Cognitive functioning in a cohort of high-grade glioma patients.

BACKGROUND: High grade gliomas are associated with cognitive problems. The aim of the study was to investigate cognitive functioning in a cohort of patients with high grade glioma, according to isocitrate dehydrogenase (IDH) and methyl guanine methyl transferase (MGMT) status and other clinical characteristics. PATIENTS AND METHODS: The patients with the high-grade glioma treated in Slovenia in given period of time were included in study. Postoperatively they completed neuropsychological assessment consisting of Slovenian Verbal Learning Test, Slovenian Controlled Oral Word Association Test, Trail Making Test Part A and B and self-evaluation questionnaire. We analysed results (z-scores and dichotomized results) also according to IDH mutation and MGMT methylation. We examined differences between groups using T-test, Mann-Whitney U, χ2 and Kendall's Tau tests. RESULTS: Out of 275 patients in the cohort, we included 90. Forty-six percent of patients were unable to participate due to poor performance status and other conditions related to tumour. Patients with the IDH mutation were younger, with better performance status, larger proportions of grade III tumours and MGMT methylation. In this group cognitive functioning is significantly better in the domains of immediate recall, short delayed recall and delayed recall, and in the fields of executive functioning and recognition. There were no differences in cognitive functioning in regard to MGMT status. Grade III tumours were associated with more frequent MGMT methylation. Self-assessment proved week tool, associated only with immediate recall. CONCLUSIONS: We found no differences in cognitive functioning according to MGMT status, but cognition was better when IDH mutation was present. In a cohort study of patients with high-grade glioma, almost half were unable to participate in a study, which points to an overrepresentation of patients with better cognitive functioning in the research.

Cognitive functioning is prognostic in patients with IDH1-wild type and MGMT-unmethylated high-grade gliomas.

AIM: To investigate the prognostic factors of survival in patients with high-grade gliomas without isocitrate dehydrogenase-1 (IDH) mutation and O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation. METHODS: The study enrolled Slovenian patients with high-grade gliomas. Postoperatively, they completed a battery of neuropsychological tests. Demographics and clinical data were collected. The results of cognitive tests were converted to standardized scores and dichotomized based on impairment. A univariate Cox proportional hazard regression model was used to determine clinical predictors, and a multivariate Cox model was used to determine the prognostic value of cognitive test results. Kaplan-Meier curves were constructed, and survival was compared with the log rank test. RESULTS: The study enrolled 49 patients with IDH wild-type, MGMT-unmethylated high-grade gliomas. The median time to progression was 9.92 months (7.25, 12.59) and the overall median survival was 12.19 months (8.95, 15.4). Age and the extent of surgery were significant prognostic factors for survival. After controlling for these factors, cognitive functioning in the domain of verbal fluency remained a significant predictor of survival outcomes. CONCLUSION: Cognitive functioning in the domain of verbal fluency was associated with overall survival independently of age and the extent of surgery. Cognitive functioning could be an important stratifying tool in this group of patients lacking other predictors.

The Value of FET PET/CT in Recurrent Glioma with a Different IDH Mutation Status: The Relationship between Imaging and Molecular Biomarkers.

The evaluation of treatment response remains a challenge in glioma cases because the neuro oncological therapy can lead to the development of treatment-related changes (TRC) that mimic true progression (TP). Positron emission tomography (PET) using O-(2-[18F] fluoroethyl-)-L-tyrosine (18F-FET) has been shown to be a useful tool for detecting TRC and TP. We assessed the diagnostic performance of different 18F-FET PET segmentation approaches and different imaging biomarkers for differentiation between late TRC and TP in glioma patients. Isocitrate dehydrogenase (IDH) status was evaluated as a predictor of disease outcome. In our study, the proportion of TRC in IDH wild type (IDHwt) and IDH mutant (IDHm) subgroups was without significant difference. We found that the diagnostic value of static and dynamic biomarkers of 18F-FET PET for discrimination between TRC and TP depends on the IDH mutation status of the tumor. Dynamic 18F-FET PET acquisition proved helpful in the IDH wild type (IDHwt) subgroup, as opposed to the IDH mutant (IDHm) subgroup, providing an early indication to discontinue dynamic imaging in the IDHm subgroup.

Glioblastoma in Patients over 70 Years of Age.

BACKGROUND: Glioblastoma has in last 20 years seen the steady increase of incidence, which is most prominent in the group of older patients. These older than 70 years have significantly poorer prognosis than other patients and are considered a distinct group of glioblastoma patients. Modified prognostic factors are being used in these patients and this information is lately supplemented with the genetic and epigenetic information on tumour. The therapy is now often tailored accordingly. The aim of our study was to analyse the current treatment of the glioblastoma patients over 70 years of age to determine the impact of clinical prognostic factors. PATIENTS AND METHODS: Among patients treated at the Institute of Oncology Ljubljana between 1997 and 2015, we found that 207 were older than 70 years. We analysed their survival, clinical prognostic factors (age, performance status) treatment modalities (extent of surgery, radiation dose, chemotherapy). RESULTS: Median survival of patients older than 70 years was 5.3 months which was statistically significant inferior to the survival of younger patients (p < 0.001). The clinical prognostic factors that influenced survival the most were performance status (p < 0.001), extent of surgical resection (p < 0.001), addition of temozolomide (p < 0.001) and addition of radiotherapy (p = 0.006). Patients receiving concomitant radiochemotherapy with temozolomide followed by adjuvant temozolomide, had same median survival as patients receiving adjuvant temozolomide after completion of radiotherapy. CONCLUSIONS: The increase of the number of older patients with glioblastoma corresponds to the increase in the life expectancy but in Slovenia also to the increased availability of diagnostic procedures. Clinical prognostic markers are helpful in decision on the aggressiveness of treatment. Radiotherapy and temozolomide have the biggest impact on survival, but the radiotherapy dose seems to be of secondary importance. In selected patients, chemotherapy alone might be sufficient to achieve an optimal effect. Patients that were fitter, had more aggressive surgery, and received temozolomide fared the best. The scheduling of the temozolomide seems to have limited impact on survival as in our study, there was no difference weather patients received temozolomide concomitant with radiotherapy or after the radiotherapy. Thus far, our findings corroborate the usefulness of recursive partitioning analysis (RPA) classes in clinical decisions.

Long-term survival in glioblastoma: methyl guanine methyl transferase (MGMT) promoter methylation as independent favourable prognostic factor.

BACKGROUND: In spite of significant improvement after multi-modality treatment, prognosis of most patients with glioblastoma remains poor. Standard clinical prognostic factors (age, gender, extent of surgery and performance status) do not clearly predict long-term survival. The aim of this case-control study was to evaluate immuno-histochemical and genetic characteristics of the tumour as additional prognostic factors in glioblastoma. PATIENTS AND METHODS: Long-term survivor group were 40 patients with glioblastoma with survival longer than 30 months. Control group were 40 patients with shorter survival and matched to the long-term survivor group according to the clinical prognostic factors. All patients underwent multimodality treatment with surgery, postoperative conformal radiotherapy and temozolomide during and after radiotherapy. Biopsy samples were tested for the methylation of MGMT promoter (with methylation specific polymerase chain reaction), IDH1 (with immunohistochemistry), IDH2, CDKN2A and CDKN2B (with multiplex ligation-dependent probe amplification), and 1p and 19q mutations (with fluorescent in situ hybridization). RESULTS: Methylation of MGMT promoter was found in 95% and in 36% in the long-term survivor and control groups, respectively (p < 0.001). IDH1 R132H mutated patients had a non-significant lower risk of dying from glioblastoma (p = 0.437), in comparison to patients without this mutation. Other mutations were rare, with no significant difference between the two groups. CONCLUSIONS: Molecular and genetic testing offers additional prognostic and predictive information for patients with glioblastoma. The most important finding of our analysis is that in the absence of MGMT promoter methylation, longterm survival is very rare. For patients without this mutation, alternative treatments should be explored.

Glioblastoma patients in Slovenia from 1997 to 2008.

BACKGROUND: Glioblastoma is the most common primary brain tumour. It has a poor prognosis despite some advances in treatment that have been achieved over the last ten years. In Slovenia, 50 to 60 glioblastoma patients are diagnosed each year. In order to establish whether the current treatment options have any influence on the survival of the Slovenian glioblastoma patients, their data in the period from the beginning of the year 1997 to the end of the year 2008 have been analysed. PATIENTS AND METHODS: All patients treated at the Institute of Oncology Ljubljana from 1997 to 2008 were included in the retrospective study. Demographics, treatment details, and survival time after the diagnosis were collected and statistically analysed for the group as a whole and for subgroups. RESULTS: From 1997 to 2008, 527 adult patients were diagnosed with glioblastoma and referred to the Institute of Oncology for further treatment. Their median age was 59 years (from 20 to 85) and all but one had the diagnosis confirmed by a pathologist. Gross total resection was reported by surgeons in 261 (49.5%) patients; good functional status (WHO 0 or 1) after surgery was observed in 336 (63.7%) patients, radiotherapy was performed in 422 (80.1%) patients, in 317 (75.1%) of them with radical intent, and 198 (62.5 %) of those received some form of systemic treatment (usually temozolomide). The median survival of all patients amounted to 9.7 months. There was no difference in median survival of all patients or of all treated patients before or after the chemo-radiotherapy era. However, the overall survival of patients treated with radical intent was significantly better (11.4 months; p < 0.05). A better survival was also noticed in radically treated patients who received additional temozolomide therapy (11.4 vs. 13.1 months; p = 0.014). The longer survival was associated with a younger age and a good performance status as well as with a more extensive tumour resection. In patients treated with radical intent, having a good performance status, and receiving radiotherapy and additional temozolomide therapy, the survival was significantly longer, based on multivariate analysis. CONCLUSIONS: We observed a gradual increase in the survival of glioblastoma patients who were treated with radical intent over the last ten years. Good functional surgery, advances in radiotherapy and addition of temozolomide all contributed to this increase. Though the increased survival seems to be more pronounced in certain subgroups, we have still not been able to exactly define them. Further research, especially in tumour biology and genetics is needed.

A phase II trial of low-dose gemcitabine in a prolonged infusion and cisplatin for malignant pleural mesothelioma.

After a favorable experience with gemcitabine at a low dose in a prolonged infusion in combination with cisplatin for advanced non-small-cell lung cancer, here, we present the results from a phase II trial for patients with malignant pleural mesothelioma. Eligible patients had biopsy-proven malignant pleural mesothelioma, were chemo-naive, Eastern Cooperative Oncology Group performance status 0-2, had normal hematopoietic liver and renal function, and gave informed consent. Treatment consisted of gemcitabine 250 mg/m in a 6-h infusion on days 1 and 8 and cisplatin at 75 mg/m on day 2 of a 3-week cycle for four cycles, followed by two additional cycles without cisplatin. Seventy-eight patients (58 men, 20 women; age 33-82 years, median 58) were recruited into the trial. The histologic types were as follows: epitheloid 56 (71.8%); four sarcomatoid (5.1%); mixed 15 (19.2%); and mesothelioma, three not otherwise specified (3.8%). Grades 3-4 toxicity included two (2.6%) patients with anemia, 18 (23.1%) with neutropenia, and one with nausea/vomiting. Reversible thrombocytosis with platelets over 1000-10/l was recorded in 10 (12.8%) patients and grade 2 alopecia in 60 (76.9%). Four (5.1%) patients showed a complete response and 35 (44.9%) showed a partial response with a response rate of 39/78 (50%). Minimal response or stable disease was seen in 35 (44.9%), whereas only four (5.1%) patients progressed during treatment. Most patients reported symptomatic improvement with a higher or a stable quality of life score in 70 (89.7%) cases. The median progression-free survival was 8.0 months (confidence interval 6.9-9.0). The median overall survival was 17.0 months (confidence interval 14.7-19.2). One-year, two-year, and three-year survival rates were 67.3, 32.7, and 19.8%, respectively. Epitheloid histological type was the only statistically significant favorable prognostic factor for progression-free survival and overall survival. Because of the acceptable toxicity, remarkable activity, and reasonable cost, this treatment should be further explored.

Intermittent chemotherapy and erlotinib for nonsmokers or light smokers with advanced adenocarcinoma of the lung: a phase II clinical trial.

BACKGROUND: Intermittent application of chemotherapy and tyrosine kinase inhibitors may avoid antagonism between the two classes of drugs. This hypothesis was tested in a Phase II clinical trial. PATIENTS AND METHODS: Eligible patients were nonsmokers or light smokers, chemo-naïve, with metastatic adenocarcinoma of the lung. TREATMENT: 4 to 6 cycles of gemcitabine 1250 mg/m(2) on days 1 and 4, cisplatin 75 mg/m(2) on day 2, and erlotnib 150 mg daily on days 5-15, followed by erlotinib as maintenance. RESULTS: 24 patients entered the trial. Four pts had grade 3 toxicity. Complete remission (CR) and partial remission (PR) were seen in 5 pts and 9 pts, respectively (response rate 58%). Median time to progression (TTP) was 13.4 months and median overall survival (OS) was 23 months. When compared to patients with negative or unknown status of EGFR mutations, 8 patients with EGFR gene activating mutations had significantly superior experience: 4 CR and 4 PR, with median TTP 21.5 months and OS 24.2 months (P < .05). CONCLUSIONS: Intermittent schedule with gemcitabine, cisplatin and erlotinib has mild toxicity. For patients who are positive for EGFR gene activating mutations, this treatment offers excellent response rate, time to progression and survival.

Two schedules of chemotherapy for patients with non-small cell lung cancer in poor performance status: a phase II randomized trial.

We present experience from a phase II randomized clinical trial, comparing standard gemcitabine as monotherapy with low-dose gemcitabine in long infusion in a doublet with cisplatin at reduced dose for patients with non-small cell lung cancer (NSCLC) and who are unfit for standard platin-based chemotherapy. Eligible patients had microscopically confirmed NSCLC in stage IIIB (wet) or IV, were chemo-naive, and were in poor performance status or presented with significant comorbidity. Standard treatment with gemcitabine, 1250 mg/m in 20-30 min on days 1 and 8 as monotherapy (arm A) was compared with low-dose gemcitabine in long infusion (200 mg/m in 6 h on day 1) and cisplatin at 60 mg/m on day 2 (arm B). Both treatment schedules were repeated every 3 weeks until disease progression, unacceptable toxicity, or to a maximum of six cycles. A total of 112 patients (83 male, 29 female, median age 66 years) were randomized between arm A (57 patients) and B (55 patients). The two groups were balanced for prognostic factors. Fifty-three patients in arm A and 52 in arm B received at least one application of chemotherapy and were evaluable for toxicity and response. The median number of cycles was four and five for arms A and B, respectively. Except for grade 3 anemia (one patient in arm A and two in arm B), no other major toxicity was seen. Regarding response to treatment, arm B was superior: 1 complete response and 13 partial remissions (response rate 26.9%) as compared with five partial remissions (response rate 9.4%) in arm A (P<0.01). The median time to progression was 3.8 and 5.6 months, and the median survival was 4.3 and 6.8 months for arms A and B, respectively (P<0.05). Treatment with low-dose gemcitabine in long infusion and cisplatin at reduced dose has very low toxicity, is effective, was found to be superior to monotherapy with gemcitabine in standard doses, and is suitable for patients with NSCLC who cannot tolerate a standard platin-based doublet.

Genetic markers in oligodendroglial tumours.

BACKGROUND: Oliogodendrogliomas are brain tumours composed of the cells resembling oligodendrocytes. They represent the third most common glial tumour, comprising 2.5% of all primary brain tumours and 5-20% of all gliomas. CONCLUSIONS: Oligodendroglial tumours with 1p and 19q loss demonstrate a better overall prognosis due to more indolent clinical behaviour and higher sensitivity to treatment. Additionally, 1p and 19q loss is a marker of clinical utility, helping to assess tumour sensitivity to chemotherapy and harbouring the potential for improving the diagnosis and survival of oligodendroglioma patients as well as future clinical practice.

Gemcitabine in brief versus prolonged low-dose infusion, both combined with cisplatin, for advanced non-small cell lung cancer: a randomized phase II clinical trial.

OBJECTIVE: Gemcitabine in low dose in prolonged infusion is a treatment with documented activity against a variety of tumors. We here report the first randomized trial to compare standard brief and low-dose prolonged infusion of gemcitabine. PATIENTS AND METHODS: Eligible patients had non-small cell lung cancer in stage IIIB (wet) or IV, Karnofsky performance status 100 to 70 (Eastern Cooperative Oncology Group 0-2), measurable disease, were chemonaïve and fulfilled the standard criteria for chemotherapy. In arm A (standard treatment), gemcitabine was given at 1250 mg/m(2) in 20 to 30 minutes and in arm B (prolonged infusion) at 250 mg/m(2) in 6 hours infusion. All patients received gemcitabine on days 1 and 8 and cisplatin at 75 mg/m(2) on day 2 of a 3-week cycle for four cycles, followed by two cycles of gemcitabine as monotherapy. RESULTS: A total of 249 patients (188 men and 61 women, median age 58 years) were randomized between arm A (125 patients) and arm B (124 patients). Adenocarcinoma (53.9%) was the predominant histologic type; 92% of patients were in stage IV. The two groups were balanced for prognostic factors; however, group A had fewer patients with significant weight loss and no patient with lung cancer as a second malignancy or after radiotherapy for brain metastases. Grade 3 or greater toxicity was rare: anemia in 0.8 and 3.2%, neutropenia in 21.6 and 22.6%, thrombocytopenia in 0 and 1.6%, and nausea/vomiting in 4 and 8.1% for arms A and B, respectively. Alopecia was seen in 54.5% of patients in arm B, as compared with 9.7% in arm A. No patient died of treatment-related toxicity. During cycle 5, 47.7% of patients in arm A and 60.7% in arm B reported improved well-being, as compared with the status before chemotherapy. Patients in arm A had no complete remission, 32.8% partial responses, 48% minimal responses or stable disease, 13.6% progressions, and 5.6% were not evaluable. For arm B, the corresponding figures are as follows: complete remission 0.8%, partial responses 46% (for overall response rate of 46.8%), minimal responses or stable disease 36.3%, progression 12.1%, and not evaluable 4.8%. Median progression-free survival was 5.5 and 6.0 months, median overall survival was 10.1 and 10.0 months, and 1-year survival was 46.6 and 41.1% for arms A and B, respectively. For the 71 patients with squamous carcinoma, arm B seems superior to arm A, as seen by the higher overall response rate (51.3 versus 35.5%), longer median progression-free survival (6.2 versus 4.9 months), and longer median survival (11.3 versus 8.5 months). However, because of the small number of patients, these differences did not reach the level of statistical significance. CONCLUSION: In the treatment of advanced non-small cell lung cancer, gemcitabine in low dose in prolonged infusion in combination with cisplatin has low toxicity and has activity comparable with gemcitabine in higher dose in standard brief infusion. Low-dose gemcitabine may be preferred for incurable cancer among economically deprivileged patients. In addition, apparent superior activity against squamous carcinoma opens new perspectives and deserves further research.

Gemcitabine, cisplatin, and hyperfractionated accelerated radiotherapy for locally advanced non-small cell lung cancer.

BACKGROUND: Due to potent radiosensitization and potential serious or fatal toxicity, concurrent gemcitabine and irradiation should only be applied within clinical trials. We here present experience from a phase I-II clinical trial for patients with locally advanced non-small cell lung cancer (NSCLC) treated with hyperfractionated accelerated radiotherapy and concurrent low-dose gemcitabine. METHODS: Eligible patients had locally advanced inoperable NSCLC without pleural effusion, Eastern Cooperative Oncology Group performance status 0-1, were chemotherapy naïve and had no previous radiotherapy to the chest, and had adequate hematopoietic, liver, and kidney function. Routine brain computed tomography was not performed, and positron emission tomography/computed tomography was not available. Treatment consisted of three parts: induction chemotherapy with gemcitabine and cisplatin in standard doses, local treatment with concurrent chemotherapy and radiotherapy, and consolidation chemotherapy. Patients were irradiated with opposed AP-PA and oblique fields, using 2.5-D treatment planning. Although corrections for inhomogeneous tissue were made, volume of total lung receiving > or =20 Gy (V20) could not be determined. The trial started as phase I, aimed to determine the dose-limiting toxicity and maximal tolerated dose (MTD) for concurrent hyperfractionated radiotherapy (1.4 Gy twice daily) and gemcitabine 55 mg/m twice weekly as a radiosensitizer. Phase II of the trial then continued at the level of MTD. RESULTS: Twenty-eight patients with NSCLC, nine patients with stage IIIA, 16 patients with IIIB, and three patients with an inoperable recurrence after previous surgery, entered the trial. The first 12 patients entered Phase I of the trial at the initial level of 42 Gy in 30 fractions in 3 weeks. Dose-limiting toxicity was acute esophagitis; 47.6 Gy in 34 fractions in 3.5 weeks was the MTD for this regimen of concurrent chemotherapy and radiotherapy. In phase II of the trial, this dose was applied to the next 16 patients. Among all 28 patients, 13 had grade 3 or 4 acute toxicity: esophagitis (eight patients), neutropenia (eight patients), thrombocytopenia (four patients), and anemia (two patients). No pulmonary toxicity and no persistent or serious late toxicity were seen. Local and/or regional relapse was documented in nine patients, distant in five and both locoregional and distant in 10 patients. The most common sites of distant spread were the brain and lung in eight and six patients, respectively. At 2 years, progression-free survival was 43% and overall survival was 57%. After 43 to 85 months of follow-up, seven patients are alive, of whom six (21%) are without evidence of disease and may be regarded as long-term survivors. Among the long-term survivors, one was in the group irradiated to 42 Gy and six in the groups irradiated to 47.6 Gy. CONCLUSION: Judging from current standards, the methods used in diagnostics and in planning of radiotherapy were suboptimal. Using modern radiotherapy planning, a higher MTD, possibly a different profile of toxicity, and better long-term results may be expected. The high incidence of brain relapse emphasizes the need for careful screening for unsuspected brain disease before treatment and the importance of clinical studies on prophylactic cranial irradiation for patients with locally advanced NSCLC. Although the small number of patients in this study precludes any definitive conclusion, it appears that our program of concurrent chemotherapy and radiotherapy offers a chance for disease control at least comparable to previously described programs for inoperable lung cancer.