Renata Ursu

Intracerebral administration of CpG oligonucleotide for patients with recurrent glioblastoma: a phase II study

Immunostimulating oligodeoxynucleotides containing CpG motifs (CpG-ODN) have shown promising efficacy in cancer models when injected locally. In a phase I clinical trial, intratumoral infusions of CpG-ODN in glioblastoma (GBM) patients were well tolerated at doses up to 20 mg. This phase II trial was designed to study the efficacy of a local treatment by CpG-ODN in patients with recurrent GBMs. Patients with recurrent GBM occurring at least 3 months after radiotherapy, and previously treated with 1 or 2 regimens of chemotherapy received 20 mg of CpG-ODN (CpG-28) by convection-enhanced delivery. The primary endpoint was the percentage of patients without tumor progression 6 months after inclusion. Secondary endpoints were tolerance, survival, and radiological response. Thirty-four patients were enrolled in two centers between November 2004 and March 2006. Thirty-one patients received CpG-ODN treatment. The progression-free survival (PFS) at 6 months was 19%. One partial response and 3 minor responses were observed. The median overall survival was 28 weeks. Eight patients (24%) were alive 1 year after inclusion and 5 patients (15%) were alive after 2 years. Treatment was usually well tolerated. As reported previously, the most common toxicities were lymphopenia, mild fever, seizures, and transient neurological worsening. Despite a few cases showing a radiological response, CpG-28 showed modest activity on the 6-month PFS in this patient population. The molecular or clinical characteristics of a subgroup of patients that could potentially benefit from such an approach remain to be defined.

Upfront association of carboplatin plus pemetrexed in patients with brain metastases of lung adenocarcinoma

Approximately 10% of patients with non-small cell lung cancer (NSCLC) have brain metastases at the time of diagnosis. When surgical resection is not possible, whole brain radiotherapy is the standard of care, with a cerebral response rate of approximately 30%. We report our experience with an upfront association of carboplatin and pemetrexed (areas under the curve, 5 and 500 mg/m(2), respectively), every 3 weeks, in 30 patients presenting with newly diagnosed brain metastases and NSCLC. Cerebral MRIs were performed every 6-9 weeks. The radiologic response rates were assessed according to Response Evaluation Criteria in Solid Tumors. Overall survival was also determined. Twenty-six patients were evaluable for response, and the objective cerebral response rate (complete and partial response) in the intent-to-treat population was 40% (12 of 30 patients). Event-free survival was 31 weeks, and median overall survival was 39 weeks. The upfront association of carboplatin plus pemetrexed allows simultaneous treatment of cerebral and systemic disease in patients with NSCLC with newly diagnosed brain metastases and appears to be particularly interesting in terms of radiologic response and overall survival. Further clinical studies are warranted.

Immunotherapeutic approach with oligodeoxynucleotides containing CpG motifs (CpG-ODN) in malignant glioma.

Bacterial DNA and synthetic oligodeoxynucleotides containing CpG motifs (CpG-ODNs) are strong activators of both innate and specific immunity, driving the immune response towards the Th1 phenotype. In cancer patients, CpG-ODNs can be used to activate the innate immunity and trigger a tumor-specific immune response. Several clinical trials are on-going worldwide in various cancers. In this chapter, we will focus on the potential applications of CpG-ODNs in glioma. So far, CpG-ODN has mainly been used by intratumoral injections. Indeed, human gliomas display a locally invasive pattern of growth and rarely metastasize, making local treatment clinically relevant.

Immunotherapy with CpG-ODN in neoplastic meningitis: A phase I trial.

TLR‐9 agonists are immunostimulating agents that have antitumor effects in animal models. A phase I trial was conducted to define the safety profile of subcutaneous injections, combined with intrathecally administration of CpG‐28, a TRL 9 agonist, in patients with neoplastic meningitis (NM). Cohorts of 3–6 patients with NM were treated for 5 weeks with escalating doses of CpG‐28. The primary endpoint was tolerance. Secondary endpoints were progression free survival (PFS) and overall survival (OS). Twenty‐nine patients were treated with CpG‐28. The primary cancers were malignant glioma, lung carcinoma, breast cancer, melanoma or melanocytoma, ependymoma, and colorectal cancer. The median age was 56 years and median Karnovsky Performance status (KPS) was 70%. The treatment was well tolerated. Adverse effects that were possibly or probably related to the studied drug were grade 2 lymphopenia, anemia and neutropenia, local erythema at injection sites, fever and seizure. There were five serious adverse events: two confusions, two infections of ventricular devices and one grade 4 thrombopenia and neutropenia. The median PFS was 7 weeks and median OS was 15 weeks. Interestingly, the median survival was slightly (but not significantly) higher in the eight patients who were concomitantly treated with bevacizumab (19 weeks vs 15 weeks; P = 0.11). CpG‐28 was well tolerated at doses up to 0.3 mg/kg subcutaneously and 18 mg intrathecally. Additional trials are warranted.

Superficial siderosis of the central nervous system: a rare cause of dementia with therapeutic consequences

A 75-year-old patient was evaluated for dementia. His past medical history included an ischaemic cardiomyopathy treated with aspirin daily. His neurological examination showed mild ataxia syndrome and central deafness. The neuropsychological examination did not suggest Alzheimers disease. No specific aetiology was found from biological investigations, but MRI scans revealed a superficial siderosis, which was further confirmed with CSF exams. This case highlights the interest of MRI with echo-gradient-T2 weighted sequences in patients investigated for memory disorders. Once the diagnosis is known, specific preventive measures have to be taken: searching for a treatable source of bleeding and the interruption of antiplatelet aggregation or anticoagulant treatments.

Recurrent glioblastomas in the elderly after maximal first-line treatment: does preserved overall condition warrant a maximal second-line treatment?

A growing literature supports maximal safe resection followed by standard combined chemoradiotherapy (i.e. maximal first-line therapy) for selected elderly glioblastoma patients. To assess the prognostic factors from recurrence in elderly glioblastoma patients treated by maximal safe resection followed by standard combined chemoradiotherapy as first-line therapy. Multicentric retrospective analysis comparing the prognosis and optimal oncological management of recurrent glioblastomas between 660 adult patients aged of < 70 years (standard group) and 117 patients aged of ≥70 years (elderly group) harboring a supratentorial glioblastoma treated by maximal first-line therapy. From recurrence, both groups did not significantly differ regarding Karnofsky performance status (KPS) (p = 0.482). Oncological treatments from recurrence significantly differed: patients of the elderly group received less frequently oncological treatment from recurrence (p < 0.001), including surgical resection (p < 0.001), Bevacizumab therapy (p < 0.001), and second line chemotherapy other than Temozolomide (p < 0.001). In multivariate analysis, Age ≥70 years was not an independent predictor of overall survival from recurrence (p = 0.602), RTOG-RPA classes 5–6 (p = 0.050) and KPS at recurrence <70 (p < 0.001), available in all cases, were independent significant predictors of shorter overall survival from recurrence. Initial removal of ≥ 90% of enhancing tumor (p = 0.004), initial completion of the standard combined chemoradiotherapy (p = 0.007), oncological treatment from recurrence (p < 0.001), and particularly surgical resection (p < 0.001), Temozolomide (p = 0.046), and Bevacizumab therapy (p = 0.041) were all significant independent predictors of longer overall survival from recurrence. Elderly patients had substandard care from recurrence whereas age did not impact overall survival from recurrence contrary to KPS at recurrence <70. Treatment options from recurrence should include repeat surgery, second line chemotherapy and anti-angiogenic agents.

P4-27 Hemosiderose superficielle du SNC : Un diagnostic de démence à ne pas négliger

L’Hemosiderose Superficielle du SNC est une pathologie rare (environ 90 cas rapportes dans la litterature) mais dont la frequence dans les demences est vraisemblablement sousestimee. L’Hemosiderose Superficielle du SNC est definie par la presence de depots d’hemosiderine a la surface du systeme nerveux central et est la consequence d’hemorragies sous-arachnoidiennes chroniques ou repetees. La triade caracteristique est constituee par l’association d’une surdite, d’une ataxie cerebelleuse et d’un syndrome pyramidal. Les troubles cognitifs existent dans 24% des observations (Fearnly et al., 1995). Van Harsjamp et al. (2005) rapportent 6 cas ayant un profil cognitif similaire : syndrome dysexecutif (fluences verbales, test de Hayling) et de troubles de la memoire visuelle (rappel de la figure de Rey). Nous rapportons ici le cas d’un patient adresse pour bilan de troubles de la memoire. Mr B., 60 ans, a comme antecedents une HTA, un diabete de type II, deux traumatismes crâniens 18 ans auparavant et une surdite progressive depuis 10 ans. Les troubles cognitifs evoluent depuis plusieurs mois avec a l’admission une desorientation temporo-spatiale, des troubles du langage, un syndrome frontal (grasping, perseverations, comportements d’imitation). L’examen neurologique retrouve un syndrome cerebelleux statique et cinetique. Les tests neuropsychologiques montrent une deterioration cognitive globale : MoCa : 14/30, passation du RL-RI 16 impossible, MIS a 5/8. L’etude du langage retrouve de nombreuses paraphasies verbales et semantiques : DO 80 : 57/80, reduction de la fluence verbale phonologique et semantique, troubles de la lecture. La comprehension est relativement preservee. Il existe une apraxie ideo-motrice. L’IRM cerebrale met en evidence un hyposignal T2 mesencephalique, cerebelleux et de la partie interne des lobes temporaux. L’IRM medullaire retrouve un hyposignal T2 peri-medullaire et du cone terminal. La cause du saignement chronique n’a pas ete retrouvee. Discussion L’Hemosiderose Superficielle du SNC est une cause rare de demence mais potentiellement curable lorsque la cause du saignement est mise en evidence (50% ces cas). Le delai diagnostic apres le premier symptome varie de 1 a 37 ans (Le Rhun et al., 2008). Les anomalies IRM (hyposignal T2) sont la base du diagnostic mais peuvent parfois etre difficiles a mettre en evidence et la sequence echo de gradient T2* apparait comme la plus sensible. Des essais de traitement par chelateurs du fer ont montre des resultats varies et un patient s’est ameliore sous corticoides (le Rhun et al., 2008). L’Hemosiderose Superficielle du SNC contre-indique bien evidemment les antiaggregeants et les anticoagulants.

Prognostic factors for survival in adult patients with recurrent glioblastoma: a decision-tree-based model

We assessed prognostic factors in relation to OS from progression in recurrent glioblastomas. Retrospective multicentric study enrolling 407 (training set) and 370 (external validation set) adult patients with a recurrent supratentorial glioblastoma treated by surgical resection and standard combined chemoradiotherapy as first-line treatment. Four complementary multivariate prognostic models were evaluated: Cox proportional hazards regression modeling, single-tree recursive partitioning, random survival forest, conditional random forest. Median overall survival from progression was 7.6 months (mean, 10.1; range, 0–86) and 8.0 months (mean, 8.5; range, 0–56) in the training and validation sets, respectively (p = 0.900). Using the Cox model in the training set, independent predictors of poorer overall survival from progression included increasing age at histopathological diagnosis (aHR, 1.47; 95% CI [1.03–2.08]; p = 0.032), RTOG–RPA V–VI classes (aHR, 1.38; 95% CI [1.11–1.73]; p = 0.004), decreasing KPS at progression (aHR, 3.46; 95% CI [2.10–5.72]; p < 0.001), while independent predictors of longer overall survival from progression included surgical resection (aHR, 0.57; 95% CI [0.44–0.73]; p < 0.001) and chemotherapy (aHR, 0.41; 95% CI [0.31–0.55]; p < 0.001). Single-tree recursive partitioning identified KPS at progression, surgical resection at progression, chemotherapy at progression, and RTOG–RPA class at histopathological diagnosis, as main survival predictors in the training set, yielding four risk categories highly predictive of overall survival from progression both in training (p < 0.0001) and validation (p < 0.0001) sets. Both random forest approaches identified KPS at progression as the most important survival predictor. Age, KPS at progression, RTOG–RPA classes, surgical resection at progression and chemotherapy at progression are prognostic for survival in recurrent glioblastomas and should inform the treatment decisions.

NIMG-44IMPACT OF ANGIOTENSIN-II RECEPTOR BLOCKERS ON VASOGENIC EDEMA IN GLIOBLASTOMA PATIENTS

Glioblastoma patients often require chronic administration of steroids due to peri-tumoral edema. Preliminary studies showed that treatment with Angiotensin-II Receptor Blockers (ARBs) for high blood pressure might be associated with reduced peri-tumoral edema. In this study, we aim to radiologically assess the effect of ARBs on peri-tumoral edema. We conducted a cross-sectional survey on patients with newly diagnosed GBM. Patients treated with ARBs for high blood pressure were paired to non ARB-treated patients based on similar age, tumor location and tumor size. Patients taking steroids at the time of pre-operative Magnetic Resonance Imaging were excluded from the study. In each pair of patients, we compared the volumes of peri-tumoral hyper T2-Fluid Attenuated Inversion Recovery (FLAIR) signal and the Apparent Diffusion Coefficient (ADC) in the same area. Eleven (11) ARB-treated patients were selected and paired to 11 non ARB-treated controls. Volumes of peri-tumoral hyper T2-FLAIR signal were significantly lower in the ARB-treated group than in the non ARB-treated group (p = 0.02). Additionally, peri-tumoral ADCs were also significantly lower in the treated group (p = 0.02), suggesting that the peri-tumoral area in this group had less edematous features. These results suggest that ARBs may reduce the volume of peri-tumoral hyper T2-FLAIR signal by decreasing edema.

P08.24PREDICTIVE FACTORS OF PERITUMORAL EDEMA IN BRAIN METASTASES

OBJECT: To investigate peritumoral edema and its prognostic factors in brain metastases of lung and breast cancers, and more specifically to evaluate the effect of treatment with angiotensine-II (Ang2) inhibitors. This treatment was shown in a recent study to display a significant effect in primary brain tumor edema. MATERIALS AND METHODS: We retrospectively reviewed the medical files of all patients with newly diagnosed brain metastases consulting in our institution in the years 2012 and 2013. We measured the maximal diameter of lesions DL (contrast enhancement) and peritumoral edema DE (diameter of edema minus contrast enhancement) on the first diagnostic imaging of brain metastasis. Patients under steroids or files with insufficient informations were excluded from analysis. RESULTS: A total of 157 medical files were reviewed from which 54 patients with 170 metastases were selected for analysis. There were 87 metastases of lung adenocarcinomas, 35 of small cell carcinomas, 18 of epidermoiid lung cancer, 7 of undifferentiated and 23 of breast cancer. Median DL was 9.35mm (1-74.3), median DE was 5,98mm (0-69,5). There was no significant difference in DL or DE between the histology groups. Younger age (<65 years old), female gender and treatment with Ang2 inhibitors seem to be associated with statistically less peritumoral edema (p = 0,005; p = 0,022; p = 0,005, respectively). This finding was persistent even when the 23 metastases of breast cancer were taken out from the analysis. Both DL and DE were smaller in the 25 patients under treatment with Ang2 inhibitors (n = 84 metastases) than in the 29 patients without such treatment (n = 86 metastases) (mean DL: 10.2 vs 13.4 mm, p= 0.036; mean DE 9.5 vs 15.9 mm, p= 0.005, respectively) The delay between the diagnosis of the primary tumors and brain metastases did not have any impact on the peritumoral edema. Moreover, the diameter of edema did not seem to be associated with the location, the size or the number of lesions, neither with the pattern of contrast enhancement (annular, homogenic or necrotic). Different patterns of contrast enhancement and sizes of edema were observed even within the same patient with multiple metastases. From the main 157 files reviewed, multiple metastases were more frequent in breast cancer patients (9 patients out of 10) compared to lung adenocarcinomas (29/81) and other lung cancers (13/25). CONCLUSION: In this series of patients with lung and breast cancer, younger age (<65 years old), female gender and treatment with Ang2 inhibitors seem to be associated with statistically smaller brain metastases and peritumoral edema Peritumoral edema did not seem to be associated with any other factors like histology, delayed brain metastasis diagnosis, size, location, number of lesions or contrast enhancing pattern.