Combination of radiosurgery and immunotherapy in brain metastases: balance between efficacy and toxicities.

PURPOSE OF REVIEW: The incidence of brain metastasis is high and still increasing. Among local therapies, stereotactic radiosurgery (SRS) is an effective treatment option, optimally sparing normal brain, even for multiple brain metastases. Immune checkpoint inhibitors (ICIs) become the new standard of care in an increasing number of cancers, and the combination SRS and ICI is often proposed to patients, but few data have been published on the efficacy and the toxicity of this association. RECENT FINDINGS: Explaining this lack of consensus: retrospective studies with different primary cancers, various treatment lines and unknown levels of steroid exposure. Concerning the toxicity, the independent association of radionecrosis with brain-PTV volume was confirmed, and a decreased dose of SRS is now tested in a randomized study. Finally, a 'concurrent' delivery of SRS and ICI (within a 4 weeks' interval) seems the optimal schedule; fractionated radiosurgery for large brain metastasis should be favored. Radio-sensitizing nanoparticles and devices aiming to increase the permeability of the blood brain barrier should be considered in future combinations. SUMMARY: The efficacy/toxicity balance of SRS-ICI combination should be regularly re-evaluated, anticipating continued progress in ICI and SRS delivery, with more long-survivors potentially exposed to long-term toxicities. Patients should be included in clinical trials and clearly informed to participate more closely in the final choice.

Clinico-Radio-Histo-Molecular and Neurocognitive Characteristics of Diffuse Gliomas in Adolescent and Young Adults: A Comprehensive Review.

BACKGROUND: Diffuse gliomas are the most frequent neoplasms in adolescent and young adults (AYAs), especially high-grade gliomas, which have the highest mortality rate. Recent histo-molecular advances are in favour of specialized therapeutic management of AYA patients, which we have analysed in this comprehensive review of the literature. SUMMARY: A literature search was conducted to identify all studies concerning diffuse gliomas and AYAs (15-39 years). We assessed epidemiology, clinical and imaging findings, histo-molecular characteristics, neurosurgical and neuro-oncological management, prognosis, and health-related quality of life. KEY MESSAGES: Diffuse gliomas remain the most frequent brain tumours in the AYA population. Symptoms mainly depend on the tumour location, which varies due to histo-molecular profiles. Specific imaging patterns of histo-molecular subtypes of diffuse gliomas are identified; however, no specific pattern related to the age group has been identified. The literature review favours optimizing the extent of surgical resection for diffuse gliomas, whichever the grade, and suggests a dedicated management for these patients. It seems more relevant to consider the treatment according to the histo-molecular profile of the diffuse glioma rather than the age group. Clinical trials will allow AYA patients to benefit from innovative therapies that could improve their outcome. This literature review suggests the need for a close and long-term psychological follow-up for AYA patients with brain tumour during the transitional care, during adulthood, as well as for their family members. Collaborative efforts are needed between paediatric and adult neurosurgical and neuro-oncological teams, to move forward in the therapeutic management of AYA patients harbouring diffuse gliomas.

Characteristics of Anaplastic Oligodendrogliomas Short-Term Survivors: A POLA Network Study.

BACKGROUND: Anaplastic oligodendrogliomas IDH-mutant and 1p/19q codeleted (AO) occasionally have a poor outcome. Herein we aimed at analyzing their characteristics. METHODS: We retrospectively analyzed the characteristics of 44 AO patients with a cancer-specific survival <5 years (short-term survivors, STS) and compared them with those of 146 AO patients with a survival ≥5 years (classical survivors, CS) included in the POLA network. RESULTS: Compared to CS, STS were older (P = .0001), less frequently presented with isolated seizures (P < .0001), more frequently presented with cognitive dysfunction (P < .0001), had larger tumors (P = .= .003), a higher proliferative index (P = .= .0003), and a higher number of chromosomal arm abnormalities (P = .= .02). Regarding treatment, STS less frequently underwent a surgical resection than CS (P = .= .0001) and were more frequently treated with chemotherapy alone (P = .= .009) or with radiotherapy plus temozolomide (P = .= .05). Characteristics independently associated with STS in multivariate analysis were cognitive dysfunction, a number of mitosis > 8, and the absence of tumor resection. Based on cognitive dysfunction, type of surgery, and number of mitosis, patients could be classified into groups of standard (18%) and high (62%) risk of <5 year survival. CONCLUSION: The present study suggests that although STS poor outcome appears to largely result from a more advanced disease at diagnosis, surgical resection may be particularly important in this population.

Discriminating surgical bed cysts from bacterial brain abscesses after Carmustine wafer implantation in newly diagnosed IDH-wildtype glioblastomas.

Carmustine wafers can be implanted in the surgical bed of high-grade gliomas, which can induce surgical bed cyst formation, leading to clinically relevant mass effect. An observational retrospective monocentric study was conducted including 122 consecutive adult patients with a newly diagnosed supratentorial glioblastoma who underwent a surgical resection with Carmustine wafer implantation as first line treatment (2005-2018). Twenty-two patients (18.0%) developed a postoperative contrast-enhancing cyst within the surgical bed: 16 surgical bed cysts and six bacterial abscesses. All patients with a surgical bed cyst were managed conservatively, all resolved on imaging follow-up, and no patient stopped the radiochemotherapy. Independent risk factors of formation of a postoperative surgical bed cyst were age ≥ 60 years (p = 0.019), number of Carmustine wafers implanted ≥ 8 (p = 0.040), and partial resection (p = 0.025). Compared to surgical bed cysts, the occurrence of a postoperative bacterial abscess requiring surgical management was associated more frequently with a shorter time to diagnosis from surgery (p = 0.009), new neurological deficit (p < 0.001), fever (p < 0.001), residual air in the cyst (p = 0.018), a cyst diameter greater than that of the initial tumor (p = 0.027), and increased mass effect and brain edema compared to early postoperative MRI (p = 0.024). Contrast enhancement (p = 0.473) and diffusion signal abnormalities (p = 0.471) did not differ between postoperative bacterial abscesses and surgical bed cysts. Clinical and imaging findings help discriminate between surgical bed cysts and bacterial abscesses following Carmustine wafer implantation. Surgical bed cysts can be managed conservatively. Individual risk factors will help tailor their steroid therapy and imaging follow-up.

Adjuvant and concurrent temozolomide for 1p/19q non-co-deleted anaplastic glioma (CATNON; EORTC study 26053-22054): second interim analysis of a randomised, open-label, phase 3 study.

BACKGROUND: The CATNON trial investigated the addition of concurrent, adjuvant, and both current and adjuvant temozolomide to radiotherapy in adults with newly diagnosed 1p/19q non-co-deleted anaplastic gliomas. The benefit of concurrent temozolomide chemotherapy and relevance of mutations in the IDH1 and IDH2 genes remain unclear. METHODS: This randomised, open-label, phase 3 study done in 137 institutions across Australia, Europe, and North America included patients aged 18 years or older with newly diagnosed 1p/19q non-co-deleted anaplastic gliomas and a WHO performance status of 0-2. Patients were randomly assigned (1:1:1:1) centrally using a minimisation technique to radiotherapy alone (59·4 Gy in 33 fractions; three-dimensional conformal radiotherapy or intensity-modulated radiotherapy), radiotherapy with concurrent oral temozolomide (75 mg/m2 per day), radiotherapy with adjuvant oral temozolomide (12 4-week cycles of 150-200 mg/m2 temozolomide given on days 1-5), or radiotherapy with both concurrent and adjuvant temozolomide. Patients were stratified by institution, WHO performance status score, age, 1p loss of heterozygosity, the presence of oligodendroglial elements on microscopy, and MGMT promoter methylation status. The primary endpoint was overall survival adjusted by stratification factors at randomisation in the intention-to-treat population. A second interim analysis requested by the independent data monitoring committee was planned when two-thirds of total required events were observed to test superiority or futility of concurrent temozolomide. This study is registered with ClinicalTrials.gov, NCT00626990. FINDINGS: Between Dec 4, 2007, and Sept 11, 2015, 751 patients were randomly assigned (189 to radiotherapy alone, 188 to radiotherapy with concurrent temozolomide, 186 to radiotherapy and adjuvant temozolomide, and 188 to radiotherapy with concurrent and adjuvant temozolomide). Median follow-up was 55·7 months (IQR 41·0-77·3). The second interim analysis declared futility of concurrent temozolomide (median overall survival was 66·9 months [95% CI 45·7-82·3] with concurrent temozolomide vs 60·4 months [45·7-71·5] without concurrent temozolomide; hazard ratio [HR] 0·97 [99·1% CI 0·73-1·28], p=0·76). By contrast, adjuvant temozolomide improved overall survival compared with no adjuvant temozolomide (median overall survival 82·3 months [95% CI 67·2-116·6] vs 46·9 months [37·9-56·9]; HR 0·64 [95% CI 0·52-0·79], p<0·0001). The most frequent grade 3 and 4 toxicities were haematological, occurring in no patients in the radiotherapy only group, 16 (9%) of 185 patients in the concurrent temozolomide group, and 55 (15%) of 368 patients in both groups with adjuvant temozolomide. No treatment-related deaths were reported. INTERPRETATION: Adjuvant temozolomide chemotherapy, but not concurrent temozolomide chemotherapy, was associated with a survival benefit in patients with 1p/19q non-co-deleted anaplastic glioma. Clinical benefit was dependent on IDH1 and IDH2 mutational status. FUNDING: Merck Sharpe & Dohme.

Is function-based resection using intraoperative awake brain mapping feasible and safe for solitary brain metastases within eloquent areas?

To assess feasibility and safety of function-based resection under awake conditions for solitary brain metastasis patients. Retrospective, observational, single-institution case-control study (2014-2019). Inclusion criteria are adult patients, solitary brain metastasis, supratentorial location within eloquent areas, and function-based awake resection. Case matching (1:1) criteria between metastasis group and control group (high-grade gliomas) are sex, tumor location, tumor volume, preoperative Karnofsky Performance Status score, age, and educational level. Twenty patients were included. Intraoperatively, all patients were cooperative; no obstacles precluded the procedure from being performed. A positive functional mapping was achieved at both cortical and subcortical levels, allowing for a function-based resection in all patients. The case-matched analysis showed that intraoperative and postoperative events were similar, except for a shorter duration of the surgery (p<0.001) and of the awake phase (p<0.001) in the metastasis group. A total resection was performed in 18 cases (90%, including 10 supramarginal resections), and a partial resection was performed in two cases (10%). At three months postoperative months, none of the patients had worsening of their neurological condition or uncontrolled seizures, three patients had an improvement in their seizure control, and seven patients had a Karnofsky Performance Status score increase ≥10 points. Function-based resection under awake conditions preserving the brain connectivity is feasible and safe in the specific population of solitary brain metastasis patients and allows for high resection rates within eloquent brain areas while preserving the overall and neurological condition of the patients. Awake craniotomy should be considered to optimize outcomes in brain metastases in eloquent areas.

Development of a disease-specific graded prognostic assessment index for the management of sarcoma patients with brain metastases (Sarcoma-GPA).

BACKGROUND: Brain metastases from sarcomatous lesions pose a management challenge owing to their rarity and the histopathological heterogeneity. Prognostic indices such as the Graded Prognostic Assessment (GPA) index have been developed for several primary tumour types presenting with brain metastases (e.g. lung, breast, melanoma), tailored to the specifics of different primary histologies and molecular profiles. Thus far, a prognostic index to direct treatment decisions is lacking for adult sarcoma patients with brain metastases. METHODS: We performed a multicentre analysis of a national group of expert sarcoma tertiary centres (French Sarcoma Group, GSF-GETO) with the participation of one Canadian and one Swiss centre. The study cohort included adult patients with a diagnosis of a bone or soft tissue sarcoma presenting parenchymal or meningeal brain metastases, managed between January 1992 and March 2012. We assessed the validity of the original GPA index in this patient population and developed a disease-specific Sarcoma-GPA index. RESULTS: The original GPA index is not prognostic for sarcoma brain metastasis patients. We have developed a dedicated Sarcoma-GPA index that identifies a sub-group of patients with particularly favourable prognosis based on histology, number of brain lesions and performance status. CONCLUSIONS: The Sarcoma-GPA index provides a novel tool for sarcoma oncologists to guide clinical decision-making and outcomes research.

MRI Atlas of IDH Wild-Type Supratentorial Glioblastoma: Probabilistic Maps of Phenotype, Management, and Outcomes.

Background Tumor location is a main prognostic parameter in patients with glioblastoma. Probabilistic MRI-based brain atlases specifying the probability of tumor location associated with important demographic, clinical, histomolecular, and management data are lacking for isocitrate dehydrogenase (IDH) wild-type glioblastomas. Purpose To correlate glioblastoma location with clinical phenotype, surgical management, and outcomes by using a probabilistic analysis in a three-dimensional (3D) MRI-based atlas. Materials and Methods This retrospective study included all adults surgically treated for newly diagnosed IDH wild-type supratentorial glioblastoma in a tertiary adult surgical neuro-oncology center (2006-2016). Semiautomated tumor segmentation and spatial normalization procedures to build a 3D MRI-based atlas were validated. The authors performed probabilistic analyses by using voxel-based lesion symptom mapping technology. The Liebermeister test was used for binary data, and the generalized linear model was used for continuous data. Results A total of 392 patients (mean age, 61 years ± 13; 233 men) were evaluated. The authors identified the preferential location of glioblastomas according to subventricular zone, age, sex, clinical presentation, revised Radiation Therapy Oncology Group-Recursive Partitioning Analysis class, Karnofsky performance status, O6-methylguanine DNA methyltransferase promoter methylation status, surgical management, and survival. The superficial location distant from the eloquent area was more likely associated with a preserved functional status at diagnosis (348 of 392 patients [89%], P < .05), a large surgical resection (173 of 392 patients [44%], P < .05), and prolonged overall survival (163 of 334 patients [49%], P < .05). In contrast, deep location and location within eloquent brain areas were more likely associated with an impaired functional status at diagnosis (44 of 392 patients [11%], P < .05), a neurologic deficit (282 of 392 patients [72%], P < .05), treatment with biopsy only (183 of 392 patients [47%], P < .05), and shortened overall survival (171 of 334 patients [51%], P < .05). Conclusion The authors identified the preferential location of isocitrate dehydrogenase wild-type glioblastomas according to parameters of interest and provided an image-based integration of multimodal information impacting survival results. This suggests the role of glioblastoma location as a surrogate and multimodal parameter integrating several known prognostic factors. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Huang in this issue.

Interim results from the CATNON trial (EORTC study 26053-22054) of treatment with concurrent and adjuvant temozolomide for 1p/19q non-co-deleted anaplastic glioma: a phase 3, randomised, open-label intergroup study.

BACKGROUND: The role of temozolomide chemotherapy in newly diagnosed 1p/19q non-co-deleted anaplastic gliomas, which are associated with lower sensitivity to chemotherapy and worse prognosis than 1p/19q co-deleted tumours, is unclear. We assessed the use of radiotherapy with concurrent and adjuvant temozolomide in adults with non-co-deleted anaplastic gliomas. METHODS: This was a phase 3, randomised, open-label study with a 2 × 2 factorial design. Eligible patients were aged 18 years or older and had newly diagnosed non-co-deleted anaplastic glioma with WHO performance status scores of 0-2. The randomisation schedule was generated with the electronic EORTC web-based ORTA system. Patients were assigned in equal numbers (1:1:1:1), using the minimisation technique, to receive radiotherapy (59·4 Gy in 33 fractions of 1·8 Gy) alone or with adjuvant temozolomide (12 4-week cycles of 150-200 mg/m2 temozolomide given on days 1-5); or to receive radiotherapy with concurrent temozolomide 75 mg/m2 per day, with or without adjuvant temozolomide. The primary endpoint was overall survival adjusted for performance status score, age, 1p loss of heterozygosity, presence of oligodendroglial elements, and MGMT promoter methylation status, analysed by intention to treat. We did a planned interim analysis after 219 (41%) deaths had occurred to test the null hypothesis of no efficacy (threshold for rejection p<0·0084). This trial is registered with ClinicalTrials.gov, number NCT00626990. FINDINGS: At the time of the interim analysis, 745 (99%) of the planned 748 patients had been enrolled. The hazard ratio for overall survival with use of adjuvant temozolomide was 0·65 (99·145% CI 0·45-0·93). Overall survival at 5 years was 55·9% (95% CI 47·2-63·8) with and 44·1% (36·3-51·6) without adjuvant temozolomide. Grade 3-4 adverse events were seen in 8-12% of 549 patients assigned temozolomide, and were mainly haematological and reversible. INTERPRETATION: Adjuvant temozolomide chemotherapy was associated with a significant survival benefit in patients with newly diagnosed non-co-deleted anaplastic glioma. Further analysis of the role of concurrent temozolomide treatment and molecular factors is needed. FUNDING: Schering Plough and MSD.

The DNA methylome of DDR genes and benefit from RT or TMZ in IDH mutant low-grade glioma treated in EORTC 22033.

The optimal treatment for patients with low-grade glioma (LGG) WHO grade II remains controversial. Overall survival ranges from 2 to over 15 years depending on molecular and clinical factors. Hence, risk-adjusted treatments are required for optimizing outcome and quality of life. We aim at identifying mechanisms and associated molecular markers predictive for benefit from radiotherapy (RT) or temozolomide (TMZ) in LGG patients treated in the randomized phase III trial EORTC 22033. As candidate biomarkers for these genotoxic treatments, we considered the DNA methylome of 410 DNA damage response (DDR) genes. We first identified 62 functionally relevant CpG sites located in the promoters of 24 DDR genes, using the LGG data from The Cancer Genome Atlas. Then we tested their association with outcome [progression-free survival (PFS)] depending on treatment in 120 LGG patients of EORTC 22033, whose tumors were mutant for isocitrate dehydrogenase 1 or 2 (IDHmt), the molecular hallmark of LGG. The results suggested that seven CpGs of four DDR genes may be predictive for longer PFS in one of the treatment arms that comprised MGMT, MLH3, RAD21, and SMC4. Most interestingly, the two CpGs identified for MGMT are the same, previously selected for the MGMT-STP27 score that is used to determine the methylation status of the MGMT gene. This score was higher in the LGG with 1p/19q codeletion, in this and other independent LGG datasets. It was predictive for PFS in the TMZ, but not in the RT arm of EORTC 22033. The results support the hypothesis that a high score predicts benefit from TMZ treatment for patients with IDHmt LGG, regardless of the 1p/19q status. This MGMT methylation score may identify patients who benefit from first-line treatment with TMZ, to defer RT for long-term preservation of cognitive function and quality of life.

Extent of resection and Carmustine wafer implantation safely improve survival in patients with a newly diagnosed glioblastoma: a single center experience of the current practice.

For newly diagnosed glioblastomas treated with resection in association with the standard combined chemoradiotherapy, the impact of Carmustine wafer implantation remains debated regarding postoperative infections, quality of life, and feasibility of adjuvant oncological treatments. To assess together safety, tolerance and efficacy of Carmustine wafer implantation and of extent of resection for glioblastoma patients in real-life experience. Observational retrospective monocentric study including 340 consecutive adult patients with a newly diagnosed supratentorial glioblastoma who underwent surgical resection with (n = 123) or without (n = 217) Carmustine wafer implantation as first-line oncological treatment. Carmustine wafer implantation and extent of resection did not significantly increase postoperative complications, including postoperative infections (p = 0.269, and p = 0.446, respectively). Carmustine wafer implantation and extent of resection did not significantly increase adverse events during adjuvant oncological therapies (p = 0.968, and p = 0.571, respectively). Carmustine wafer implantation did not significantly alter the early postoperative Karnofsky performance status (p = 0.402) or the Karnofsky performance status after oncological treatment (p = 0.636) but a subtotal or total surgical resection significantly improved those scores (p < 0.001, and p < 0.001, respectively). Carmustine wafer implantation, subtotal and total resection, and standard combined chemoradiotherapy were independently associated with longer event-free survival (adjusted Hazard Ratio (aHR), 0.74 [95% CI 0.55-0.99], p = 0.043; aHR, 0.70 [95% CI 0.54-0.91], p = 0.009; aHR, 0.40 [95% CI 0.29-0.55], p < 0.001, respectively) and with longer overall survival (aHR, 0.69 [95% CI 0.49-0.96], p = 0.029; aHR, 0.52 [95% CI 0.38-0.70], p < 0.001; aHR, 0.58 [95% CI 0.42-0.81], p = 0.002, respectively). Carmustine wafer implantation in combination with maximal resection, followed by standard combined chemoradiotherapy is safe, efficient, and well-tolerated in newly diagnosed supratentorial glioblastomas in adults.

Temozolomide chemotherapy versus radiotherapy in high-risk low-grade glioma (EORTC 22033-26033): a randomised, open-label, phase 3 intergroup study.

BACKGROUND: Outcome of low-grade glioma (WHO grade II) is highly variable, reflecting molecular heterogeneity of the disease. We compared two different, single-modality treatment strategies of standard radiotherapy versus primary temozolomide chemotherapy in patients with low-grade glioma, and assessed progression-free survival outcomes and identified predictive molecular factors. METHODS: For this randomised, open-label, phase 3 intergroup study (EORTC 22033-26033), undertaken in 78 clinical centres in 19 countries, we included patients aged 18 years or older who had a low-grade (WHO grade II) glioma (astrocytoma, oligoastrocytoma, or oligodendroglioma) with at least one high-risk feature (aged >40 years, progressive disease, tumour size >5 cm, tumour crossing the midline, or neurological symptoms), and without known HIV infection, chronic hepatitis B or C virus infection, or any condition that could interfere with oral drug administration. Eligible patients were randomly assigned (1:1) to receive either conformal radiotherapy (up to 50·4 Gy; 28 doses of 1·8 Gy once daily, 5 days per week for up to 6·5 weeks) or dose-dense oral temozolomide (75 mg/m2 once daily for 21 days, repeated every 28 days [one cycle], for a maximum of 12 cycles). Random treatment allocation was done online by a minimisation technique with prospective stratification by institution, 1p deletion (absent vs present vs undetermined), contrast enhancement (yes vs no), age (<40 vs ≥40 years), and WHO performance status (0 vs ≥1). Patients, treating physicians, and researchers were aware of the assigned intervention. A planned analysis was done after 216 progression events occurred. Our primary clinical endpoint was progression-free survival, analysed by intention-to-treat; secondary outcomes were overall survival, adverse events, neurocognitive function (will be reported separately), health-related quality of life and neurological function (reported separately), and correlative analyses of progression-free survival by molecular markers (1p/19q co-deletion, MGMT promoter methylation status, and IDH1/IDH2 mutations). This trial is closed to accrual but continuing for follow-up, and is registered at the European Trials Registry, EudraCT 2004-002714-11, and at ClinicalTrials.gov, NCT00182819. FINDINGS: Between Sept 23, 2005, and March 26, 2010, 707 patients were registered for the study. Between Dec 6, 2005, and Dec 21, 2012, we randomly assigned 477 patients to receive either radiotherapy (n=240) or temozolomide chemotherapy (n=237). At a median follow-up of 48 months (IQR 31-56), median progression-free survival was 39 months (95% CI 35-44) in the temozolomide group and 46 months (40-56) in the radiotherapy group (unadjusted hazard ratio [HR] 1·16, 95% CI 0·9-1·5, p=0·22). Median overall survival has not been reached. Exploratory analyses in 318 molecularly-defined patients confirmed the significantly different prognosis for progression-free survival in the three recently defined molecular low-grade glioma subgroups (IDHmt, with or without 1p/19q co-deletion [IDHmt/codel], or IDH wild type [IDHwt]; p=0·013). Patients with IDHmt/non-codel tumours treated with radiotherapy had a longer progression-free survival than those treated with temozolomide (HR 1·86 [95% CI 1·21-2·87], log-rank p=0·0043), whereas there were no significant treatment-dependent differences in progression-free survival for patients with IDHmt/codel and IDHwt tumours. Grade 3-4 haematological adverse events occurred in 32 (14%) of 236 patients treated with temozolomide and in one (<1%) of 228 patients treated with radiotherapy, and grade 3-4 infections occurred in eight (3%) of 236 patients treated with temozolomide and in two (1%) of 228 patients treated with radiotherapy. Moderate to severe fatigue was recorded in eight (3%) patients in the radiotherapy group (grade 2) and 16 (7%) in the temozolomide group. 119 (25%) of all 477 patients had died at database lock. Four patients died due to treatment-related causes: two in the temozolomide group and two in the radiotherapy group. INTERPRETATION: Overall, there was no significant difference in progression-free survival in patients with low-grade glioma when treated with either radiotherapy alone or temozolomide chemotherapy alone. Further data maturation is needed for overall survival analyses and evaluation of the full predictive effects of different molecular subtypes for future individualised treatment choices. FUNDING: Merck Sharpe & Dohme-Merck & Co, Canadian Cancer Society, Swiss Cancer League, UK National Institutes of Health, Australian National Health and Medical Research Council, US National Cancer Institute, European Organisation for Research and Treatment of Cancer Cancer Research Fund.

Systematic review and meta-analysis of phase I/II targeted therapy combined with radiotherapy in patients with glioblastoma multiforme: quality of report, toxicity, and survival.

To perform a systematic review and meta-analysis of severe adverse events (SAE) reported in early trials combining molecularly targeted therapies (MTT) with radiotherapy (RT), and to compare them to standard therapy. A summary data meta-analysis was performed and compared to the historical standard. Inclusion criteria were phase I and/or II trials published between 2000 and 2011, with glioblastoma multiforme patients treated with RT and MTT. Pooled incidence rates (IR) of SAE were estimated as well as the pooled median progression-free survival (PFS) and overall survival (OS). Nineteen prospective trials (9 phase I, 1 phase I/II and 9 phase II) out of 29 initially selected were included (n = 755 patients). The exact number of patients who had experienced SAE was mentioned in 37 % of the trials, concerning only 17 % of the patients. Information such as the period during which adverse events were monitored, the planned treatment duration, and late toxicity were not reported in the trials. The pooled IR of overall SAE was 131.2 (95 % CI 88.8-193.7) per 1000 person-months compared to 74.7 (63.6-87.8) for standard therapy (p < 0.01). Significant differences were observed for gastrointestinal events (p = 0.05) and treatment-related deaths (p = 0.02), in favour of standard therapy. No significant difference was observed in PFS and OS. Reporting a summary of toxicity data in early clinical trials should be stringently standardized. The use of MTT with RT compared to standard therapy increased SAE while yielded comparable survival in glioblastoma multiforme patients.

Combining intraoperative carmustine wafers and Stupp regimen in multimodal first-line treatment of primary glioblastomas.

BACKGROUND: The study investigated if intraoperative use of carmustine wafers, particularly in combination with Stupp regimen, is a viable and safe first-line treatment option of glioblastomas. METHODS: Eighty-three consecutive adult patients (50 men; mean age 60 years) with newly diagnosed supratentorial primary glioblastomas that underwent surgical resection with intraoperative carmustine wafers implantation (n = 7.1 ± 1.7) were retrospectively studied. RESULTS: The median overall survival (OS) was 15.8 months with 56 patients dying over the course of the study. There was no significant association between the number of implanted carmustine wafers and complication rates (four surgical site infections, one death). The OS was significantly longer in Stupp regimen patients (19.5 months) as compared with patients with other postoperative treatments (13 months; p = 0.002). In addition patients with eight or more implanted carmustine wafers survived longer (24.5 months) than patients with seven or less implanted wafers (13 months; p = 0.021). Finally, regardless of the number of carmustine wafers, median OS was significantly longer in patients with a subtotal or total resection (21.5 months) than in patients with a partial resection (13 months; p = 0.011). CONCLUSIONS: The intraoperative use of carmustine wafers in combination with Stupp regimen is a viable first-line treatment option of glioblastomas. The prognostic value of this treatment association should be evaluated in a multicenter trial, ideally in a randomized and placebo-controlled one.

Tandem high-dose chemotherapy and autologous stem cell rescue in children with newly diagnosed high-risk medulloblastoma or supratentorial primitive neuro-ectodermic tumors.

BACKGROUND: To assess the feasibility and effectiveness of high-dose chemotherapy (HDC) with stem cell support followed by conventional craniospinal radiotherapy (RT) as treatment for children older than 5 years of age with newly diagnosed high-risk medulloblastoma (MB) or supratentorial PNET (sPNET). PROCEDURE: Between May 2001 and April 2010, 24 children older than 5 years of age (MB = 21; sPNET = 3), fulfilling inclusion criteria at diagnosis, were treated at Gustave Roussy. After conventional chemotherapy, they received two courses of high-dose thiotepa (600 mg/m(2)) followed by craniospinal RT. RESULTS: The median follow-up was 4.4 years (range, 0.8-11.3 years). For children with metastatic MB, the 5-year event-free survival (EFS) and overall survival (OS) were 72% and 83%, respectively. The toxicity was manageable. No toxic death occurred. At the most recent evaluation, among the 24 children who had at least one Full Scale Intellectual Quotient (FSIQ) examination at a median follow-up of 3.79 years after diagnosis, the mean estimated FSIQ was 82 (range, 56-114). CONCLUSIONS: In children with metastatic MB, tandem HDCT with ASCT followed by conventional craniospinal RT proved its feasibility without jeopardizing survival.

High-dose busulfan-thiotepa with autologous stem cell transplantation followed by posterior fossa irradiation in young children with classical or incompletely resected medulloblastoma.

BACKGROUND: The aim of the study is to evaluate the outcome of young children with high risk localized medulloblastomas (newly diagnosed classical or incompletely resected) treated by high-dose busulfan-thiotepa with autologous stem cell rescue (ASCT) followed by focal radiation therapy (RT). PROCEDURE: Between September 1994 and January 2010, 19 children younger than 5 years old at diagnosis fulfilling the above inclusion criteria were treated at the Institute Gustave Roussy. After conventional chemotherapy, they received busulfan at a dose of 600 mg/m(2) and thiotepa at a dose of 900 mg/m(2) followed by ASCT. Focal RT was delivered at least 70 days after ASCT. RESULTS: The median follow-up was 40.5 months (range, 14.5-191.2 months). The 3-year event-free survival (EFS) and OS were 68% (95% CI 45-84%) and 84% (95% CI 61-94%), respectively. Acute toxicity consisted mainly in hepatic veno-occlusive disease (6/19 patients) and bone marrow aplasia (all patients). No toxic death occurred. The Full Scale Intellectual Quotient tended to decrease over time at a mean rate of 0.9 point per year from the date of diagnosis. CONCLUSIONS: This intensive treatment resulted in a high overall survival rate in young children with newly diagnosed non-metastatic classic or incompletely resected MB. In spite of a high incidence of hepatic veno-occlusive disease (32%), the acute toxicity was manageable. Delayed neuropsychological side effects remain main concerns. These results should to be confirmed in a larger cohort.

Rationale for the use of upfront whole brain irradiation in patients with brain metastases from breast cancer.

Breast cancer is the second most common cause of brain metastases and deserves particular attention in relation to current prolonged survival of patients with metastatic disease. Advances in both systemic therapies and brain local treatments (surgery and stereotactic radiosurgery) have led to a reappraisal of brain metastases management. With respect to this, the literature review presented here was conducted in an attempt to collect medical evidence-based data on the use of whole-brain radiotherapy for the treatment of brain metastases from breast cancer. In addition, this study discusses here the potential differences in outcomes between patients with brain metastases from breast cancer and those with brain metastases from other primary malignancies and the potential implications within a treatment strategy.

Radiotherapy of high-grade gliomas: current standards and new concepts, innovations in imaging and radiotherapy, and new therapeutic approaches.

The current standards in radiotherapy of high-grade gliomas (HGG) are based on anatomic imaging techniques, usually computed tomography (CT) scanning and magnetic resonance imaging (MRI). The guidelines vary depending on whether the HGG is a histological grade 3 anaplastic glioma (AG) or a grade 4 glioblastoma multiforme (GBM). For AG, T2-weighted MRI sequences plus the region of contrast enhancement in T1 are considered for the delineation of the gross tumor volume (GTV), and an isotropic expansion of 15 to 20 mm is recommended for the clinical target volume (CTV). For GBM, the Radiation Therapy Oncology Group favors a two-step technique, with an initial phase (CTV1) including any T2 hyperintensity area (edema) plus a 20 mm margin treated with up to 46 Gy in 23 fractions, followed by a reduction in CTV2 to the contrast enhancement region in T1 with an additional 25 mm margin. The European Organisation of Research and Treatment of Cancer recommends a single-phase technique with a unique GTV, which comprises the T1 contrast enhancement region plus a margin of 20 to 30 mm. A total dose of 60 Gy in 30 fractions is usually delivered for GBM, and a dose of 59.4 Gy in 33 fractions is typically given for AG. As more than 85% of HGGs recur in field, dose-escalation studies have shown that 70 to 75 Gy can be delivered in 6 weeks with relevant toxicities developing in <10% of the patients. However, the only randomized dose-escalation trial, in which the boost dose was guided by conventional MRI, did not show any survival advantage of this treatment over the reference arm. HGGs are amongst the most infiltrative and heterogeneous tumors, and it was hypothesized that the most highly aggressive areas were missed; thus, better visualization of these high-risk regions for radiation boost could decrease the recurrence rate. Innovations in imaging and linear accelerators (LINAC) could help deliver the right doses of radiation to the right subvolumes according to the dose-painting concept. Advanced imaging techniques provide functional information on cellular density (diffusion MRI), angiogenesis (perfusion MRI), metabolic activity and cellular proliferation [positron emission tomography (PET) and magnetic resonance spectroscopy (MRS)]. All of these non-invasive techniques demonstrated good association between the images and histology, with up to 40% of HGGs functionally presenting a high activity within the non-contrast-enhanced areas in T1. New LINAC technologies, such as intensity-modulated and stereotactic radiotherapy, help to deliver a simultaneous integrated boost (SIB) > 60 Gy. Trials delivering a SIB into a biological GTV showed the feasibility of this treatment, but the final results, in terms of clinical benefits for HGG patients, are still pending. Many issues have been identified: the variety of MRI and PET machines (and amino-acid tracers), the heterogeneity of the protocols used for image acquisition and post-treatment, the geometric distortion and the unreliable algorithms for co-registration of brain anatomy with functional maps, and the semi-quiescent but highly invasive HGG cells. These issues could be solved by the homogenization of the protocols and software applications, the simultaneous acquisition of anatomic and functional images (PET-MRI machines), the combination of complementary imaging tools (perfusion and diffusion MRI), and the concomitant addition of some ad hoc targeted drugs against angiogenesis and invasiveness to chemoradiotherapy. The integration of these hybrid data will construct new synthetic metrics for fully individualized treatments.

Marizomib for patients with newly diagnosed glioblastoma: a randomized phase 3 trial.

BACKGROUND: Standard treatment for patients with newly diagnosed glioblastoma includes surgery, radiotherapy (RT) and temozolomide (TMZ) chemotherapy (TMZ/RT→TMZ). The proteasome has long been considered a promising therapeutic target because of its role as a central biological hub in tumor cells. Marizomib is a novel pan-proteasome inhibitor that crosses the blood brain barrier. METHODS: EORTC 1709/CCTG CE.8 was a multicenter, randomized, controlled, open label phase 3 superiority trial. Key eligibility criteria included newly diagnosed glioblastoma, age > 18 years and Karnofsky performance status > 70. Patients were randomized in a 1:1 ratio. The primary objective was to compare overall survival (OS) in patients receiving marizomib in addition to TMZ/RT→TMZ with patients receiving only standard treatment in the whole population, and in the subgroup of patients with MGMT promoter-unmethylated tumors. RESULTS: The trial was opened at 82 institutions in Europe, Canada and the US. A total of 749 patients (99.9% of planned 750) were randomized. OS was not different between the standard and the marizomib arm (median 17 vs 16.5 months; HR=1.04; p=0.64). PFS was not statistically different either (median 6.0 vs. 6.3 months; HR=0.97; p=0.67). In patients with MGMT promoter-unmethylated tumors, OS was also not different between standard therapy and marizomib (median 14.5 vs 15.1 months, HR=1.13; p=0.27). More CTCAE grade 3/4 treatment-emergent adverse events were observed in the marizomib arm than in the standard arm. CONCLUSIONS: Adding marizomib to standard temozolomide-based radiochemotherapy resulted in more toxicity, but did not improve OS or PFS in patients with newly diagnosed glioblastoma.