The Assessment of Clinical Outcomes and Prognostic Factors in Glioblastoma Patients.

AIM: To assess the outcomes of glioblastoma patients treated in our clinic over the last 10 years using a multimodality approach and cutting-edge techniques. MATERIAL AND METHODS: In our study, we included 169 glioblastoma patients who were admitted to our clinic between 2009 and 2019 and received concurrent radiotherapy (RT) + temozolomide (TMZ) after surgery. Patients were collected retrospectively and analyzed using appropriate statistical methods. RESULTS: The average follow-up period was 19 months. The average overall survival (OS) was 20.5 months. PFS and PPS were found to be 10.8 and 8.9 months, respectively. In the multivariate analysis for prognostic factors on OS, the Karnofsky Performance Score (KPS), the extent of resection (EOR), and the use of adjuvant TMZ were significant. PFS was significantly predicted by KPS, EOR, adjuvant TMZ, and planning target volume (PTV). Acute severe lymphopenia (ASL) following RT reduced the OS and PFS. There was no statistical difference in OS, PFS, recurrence patterns, or ASL incidence between the RTOG and EORTC regimens and RT techniques (IMRT vs. 3D-CRT). The association between dose-volume parameters (V3, V5, V10, V15, and V20 and V25, V30, V40, and V60 Gy) and post-treatment ASL frequency was studied. For each parameter, threshold levels were discovered. Furthermore, patients with recurrent glioblastoma who received salvage therapies had better outcomes. CONCLUSION: A multidisciplinary, and intensive treatment approach using modern techniques improved the OS of glioblastoma patients. Furthermore, in glioblastoma patients, larger RT fields were not associated with better outcomes. As a result, lymphocytesparing RT may be more beneficial in increasing patients' compliance to adjuvant TMZ, which is an important prognostic factor of OS.

Phase 2 study of AV-GBM-1 (a tumor-initiating cell targeted dendritic cell vaccine) in newly diagnosed Glioblastoma patients: safety and efficacy assessment.

BACKGROUND: Vaccine immunotherapy may improve survival in Glioblastoma (GBM). A multicenter phase II trial was designed to determine: (1) the success rate of manufacturing the Aivita GBM vaccine (AV-GBM-1), (2) Adverse Events (AE) associated with AV-GBM-1 administration, and (3) survival. METHODS: Fresh suspected glioblastoma tissue was collected during surgery, and patients with pathology-confirmed GBM enrolled before starting concurrent Radiation Therapy and Temozolomide (RT/TMZ) with Intent to Treat (ITT) after recovery from RT/TMZ. AV-GBM-1 was made by incubating autologous dendritic cells with a lysate of irradiated autologous Tumor-Initiating Cells (TICs). Eligible patients were adults (18 to 70 years old) with a Karnofsky Performance Score (KPS) of 70 or greater, a successful TIC culture, and sufficient monocytes collected. A cryopreserved AV-GBM-1 dose was thawed and admixed with 500 µg of Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) before every subcutaneous (s.c.) administration. RESULTS: Success rates were 97% for both TIC production and monocyte collection. AV-GBM-1 was manufactured for 63/63 patients; 60 enrolled per ITT; 57 started AV-GBM-1. The most common AEs attributed to AV-GBM-1 were local injection site reactions (16%) and flu-like symptoms (10%). Treatment-emergent AEs included seizures (33%), headache (37%), and focal neurologic symptoms (28%). One patient discontinued AV-GBM-1 because of seizures. Median Progression-Free Survival (mPFS) and median Overall Survival (mOS) from ITT enrollment were 10.4 and 16.0 months, respectively. 2-year Overall Survival (OS) is 27%. CONCLUSIONS: AV-GBM-1 was reliably manufactured. Treatment was well-tolerated, but there were numerous treatment-emergent central nervous system AEs. mPFS was longer than historical benchmarks, though no mOS improvement was noted. TRIAL REGISTRATION: NCT, NCT03400917 , Registered 10 January 2018.

Serum anti-Müllerian hormone as a marker of ovarian reserve after cancer treatment and/or hematopoietic stem cell transplantation in childhood: proposal for a systematic approach to gonadal assessment.

OBJECTIVE: Female patients treated with alkylating agents in childhood are at risk for ovarian impairment. We aimed at describing the pattern of residual ovarian function in a cohort of survivors of hematological malignancies and/or hematopoietic stem cell transplantation (HSCT) and assessing the relationship between cyclophosphamide equivalent dose (CED) and anti-Müllerian hormone (AMH). DESIGN AND METHODS: Gonadal health was clinically and biochemically assessed in 124 post-menarchal survivors who underwent treatment for pediatric hematological malignancies and/or HSCT between 1992 and 2019. RESULTS: Overt 'premature ovarian insufficiency' (POI) was detected in 72.1 and 3.7% of transplanted and non-transplanted patients, respectively; milder 'diminished ovarian reserve' (DOR) in 16.3 and 22.2%. In non-transplanted patients, increasing CED values were associated with lower AMH-SDS (P = 0.04), with the threshold of 7200 g/m2 being the best discriminator between DOR/POI and normal ovarian function (AUC: 0.75 on ROC analysis) and with an observed decrease of 0.14 AMH-SDS for each CED increase of 1 g/m2. In addition, age at diagnosis ≥10 years played a detrimental role on ovarian reserve (P = 0.003). In the HSCT group, irradiation was associated with a statistically significant reduction in AMH-SDS (P = 0.04). CONCLUSIONS: In non-transplanted patients, CED ≥ 7200 mg/m2 was associated with a DOR, while younger age at diagnosis played a protective role on ovarian reserve. As a result of the data collected, we propose a systematic algorithm to assess iatrogenic gonadal impairment in young female patients exposed to chemo-radiotherapy in childhood for hematological disorders.

Prognostic value of test(s) for O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation for predicting overall survival in people with glioblastoma treated with temozolomide.

BACKGROUND: Glioblastoma is an aggressive form of brain cancer. Approximately five in 100 people with glioblastoma survive for five years past diagnosis. Glioblastomas that have a particular modification to their DNA (called methylation) in a particular region (the O6-methylguanine-DNA methyltransferase (MGMT) promoter) respond better to treatment with chemotherapy using a drug called temozolomide. OBJECTIVES: To determine which method for assessing MGMT methylation status best predicts overall survival in people diagnosed with glioblastoma who are treated with temozolomide. SEARCH METHODS: We searched MEDLINE, Embase, BIOSIS, Web of Science Conference Proceedings Citation Index to December 2018, and examined reference lists. For economic evaluation studies, we additionally searched NHS Economic Evaluation Database (EED) up to December 2014. SELECTION CRITERIA: Eligible studies were longitudinal (cohort) studies of adults with diagnosed glioblastoma treated with temozolomide with/without radiotherapy/surgery. Studies had to have related MGMT status in tumour tissue (assessed by one or more method) with overall survival and presented results as hazard ratios or with sufficient information (e.g. Kaplan-Meier curves) for us to estimate hazard ratios. We focused mainly on studies comparing two or more methods, and listed brief details of articles that examined a single method of measuring MGMT promoter methylation. We also sought economic evaluations conducted alongside trials, modelling studies and cost analysis. DATA COLLECTION AND ANALYSIS: Two review authors independently undertook all steps of the identification and data extraction process for multiple-method studies. We assessed risk of bias and applicability using our own modified and extended version of the QUality In Prognosis Studies (QUIPS) tool. We compared different techniques, exact promoter regions (5'-cytosine-phosphate-guanine-3' (CpG) sites) and thresholds for interpretation within studies by examining hazard ratios. We performed meta-analyses for comparisons of the three most commonly examined methods (immunohistochemistry (IHC), methylation-specific polymerase chain reaction (MSP) and pyrosequencing (PSQ)), with ratios of hazard ratios (RHR), using an imputed value of the correlation between results based on the same individuals. MAIN RESULTS: We included 32 independent cohorts involving 3474 people that compared two or more methods. We found evidence that MSP (CpG sites 76 to 80 and 84 to 87) is more prognostic than IHC for MGMT protein at varying thresholds (RHR 1.31, 95% confidence interval (CI) 1.01 to 1.71). We also found evidence that PSQ is more prognostic than IHC for MGMT protein at various thresholds (RHR 1.36, 95% CI 1.01 to 1.84). The data suggest that PSQ (mainly at CpG sites 74 to 78, using various thresholds) is slightly more prognostic than MSP at sites 76 to 80 and 84 to 87 (RHR 1.14, 95% CI 0.87 to 1.48). Many variants of PSQ have been compared, although we did not see any strong and consistent messages from the results. Targeting multiple CpG sites is likely to be more prognostic than targeting just one. In addition, we identified and summarised 190 articles describing a single method for measuring MGMT promoter methylation status. AUTHORS' CONCLUSIONS: PSQ and MSP appear more prognostic for overall survival than IHC. Strong evidence is not available to draw conclusions with confidence about the best CpG sites or thresholds for quantitative methods. MSP has been studied mainly for CpG sites 76 to 80 and 84 to 87 and PSQ at CpG sites ranging from 72 to 95. A threshold of 9% for CpG sites 74 to 78 performed better than higher thresholds of 28% or 29% in two of three good-quality studies making such comparisons.

Timing of Chemoradiation in Newly Diagnosed Glioblastoma: Comparative Analysis Between County and Managed Care Health Care Models.

BACKGROUND: Glioblastoma multiforme (GBM) is a primary brain malignancy with significant morbidity and mortality. The current standard of treatment for GBM is surgery followed by radiotherapy and temozolomide. Despite an established treatment protocol, there exists heterogeneity in outcomes due to patients not receiving all treatments. We analyzed patients in different health care models to investigate this heterogeneity. METHODS: A retrospective analysis was performed at 2 hospitals in San Bernardino County, California, for patients with newly diagnosed GBM from 2004 to 2019. Patients younger than 18 years of age, with history of low-grade glioma, who had undergone prior treatment, and those lost to follow-up were excluded. RESULTS: A total of 57 patients were included in our study. Chemotherapy was started at 41 ± 30 and 77 ± 68 days in the health maintenance organization (HMO) and county model, respectively (P = 0.050); radiation therapy was started at 46 ± 34 and 85 ± 76 days in the HMO and county models, respectively (P = 0.036). In individuals who underwent both chemotherapy and radiation therapy (XRT), the difference in time to XRT was no longer significant (P = 0.060). Recurrence time was 309 ± 263 and 212 ± 180 days in the HMO and county groups, respectively (P = 0.379). The time to death was 412 ± 285 and 343 ± 304 days for HMO and county models, respectively (P = 0.334). CONCLUSIONS: Our study demonstrates a statistically significant difference in time to adjuvant therapies between patients within a county hospital and a managed health care organization. This information has the potential to inform future policies and care coordination for patients within the county model.

Assessment of MGMT methylation status using high-performance liquid chromatography in newly diagnosed glioblastoma.

BACKGROUND: The utility of O6-methylguanine-DNA methyltransferase (MGMT) gene promoter methylation status as a prognostic marker in patients with glioblastoma (GBM) has been established. However, the number of CpG sites that must be methylated to cause transcriptional silencing remains unclear, and no significant consensus exists on the optimal method of assessing MGMT methylation. We developed a new high-performance liquid chromatography (HPLC) method that enables accurate analysis of DNA methylation levels using long PCR products. In the present study, we analyzed the MGMT methylation status of 28 isocitrate dehydrogenase-wild-type GBMs treated with temozolomide using ion-exchange HPLC and set the optimal cutoff values. RESULTS: We designed three primers for separate regions (regions 1-3) that had 21 to 38 CpGs for PCR and validated the MGMT promoter methylation status using frozen samples. There was a strong correlation between HPLC and bisulfite sequencing results (R = 0.794). The optimal cutoff values for MGMT methylation in HPLC were determined to allow differentiation of patient prognosis by receiver operating characteristic curve analysis. The cutoff values were 34.15% for region 1, 8.84% for region 2, and 36.72% for region 3. Kaplan-Meyer curve analysis estimated that the most differentiated prognosis was enabled in the setting of 8.84% methylation of MGMT in region 2. Progression-free survival and overall survival were significantly longer for patients in this setting of region 2 methylation (p = 0.00365 and p = 0.00258, respectively). CONCLUSIONS: The combination of our HPLC method and the original primer setting provides a new standard method for determination of MGMT methylation status in patients with GBM and is useful for refining MGMT-based drug selection.

Preconditioning with INC280 and LDK378 drugs sensitizes MGMT-unmethylated glioblastoma to temozolomide: Pre-clinical assessment.

Temozolomide (TMZ) therapy is the standard of care for patients with glioblastoma (GBM). Clinical studies have shown that elevated levels of DNA repair protein O (6)-methylguanine-DNA methyltransferase (MGMT) or deficiency/defect of DNA mismatch repair (MMR) genes is associated with TMZ resistance in some, but not all, GBM tumors. Another reason for GBM treatment failure is signal redundancy due to coactivation of several functionally linked receptor tyrosine kinases (RTKs), including anaplastic lymphoma kinase (ALK) and c-Met (hepatocyte growth factor receptor). As such, these tyrosine kinases serve as potential targets for GBM therapy. Thus, we tested two novel drugs: INC280 (Capmatinib: a highly selective c-Met receptor tyrosine kinase-RTK inhibitor) and LDK378 (Ceritinib: a highly selective anaplastic lymphoma kinase-ALK inhibitor), aiming to overcome TMZ resistance in MGMT-unmethylated GBM cells in in vitro cell culture models. Treatments were examined using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, caspase-3 assay and western blot analysis. Results obtained from our experiments demonstrated that preconditioning with INC280 and LDK378 drugs exhibit increased MMR protein expression, specifically MMR protein MLH1 (MutL Homolog 1) and MSH6 (MutS Homolog 6) and sensitized TMZ in MGMT-unmethylated GBM cells via suppression of ALK and c-Met expression. INC280 and LDK378 plus TMZ also induced apoptosis by modulating downstream signaling of PI3K/AKT/STAT3. Taken together, this data indicates that co-inhibition of ALK and c-MET can enhance growth inhibitory effects in MGMT-unmethylated cells and enhance TMZ sensitivity in-vitro, suggesting c-Met inhibitors combined with ALK-targeting provide a therapeutic benefit in MGMT-unmethylated GBM patients.

Identifying Disparities in Care in Treating Glioblastoma: A Retrospective Cohort Study of Patients Treated at a Safety-net Versus Private Hospital Setting.

BACKGROUND: Patients of lower socioeconomic status (SES) may experience barriers to their oncologic care, but current data conflict over whether SES affects the prognosis of patients with glioblastoma (GB). OBJECTIVE: We sought to determine whether SES disparities impaired delivery of neuro-oncologic care and affected the prognosis of GB patients. METHODS: The records of GB patients treated from 2010 to 2014 at a safety-net hospital (SNH) or private hospital (PH), both served by 1 academic medical institution, were retrospectively reviewed and compared. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method. RESULTS: A total of 55 SNH and 39 PH GB patients were analyzed with median 11-month follow-up. SNH patients were predominantly Hispanic, low income, enrolled in Medicaid, were less likely to receive radiation (89% vs. 100%), took longer to start radiation (41 vs. 29 days), and were less likely to complete radiation treatment (80% vs. 95%). Concurrent and adjuvant temozolomide use were also lower (85% vs. 94% and 60% vs. 71%, respectively). OS and PFS were not significantly different (15 vs. 16 months and 8 vs. 11 months, respectively). On multivariate analysis, adjuvant chemotherapy and RT completion predicted for better OS, whereas hospital type, income, and insurance did not. CONCLUSION: Although GB patients at our SNH received less adjuvant treatment compared with PH, outcomes were similar. Access to multidisciplinary care staffed by academic physicians may play an important role in overcoming socioeconomic barriers to treatment availability and quality at SNHs.

Temozolomide for patients with wild-type isocitrate dehydrogenase (IDH) 1 glioblastoma using propensity score matching.

OBJECTIVE: The isocitrate dehydrogenase (IDH) 1 wild-type glioblastoma (GBM) is a major population of GBM that should be of concern in terms of the efficacy of using Temozolomide (TMZ) in adjuvant treatment. This study aimed to compare the effectiveness of TMZ with radiotherapy (RT) and RT alone in patients with IDH1wild-type GBM using a propensity score matching (PSM) approach. PATIENTS AND METHODS: Newly-diagnosed GBM patients were retrospectively analyzed. The clinical variables were collected from a hospital database. Multivariable analysis and propensity score matching (PSM) were used for adjusting the differences in characteristics among patients. The effect of TMZ on the survival of patients with GBM was evaluated by time-to-event analysis based on the multivariable model and PSM. RESULTS: One hundred and sixty-two patients were included in the unmatched analysis. Overall median survival time was 11 months (95 % CI 9.3-12.6). In the multivariable model, TMZ and RT were associated with significantly longer survival compared with RT alone (Hazard ratio [HR] 0.64, 95 %CI 0.43-0.93). After PSM, each of the 55 patients was assigned to TMZ with RT and RT alone groups. The overall median survival time of matched data was 12.0 months (95 %CI = 10.0-13.9). Additionally, the HR of TMZ with RT was 0.67 (95 %CI 0.46-0.99) in the PSM method. CONCLUSIONS: The present study revealed that the effect of TMZ with RT in IDH1 wild-type GBM patients had advantages in terms of survival by using multivariable analysis and PS approaches. In real-world settings, confounders should be explored and controlled prior to statistical analysis. Also, an economic evaluation of the specific subgroups should be conducted in the future.

Outcomes of bendamustine- or cyclophosphamide-based first-line chemotherapy in older patients with indolent B-cell lymphoma.

Clinical trials comparing bendamustine/rituximab (BR) with cyclophosphamide-based regimens (RCHOP/RCVP) have pooled various histologies of indolent B-cell lymphomas. We examined real-life outcomes of older patients with follicular (FL), mantle cell (MCL), or marginal zone/lymphoplasmacytic lymphoma (MZL/LPL), treated with these first-line regimens. We identified Medicare beneficiaries with FL, MCL, or MZL/LPL, who received either first-line BR or RCHOP/RCVP in 2009-2016, and matched groups using a propensity score. Outcomes of claims-based event-free survival (EFS), overall survival (OS), toxicity, secondary cancers, and costs were compared in the aggregate cohort (N = 2736), and in separately matched histology-specific subcohorts. In the aggregate cohort, EFS was better with BR than with RCHOP/RCVP (hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.70-0.87). Acute toxicity was lower with BR, including rates of hospitalizations (33% vs 45%), infections (21% vs 30%), cardiovascular events, and transfusions, yet OS did not differ (HR, 1.03; 95% CI, 0.91-1.17) and Medicare spending was higher. There was no difference in the cumulative incidence of secondary cancers (subhazard ratio, 1.11; 95% CI, 0.83-1.48). The EFS advantage of BR was pronounced in MCL (N = 690; HR, 0.64; 95% CI, 0.54-0.76), but less so in FL (N = 1330; HR, 0.83; 95% CI, 0.69-0.98) and absent in MZL/LPL (N = 574; HR, 0.92; 95% CI, 0.73-1.17). Despite improved EFS and lower toxicity, the shift from RCHOP/RCVP to BR in clinical practice did not improve OS for older patients with indolent B-cell lymphomas. Frequent infections and hospitalizations underscore the need for safer treatment approaches in this population. Secondary cancers do not appear to be increased after BR compared with RCHOP/RCVP.

Assessment of TP53 lesions for p53 system functionality and drug resistance in multiple myeloma using an isogenic cell line model.

Recent advances in molecular diagnostics have shown that lesions affecting both copies of the gene for tumor suppressor protein 53 (TP53) count among the most powerful predictors for high-risk disease in multiple myeloma (MM). However, the functional relevance and potential therapeutic implications of single hits to TP53 remain less well understood. Here, we have for the first time approximated the different constellations of mono- and bi-allelic TP53 lesions observed in MM patients within the frame of a single MM cell line model and assessed their potential to disrupt p53 system functionality and to impart drug resistance. Both types of common first hit: point mutation with expression of mutant p53 protein or complete loss of contribution from one of two wildtype alleles strongly impaired p53 system functionality and increased resistance to melphalan. Second hits abolished remaining p53 activity and increased resistance to genotoxic drugs even further. These results fit well with the clinical drive to TP53 single- and double-hit disease in MM patients, provide a rationale for the most commonly observed double-hit constellation (del17p+ TP53 point mutation), and underscore the potential increases in MM cell malignancy associated with any type of initial TP53 lesion.

Cost-effectiveness of tumor-treating fields added to maintenance temozolomide in patients with glioblastoma: an updated evaluation using a partitioned survival model.

PURPOSE: A first cost-effectiveness analysis has raised a strong concern regarding the cost of tumor treatment fields (TTF) added to maintenance temozolomide for patients with glioblastoma. This evaluation was based on effectiveness outcomes from an interim analysis of the pivotal trial, moreover it used a "standard" Markov model. Our objective was to update the cost-effectiveness evaluation using the more flexible potential of the "partitioned survival" model design and using the latest effectiveness data. METHODS: We developed the model with three mutually exclusive health states: stable disease, progressive disease, and dead. Good fit parametric models were developed for overall survival and progression free survival and these generated clinically plausible extrapolations beyond the observed data. We adopted the perspective of the French national health insurance and used a 20-year time horizon. Results were expressed as cost/life-years (LY) gained (LYG). RESULTS: The base case model generated incremental benefit of 0.604 LY at a cost of €453,848 which, after 4% annual discounting of benefits and costs, yielded an incremental cost effectiveness ratio (ICER) of €510,273/LYG. Using sensitivity analyses and bootstrapping methods results were found to be relatively robust and were only sensitive to TTF device costs and the modelling of overall survival. To achieve an ICER below €100,000/LYG would require a reduction in TTF device cost of approximately 85%. CONCLUSIONS: Using a different type of model and updated survival outcomes, our results show TTF remains an intervention that is not cost-effective, which greatly restrains its diffusion to potentially eligible patients.

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

BACKGROUND: Our 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 METHODS: Our 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. RESULTS: With 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). CONCLUSION: The 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.

Survival Extrapolation in Cancer Immunotherapy: A Validation-Based Case Study.

BACKGROUND: Immune-checkpoint inhibitors may provide long-term survival benefits via a cured proportion, yet data are usually insufficient to prove this upon submission to health technology assessment bodies. OBJECTIVE: We revisited the National Institute for Health and Care Excellence assessment of ipilimumab in melanoma (TA319). We used updated data from the pivotal trial to assess the accuracy of the extrapolation methods used and compared these to previously unused techniques to establish whether an alternative extrapolation may have provided more accurate survival projections. METHODS: We compared projections from the piecewise survival model used in TA319 and those produced by alternative models (fit to trial data with minimum follow-up of 3 years) to a longer-term data cut (5-year follow-up). We also compared projections to external data to help assess validity. Alternative approaches considered were parametric, spline-based, mixture, and mixture-cure models. RESULTS: Only the survival model used in TA319 and a mixture-cure model provided 5-year survival predictions close to those observed in the 5-year follow-up data set. Standard parametric, spline, and non-curative-mixture models substantially underestimated 5-year survival. Survival estimates from the TA319 model and the mixture-cure model diverge considerably after 5 years and remain unvalidated. CONCLUSIONS: In our case study, only models that incorporated an element of external information (through a cure fraction combined with background mortality rates or using registry data) provided accurate estimates of 5-year survival. Flexible models that were able to capture the complex hazard functions observed during the trial, but which did not incorporate external information, extrapolated poorly.

Re-irradiation for recurrent glioma: outcome evaluation, toxicity and prognostic factors assessment. A multicenter study of the Radiation Oncology Italian Association (AIRO).

INTRODUCTION: The prognosis of glioma is dismal, and almost all patients relapsed. At recurrence time, several treatment options are considered, but to date there is no a standard of care. The Neurooncology Study Group of the Italian Association of Radiation Oncology (AIRO) collected clinical data regarding a large series of recurrent glioma patients who underwent re-irradiation (re-RT) in Italy. METHODS: Data regarding 300 recurrent glioma patients treated from May 2002 to November 2017, were analyzed. All patients underwent re-RT. Surgical resection, followed by re-RT with concomitant and adjuvant chemotherapy was performed. Clinical outcome was evaluated by neurological examination and brain MRI performed, 1 month after radiation therapy and then every 3 months. RESULTS: Re-irradiation was performed at a median interval time (IT) of 16 months from the first RT. Surgical resection before re-RT was performed in 19% of patients, concomitant temozolomide (TMZ) in 16.3%, and maintenance chemotherapy in 29%. Total doses ranged from 9 Gy to 52.5 Gy, with a median biological effective dose of 43 Gy. The median, 1, 2 year OS were 9.7 months, 41% and 17.7%. Low grade glioma histology (p  ≪ 0.01), IT > 12 months (p = 0.001), KPS > 70 (p = 0.004), younger age (p = 0.001), high total doses delivered (p = 0.04), and combined treatment performed (p = 0.0008) were recorded as conditioning survival. CONCLUSION: our data underline re-RT as a safe and feasible treatment with limited rate of toxicity, and a combined ones as a better option for selected patients. The identification of a BED threshold able to obtain a greater benefit on OS, can help in designing future prospective studies.

Estimated lifetime survival benefit of tumor treating fields and temozolomide for newly diagnosed glioblastoma patients.

AIM: To estimate the mean lifetime survival benefit, an essential component of health economic evaluations in oncology, of adding tumor treating fields (TTFields) to maintenance temozolomide (TMZ) for newly diagnosed glioblastoma patients. METHODS: We integrated EF-14 trial data with glioblastoma epidemiology data. The model provided for an evidence-based approach to estimate lifetime survival for the material number of EF-14 trial patients still alive at 5 years. RESULTS & CONCLUSION: Patients treated with TTFields and TMZ had an incremental mean lifetime survival of 1.8 years (TTFields/TMZ: 4.2 vs TMZ alone: 2.4). Patients alive at year 2 after starting TTFields had a 20.7% probability of surviving to year 10. The results presented here provide the required incremental survival benefit necessary for a future assessment of the incremental cost-effectiveness of TTFields.

Optimal dynamic regimens with artificial intelligence: The case of temozolomide.

We determine an optimal protocol for temozolomide using population variability and dynamic optimization techniques inspired by artificial intelligence. We use a Pharmacokinetics/Pharmacodynamics (PK/PD) model based on Faivre and coauthors (Faivre, et al., 2013) for the pharmacokinetics of temozolomide, as well as the pharmacodynamics of its efficacy. For toxicity, which is measured by the nadir of the normalized absolute neutrophil count, we formalize the myelosuppression effect of temozolomide with the physiological model of Panetta and coauthors (Panetta, et al., 2003). We apply the model to a population with variability as given in Panetta and coauthors (Panetta, et al., 2003). Our optimization algorithm is a variant in the class of Monte-Carlo tree search algorithms. We do not impose periodicity constraint on our solution. We set the objective of tumor size minimization while not allowing more severe toxicity levels than the standard Maximum Tolerated Dose (MTD) regimen. The protocol we propose achieves higher efficacy in the sense that -compared to the usual MTD regimen- it divides the tumor size by approximately 7.66 after 336 days -the 95% confidence interval being [7.36-7.97]. The toxicity is similar to MTD. Overall, our protocol, obtained with a very flexible method, gives significant results for the present case of temozolomide and calls for further research mixing operational research or artificial intelligence and clinical research in oncology.

Shadow study: randomized comparison of clinic with video follow-up in glioma undergoing adjuvant temozolomide therapy.

AIM: This study was designed with a primary objective to study the rate of agreement in treatment plan and decisions between video follow-up (VF) and conventional clinic follow-up (CF). PATIENTS & METHODS: Adult patients with intermediate- to high-grade glioma on adjuvant temozolomide (TMZ) with facilities for live video call were invited to participate in the study. RESULTS: The concurrence in decision of administering TMZ between VF and CF was 100% (p < 0.00). The median cost incurred in VF was US$58.15 while that incurred in CF was US$131.23 (p < 0.00). CONCLUSION: VF can substitute CF during adjuvant TMZ administration (CTRI/2017/01/007626).