cycles of adjuvant TMZ regardless of clinical status but institutional policy was amended to allow up to 12 cycles of adjuvant therapy for patients experiencing at least stable disease and minimal toxicity. We conducted a population-based analysis to determine if extended adjuvant TMZ treatment (i.e., more than six cycles) confers a survival advantage as compared to the standard six cycles for newly diagnosed GBM patients. Patient data was collected from the Alberta Cancer Registry and patient charts. Progression free—and overall survival was determined in patients receiving six cycles of adjuvant TMZ and compared with that of patients receiving more than six cycles. Patients in whom adjuvant chemotherapy was stopped at cycle six experienced a median survival of 16.5 months, whereas, those who received more than six cycles survived for 24.6 months (p = 0.031). Extended adjuvant therapy was not associated with increased toxicity. In multivariate analysis, adjuvant monthly Temozolomide for more than six cycles was an independent prognostic factor for both progression free—and overall survival. These data suggest extended adjuvant temozolomide (i.e., more than six cycles) should be considered in patients with newly diagnosed GBM.     

Prognostic significance of O6-methylguanine-DNA methyltransferase protein expression in patients with recurrent glioblastoma treated with temozolomide

BACKGROUND: Temozolomide (TMZ) is active against newly diagnosed glioblastoma (GBM), and O(6)-methylguanine-DNA methyltransferase (MGMT) is implicated in resistance to TMZ and nitrosoureas. We evaluated the efficacy and safety of the standard 5-day TMZ regimen in patients with recurrent GBM after initial therapy including nitrosourea-based chemotherapy, in conjunction with an analysis of the prognostic value of MGMT protein expression regarding response to TMZ and survival. METHODS: From September 2003 to January 2007, 30 patients having recurrent GBM received 150-200 mg/m(2)/day of TMZ for five consecutive days every 28 days. Tumor tissue from 19 patients was analysed for MGMT protein expression using western blotting, and 17 of them were assessable for a response. RESULTS: The overall response rate was 23.5% (one complete response and three partial responses). Six patients had stable disease (35.3%). Median progression-free survival (PFS) time was 2.2 months, and median overall survival (OS) time was 9.9 months from the initiation of TMZ therapy. Patients with low MGMT protein expression had a significantly improved PFS (P = 0.016) and OS (P = 0.019) compared to those with high expression. Both low MGMT expression (P = 0.040) and re-resection at relapse (P = 0.014) persisted as significant independent favorable prognostic factors for OS. The most common grade 3 and 4 hematological toxicity was lymphopenia (22.2%). CONCLUSIONS: The standard 5-day TMZ regimen resulted in moderate antitumor activity with an acceptable safety profile in patients with nitrosourea-pretreated recurrent GBM, and protein expression of MGMT is an important prognostic factor for patients treated with TMZ even after recurrence.     

Survival following CyberKnife radiosurgery and hypofractionated radiotherapy for newly diagnosed glioblastoma multiforme

Current therapeutic goals for treatment of Glioblastoma Multiforme (GBM) involve gross total resection followed by multifractionated focal external beam radiation therapy (EBRT). Patients treated with optimal therapy have a median survival of approximately 12-15 months. In the present study, we sought to determine whether a hypofractionated dosing schedule using CyberKnife is at least as effective as multifractionated focal EBRT. A retrospective analysis was conducted on 20 histopathologically confirmed GBM patients treated with CyberKnife at Okayama Kyokuto Hospital in Japan after gross total resection (n=11), subtotal resection (n=8), or biopsy (n=1). Eight patients also received adjuvant ACNU and Vincrisitine chemotherapy according to local protocol; however, no patient received any other form of radiation besides post surgical/biopsy CyberKnife treatment. The treated tumor volumes ranged from 9.62 cm(3)-185.81 cm(3) (mean: 86.08 cm(3)). The marginal dose (D90) ranged from 19.99 Gy-41.47 Gy (mean: 34.58 Gy) with a maximum mean dose of 43.99 Gy (range: 23.33 Gy-56.89 Gy). The prescribed isodose line ranged from 50.38%-85.68% with a mean of 79.25%. Treatment was delivered in 1-8 fractions (mean: 5.65). Patients were followed from 2-36 months (mean: 16.45 months). Overall median survival was 16 months with 55% of patients alive at 12 months and 34% of patients alive at 24 months. Median survival of patients in Recursive Partitioning Analysis (RPA) classes III or IV was 32 months versus 12 months for those in RPA class V. Median survival for patients who received gross total resection was 36 months versus 8 months for those who underwent subtotal resection or biopsy. The results of this study using CyberKnife stereotactic radiosurgery (SRS) and hypofractionated radiotherapy compared favorably to historic data using focal EBRT in newly diagnosed post surgical GBM patients. A larger prospective analysis that compares CyberKnife SRS and hypofractionated radiotherapy to focal EBRT is warranted.     

Conditional probability of survival and post-progression survival in patients with glioblastoma in the temozolomide treatment era

With standard treatment for glioblastoma (GBM) consisting of surgery followed by radiotherapy (RT) with concurrent and adjuvant temozolomide (TMZ), median survival is ~14.6 months. This is not as informative to patients who have survived for some time. Conditional probability of survival may offer more relevant survival estimates. Outcomes/conditional probability of survival and post-progression survival (PPS) estimates were retrospectively reviewed in the TMZ treatment era of 882 consecutive patients with a diagnosis of GBM from January 2004 to August 2010. Median age of entire cohort was 62 years including 62 % males. Baseline performance status (PS) was 0–1 in 67, 23 % had frontal lobe tumors, 58 % received concurrent RT/TMZ ± adjuvant TMZ. Survival (OS) was similar for those with frontal lobe tumors versus other locations (P = 0.25). OS for patients receiving standard RT/TMZ ± TMZ was 14.2 months. Age, PS, extent of surgery, therapy post-surgery had significant effects on OS. OS for entire cohort at 1, 2, 3, 4, 5 years was 43.4, 17.9, 10.4, 8.4, 7.2 % respectively. Conditional probability of survival of an additional year given survival to 1, 2, 3, 4, 5 years was 41.4, 58, 80.7, 85.7, 81.5 % respectively. Conditional probability of survival for those patients receiving concurrent RT/TMZ ± adjuvant TMZ was similar. Patients who progress >18 months after their initial treatment for GBM had significantly greater 2 and 5 year PPS as well as OS. Conditional probabilities of survival may provide more meaningful life expectancy predictions for survivors of GBM than conventional survival outcomes.     

Randomized phase II study of temozolomide and radiotherapy compared with radiotherapy alone in newly diagnosed glioblastoma multiforme.

PURPOSE: Surgery remains the standard treatment for glioma, followed by radiotherapy (RT) with or without chemotherapy. Despite multidisciplinary approaches, the median survival time for patients with glioblastoma multiform (GBM) remains at less than 1 year from initial diagnosis. Temozolomide (TMZ), an oral alkylating agent, has shown promising activity in the treatment of malignant gliomas. We conducted a multicenter randomized phase II study comparing the efficacy and safety of TMZ administered concomitantly and sequentially to RT versus RT alone in patients with newly diagnosed GBM. PATIENTS AND METHODS: One hundred thirty patients with pathologically confirmed, newly diagnosed GBM were randomly assigned (110 assessable patients) to receive either TMZ 75 mg/m(2)/d orally, concomitantly with RT (60 Gy in 30 fractions; group A, n = 57), followed by six cycles of TMZ (150 mg/m(2) on days 1 through 5 and 15 to 19 every 28 days), or RT alone (60 Gy in 30 fractions; group B, n = 53). RESULTS: Median time to progression was 10.8 months in group A and 5.2 months in group B (P = .0001). One-year progression-free survival rate was 36.6% in group A and 7.7% in group B. Median overall survival (OS) time was also significantly better in group A versus group B (13.4 v 7.7 months, respectively; P < .0001), as was the 1-year OS at 56.3% v 15.7% (P < .0001), respectively. Toxicity was mainly hematologic. One patient with grade 4 myelotoxicity died as a result of sepsis. The other side effects were mild. CONCLUSION: TMZ combined with RT (concomitantly and sequentially) seems to be more effective than RT alone in patients with newly diagnosed GBM. The combined-modality treatment was well tolerated.     

A meta-analysis of temozolomide versus radiotherapy in elderly glioblastoma patients

Temozolomide (TMZ) alone has been proposed as a promising alternative to radiotherapy (RT) in elderly glioblastoma (GBM) patients. We report a meta-analysis to systematically evaluate TMZ monotherapy in older GBM patients. A systematic literature search was performed using PubMed, EMBASE and the Cochrane database. Studies comparing TMZ versus RT in elderly patients (≥65 years) with newly diagnosed GBM were eligible for inclusion. Two randomized clinical trials (RCTs) and three comparative studies were included in the analyses, which revealed an overall survival (OS) advantage for TMZ compared with RT (HR [hazard ratio] 0.86, 95 % CI [confidence interval] 0.74–1.00). However, a sensitivity analysis of 2 RCTs only supported its non-inferiority (HR 0.91, 95 % CI 0.66–1.27). Most elderly patients tolerated TMZ despite an increased risk of grade 3–4 (G3–4) toxicities, especially hematological toxicities. The quality of life was similar between the groups. In the MGMT analysis, methylated tumors were associated with a longer OS than unmethylated tumors among elderly patients receiving TMZ monotherapy (HR 0.50, 95 % CI 0.35–0.70). Moreover, in patients with methylated tumors, TMZ was more beneficial than RT alone in improving OS (TMZ vs. RT: HR 0.66, 95 % CI 0.47–0.93) whereas the opposite was true for those with unmethylated tumors (HR 1.32, 95 % CI 1.00–1.76). Although the meta-analysis demonstrated the non-inferiority to RT in improving OS, TMZ alone was not a straightforward solution for elderly GBM patients because of an increased risk of G3–4 toxicities, especially hematological toxicities. MGMT testing might be helpful for determining individualized treatment.     

Hypofractionated radiotherapy with or without concurrent temozolomide in elderly patients with glioblastoma multiforme: a review of ten-year single institutional experience

The landmark Stupp study demonstrated a survival advantage with concomitant and adjuvant temozolomide (TMZ) with standard radiotherapy (RT) in glioblastoma multiforme (GBM) patients but excluded those older than 70 years. The prospective Roa study of older GBM patients treated with hypofractionated 3-week course RT demonstrated equivalence to standard 6-week course RT. Taken together, these trials suggest hypofractionated RT with TMZ may be a reasonable treatment option for elderly GBM patients. We conducted a retrospective review of GBM patients (age ≥60 years) treated with hypofractionated RT and temozolomide at our institution between 2000 and 2010. We identified 112 patients who received hypofractionated RT, with 57 receiving concurrent and adjuvant TMZ and 55 without concurrent chemotherapy. Of the 55 patients who received hypofractionated RT alone initially, 24 subsequently received TMZ as salvage treatment at time of progression. Among the concurrent RT + TMZ patients, mean age was 70 years (range 60–86), median KPS was 80 (range 30–100) and 24/57 (42%) received prior debulking surgery. Median overall survival (OS) among the RT + TMZ patients was 6.9 months (95% CI, 4.5–8.6). Patients without concurrent chemotherapy were similar in demographics (age, sex, corticosteroid use, KPS) except 34/55 (62%) were debulked (P-value 0.045.) Median OS was 9.3 months (95% CI, 5.9–11.8) (P-value 0.351). Sub-group analysis revealed patients treated with initial hypofractionated radiation with salvage TMZ had increased median OS of 13.3 months (95% CI, 9.9–19.3) (P-value 0.012). Our results suggest concurrent and adjuvant TMZ does not confer a survival benefit in elderly GBM patients. A sequential approach may be a more effective and efficient strategy by selecting responding patients who may benefit most from subsequent salvage chemotherapy.     

Prolonged temozolomide for treatment of glioblastoma: preliminary clinical results and prognostic value of p53 overexpression

We report retrospective data on the feasibility and efficacy of prolonging adjuvant temozolomide (TMZ) more than 6?months after chemoradiotherapy completion in patients with glioblastoma (GBM). Molecular prognostic factors were assessed. Data from 46 patients were reviewed. Patients received postoperative irradiation, 60?Gy in 30 fractions, combined with concurrent TMZ, 75?mg/m². Four weeks later, adjuvant TMZ was prescribed, 150?C200?mg/m² for a total of 24 cycles unless there was progression or toxicity. Tumor samples were tested for the following prognostic factors: EGFR overexpression, 1p19q deletion, p53 overexpression and proliferation index. Overall survival (OS) was 84.8% at 6?months, 54.3% at 12?months, 26.1% at 18?months, and 21.7% at 24?months. Progression-free survival (PFS) was 73.9% at 6?months, 34.8% at 12?months, 15.2% at 18?months and 10.4% at 24?months. In the adjuvant phase, no treatment disruption for toxicity was necessary but eight patients required dose adaptation because of side effects. No significant molecular prognostic factor was evidenced for OS. We found that p53 overexpression was the only significant prognostic factor for PFS, with a median PFS of 9.3?months versus 7?months for patients without p53 overexpression (P?=?0.031). This study suggests that delivering adjuvant TMZ therapy for more than 6?months is feasible in patients with GBM. Efficacy data warrant further prospective assessment with the focus on molecular prognostic factors, such as p53 overexpression, which was found to be the only significant molecular prognostic factor for outcome.     

Hypofractionated and Low Dose Radiotherapy Combined with Temozolomide in Naive Unresectable Glioblastoma:A Pilot Study

Background/Aim:To assess safety of hypo-fractionated radiotherapy (HyRT)fol-lowed by low dose radiation therapy (LD-FRT)plus Temozolomide (TMZ)in naive unresectable Glio-blastoma.Methods:Patients (ECOG<2,age>1 8)undergone to biopsy or with gross residual tumor af-ter surgery were enrolled.HyRT (30Gy in ten fraction)plus TMZ was administered.From the second adjuvant cycle of TMZ,patients received LD-FRT (0.40Gy twice daily over 5 days,every 28 days)for two cycles.The primary endpoints were safety and toxicity.Moreover we analyzed response,overall sur-vival (OS)and progression-free survival (PFS).Results:Twenty patients were enrolled.Median dose of LD-FRT was 1 2Gy.All toxicities were reversible.Four out of 20 patients had Partial Response (PR) and 6 experienced a stable disease (SD).Median OS and PFS were 1 4 and 1 1 months,respectively. Conclusions:HyRT followed by LD-FRT plus TMZ is safe and shows good clinical outcomes.A new study is ongoing.     

Comparative analysis of temozolomide (TMZ) versus 1,3-bis (2-chloroethyl)-1 nitrosourea (BCNU) in newly diagnosed glioblastoma multiforme (GBM) patients

PURPOSE: Although TMZ replaced BCNU as the standard initial chemotherapy in the treatment of GBM, no studies have been reported comparing BCNU with TMZ. We therefore did a retrospective analysis comparing these agents as initial therapy in GBM. PATIENTS AND METHODS: Eighty-one patients with GBM in our institution received both radiation and chemotherapy as initial treatment after surgery or biopsy; 49 receiving BCNU and 32 TMZ. These were analyzed for overall survival (OS) and progression-free survival (PFS) versus the type of chemotherapy used. The influence of salvage therapy on the outcome was investigated also. RESULTS: Median OS was superior in the TMZ versus the BCNU group (15.9 vs. 11.5 months) and the curves were judged to be significantly different by the log-rank test; P < 0.02. However, PFS was not significantly different between the two groups. Bevacizumab plus irinotecan (BI) was used as salvage therapy in one-third of the TMZ patients but in none of the BCNU patients. When patients receiving BI were omitted from the TMZ group the OS curve overlapped that of BCNU patients. CONCLUSION: These data suggest that the superior OS of the TMZ-treated GBM patients was not due to better tumor control by TMZ but was possibly related to the newer salvage therapy that was available to them.     

小细胞肺癌术后放疗的临床意义分析

分析术后放疗在Ⅰ～Ⅲ期小细胞肺癌患者综合治疗中的地位。方法:回顾性分析2000年2月至2009年12月间天津医科大学附属肿瘤医院有完整记录的接受手术治疗的Ⅰ～Ⅲ期小细胞肺癌患者临床资料,分析术后放疗对小细胞肺癌患者预后的影响。采用Kaplan-Meier法及Cox回归模型分析术后放疗的价值。结果:全组患者3年生存率为45.8%,中位生存期为34个月。单因素及多因素分析均显示术后放疗没有显著增加生存率,但是显著降低了局部区域复发率。术后放疗组与未放疗组的3年生存率分别为49.7%和39.3%,中位生存期分别为36个月和30个月（P=0.260）;3年局部区域复发率分别为7.7%和28.8%（P=0.001）。pN0患者术后放疗组与未放疗组3年生存率分别为54.5%和64.3%（P=0.705）,pN1患者分别为53.8%和33.3%（P=0.067）,pN2患者分别为46.7%和22.7%（P=0.141）。结论:术后放疗可明显降低小细胞肺癌术后局部复发率,可能会提高淋巴结阳性患者生存期。建议小细胞肺癌术后淋巴结阳性患者行术后放疗。      

Impact of age and co-morbidities in patients with newly diagnosed glioblastoma: a pooled data analysis of three prospective mono-institutional phase II studies

To analyse the impact of age and co-morbidities on compliance and outcomes in GBM patients enrolled in three prospective phase II trials. GBM patients (??18?years) were treated with radiotherapy (60?Gy) or enrolled in a Fractionated Stereotactic Conformal-Radiotherapy Phase II trial (69.4?Gy). Concomitant and adjuvant chemotherapy with Temozolomide (TMZ) was administered. Charlson Index Co-morbidity (CCI) was used to assess co-morbidity. Toxicity was evaluated according to RTOG score. Survival analysis was performed by the Kaplan?CMaier. Influence of age and co-morbidity was evaluated using log-rank test. From 2001 to 2008, 146 patients were enrolled: 56 (38.4?%) aged over 65 and 90 under 65. CCI ??1 was observed in 41?% of elderly and 22?% of young group. Patients?? compliance was 97.9?% for radio-chemotherapy. Acute toxicity was mild with no difference between the groups. Global median progression-free survival (PFS) and overall survival (OS) were 12 and 18?months, respectively. Age, surgery and radiation dose correlated with survival (p?=?0.01, p?=?0.04 and p?=?0.03). CCI ??2 did not show any influence on OS. Our data show that elderly with a good performance status and few co-morbidity may be treated as younger patients; moreover, age confirms a negative impact on survival while CCI ??2 did not correlated with OS.     

Temozolomide rechallenge in recurrent malignant glioma by using a continuous temozolomide schedule: the "rescue" approach

BACKGROUND.

Despite advances in first‐line therapy, there are few data on treatment of glioblastoma multiforme (GBM) at recurrence. Temozolomide (TMZ) is well tolerated and may have activity despite prior TMZ exposure if novel dose schedules are used.

METHODS.

The authors reviewed their experience with a continuous TMZ schedule (50 mg/m² daily), given at progression after conventional 5‐day TMZ. Patients were reported in 3 groups: 1) GBM after progression on conventional TMZ; 2) GBM at first recurrence after completion of standard concomitant and adjuvant TMZ; and 3) patients with other anaplastic gliomas at second relapse on conventional TMZ.

RESULTS.

In Group 1, 21 patients with a median age of 54 years (range, 33 years‐68 years) received a median of 3 cycles (range, 2‐12 cycles) of continuous TMZ at 50 mg/m². Overall clinical benefit (complete response, partial response, and stable disease) was 47%, with 6‐month progression‐free survival (PFS) of 17%. In Group 2, 14 patients with GBM, median age 52 years (range, 38 years‐62 years) received continuous TMZ at progression after initial TMZ/radiotherapy (RT) and adjuvant TMZ. The median interval after adjuvant TMZ was 3 months (range, 2 months‐10 months). A median of 5 cycles of TMZ was given, and 6‐month PFS was 57%. In Group 3, 14 patients with a median age of 49 years (range, 34 years‐56 years) received continuous TMZ; 2 partial responses and 6 with stable disease were seen, with a 6‐month PFS of 42%. Toxicities were mild and well tolerated; lymphopenia was common but no serious opportunistic infections were identified.

CONCLUSIONS.

Although retrospective, our results demonstrate that continuous daily administration of TMZ is an active regimen despite prior TMZ therapy. The excellent tolerability of this regimen may allow future combination with other alkylating agents or with novel therapies. Cancer 2008. © 2008 American Cancer Society.     

Inhibition of cyclin E1 overcomes temozolomide resistance in glioblastoma by Mcl‐1 degradation

Glioblastoma (GBM) is one of the major causes of brain cancer‐related mortality worldwide. Temozolomide (TMZ) is an important agent against GBM. Acquired TMZ‐resistance severely limits the chemotherapeutic effect and leads to poor GBM patient survival. To study the underlying mechanism of drug resistance, two TMZ resistant GBM cell lines, A172 and U87, were generated. In this study, the TMZ resistant cells have less apoptosis and cell‐cycle change in response to the TMZ treatment. Western blot results revealed that cyclin E1 was upregulation in TMZ resistant cells. Inhibition or depletion of cyclin E1 re‐sensitized the resistant cells to the TMZ treatment, which indicated the induction of cyclin E1 is the cause of TMZ resistance in GBM cells. Furthermore, we also found the expression of cyclin E1 stabilized the expression of Mcl‐1, which contributes to the TMZ resistance in GBM cells. Finally, our in vivo xenograft data showed that the combination of flavopiridol, a cyclin E1/CDK2 inhibitor, overcomes the TMZ resistant by inducing higher apoptosis. Overall, our data provided a rationale to overcome the TMZ resistant in GBM treatment by inhibiting the cyclin E1 activity.     

Role of multidimensional assessment of frailty in predicting outcomes in older patients with glioblastoma treated with adjuvant concurrent chemo-radiation

BackgroundOur aim was to evaluate the impact of comorbidities, clinical and biological factors on outcomes in elderly GBM patients treated with surgery followed by concurrent radiation (RT) and Temozolomide (TMZ).Materials and MethodsOur sample includes 34 elderly patients with GBM who treated from January 2013 to December 2017. We collected data regarding age, extension of surgery, use of current medications, KPS, presenting symptoms, Prognostic Nutritional Index (PNI), Charlson Co-morbidity Index (CCI) and Frailty Index (FI). All of these parameters, measured before the start of RT-TMZ, were linked to clinical outcomes.ResultsWith a median follow-up of 9.7 months, the median overall survival (OS) was 12.1 months and 1-year OS was 50%. In univariable analysis high KPS and total surgery were significantly associated with better OS. Also PNI, CCI and FI were a significant predictors of OS. At multivariate analysis KPS, type of surgery and FI remained a significant predictors of OS and, based on these parameters, we generated a prognostic score that, dividing patients into three risk categories, has proven to be a survival predictor, with an increase of the risk of death by 2.2 times for each increment of the score (HR 2.2, p = .0004).ConclusionThe appropriate management of elderly cancer patients with GBM is an important concern in oncology. Our data suggest that in elderly patients in good clinical conditions and with a low FI score, extensive surgery, when feasible without adding neurological impairment, followed by adjuvant RT-TMZ, should be considered.     

Newly Diagnosed Multifocal GBM: A Monocentric Experience and Literature Review

Simple SummaryGlioblastoma is an aggressive brain tumor with a dismal prognosis. In a minority of cases, it presents with multiple lesions already at the time of diagnosis, affecting patients’ survival and treatment. Our retrospective study aims to increase the current understanding and define a treatment for this sub-entity, to improve patient survival. Chemoradiotherapy is a also safe and efficacy treatment in patients with multiple lesions. Survival advantages from extensive resection remain unclear.AbstractGlioblastomas with multiple foci at presentation (mGBMs) account for 2–35% of all GBMs. mGBMs have limited existing data and no standardized treatment. This study aims to determine their incidence, demographic and clinical features, outcome, and prognostic factors in terms of overall survival. We performed a monocentric retrospective study, reviewing patients treated at the Istituto Oncologico Veneto. Inclusion criteria were: new diagnosis of GBM and presence of multiple lesions on pre-treatment MRI. ECOG PS was used to evaluate clinical condition, RANO criteria for radiological assessment, and CTCAE v5.0 for treatment-related adverse events. The incidence of newly diagnosed mGBM was 7.2% and the study population consisted of 98 patients. Median age was 63 years, M:F ratio of 1.8:1, and a surgical approach was undertaken in 73 patients (mostly partial resection). MGMT was methylated in 47.5%, and 82 patients received active oncological treatment (65.9% radiotherapy plus temozolomide (RT + TMZ)). The disease control rate with RT + TMZ was 63%. Median OS of the entire study population was 10.2 months (95% CI 6.6–13.8), and median PFS was 4.2 months (95% CI 3.2–5.2). The ECOG PS, the extent of resection, and the RT + TMZ were significant prognostic factors in the univariate analysis for OS, but only the RT + TMZ was a significant independent OS predictor in the multivariate analysis (HR = 3.1, 95% IC 1.3–7.7, p = 0.014). The incidence of mGBM is not rare. RT + TMZ is confirmed to be an independent prognostic factor for survival and a safe and effective treatment. When feasible, RT + TMZ should be considered as a possible first-line treatment. The role of the extent of resection is still unclear.