Olaparib in recurrent isocitrate dehydrogenase mutant high-grade glioma: A phase 2 multicenter study of the POLA Network.

Background: Based on preclinical studies showing that IDH-mutant (IDHm) gliomas could be vulnerable to PARP inhibition we launched a multicenter phase 2 study to test the efficacy of olaparib monotherapy in this population. Methods: Adults with recurrent IDHm high-grade gliomas (HGGs) after radiotherapy and at least one line of alkylating chemotherapy were enrolled. The primary endpoint was a 6-month progression-free survival rate (PFS-6) according to response assessment in neuro-oncology criteria. Pre-defined threshold for study success was a PFS-6 of at least 50%. Results: Thirty-five patients with recurrent IDHm HGGs were enrolled, 77% at ≥ 2nd recurrence. Median time since diagnosis and radiotherapy were 7.5 years and 33 months, respectively. PFS-6 was 31.4% (95% CI [16.9; 49.3%]). Two patients (6%) had an objective response and 14 patients (40%) had a stable disease as their best response. Median PFS and median overall survival were 2.05 and 15.9 months, respectively. Oligodendrogliomas (1p/19q codeleted) had a higher PFS-6 (53.4% vs. 15.7%, P = .05) than astrocytomas while an initial diagnosis of grade 4 astrocytoma tended to be associated with a lower PFS-6 compared to grade 2/3 gliomas (0% vs 31.4%, P = .16). A grade 2 or 3 treatment-related adverse event was observed in 15 patients (43%) and 5 patients (14%), respectively. No patient definitively discontinued treatment due to side effects. Conclusions: Although it did not meet its primary endpoint, the present study shows that in this heavily pretreated population, olaparib monotherapy was well tolerated and resulted in some activity, supporting further PARP inhibitors evaluation in IDHm HGGs, especially in oligodendrogliomas.

Discriminating Inflammatory Radiation-Related Changes From Early Recurrence in Patients With Glioblastomas: A Preliminary Analysis of 68 Ga-PSMA-11 PET/CT Compared With 18 F-FDOPA PET/CT.

PURPOSE OF THE REPORT: Using morphological and functional imaging to discriminate recurrence from postradiation-related modifications in patients with glioblastomas remains challenging. This pilot study aimed to assess the feasibility of using 68 Ga-prostate-specific membrane antigen (PSMA) 11 PET/CT compared with 18 F-FDOPA PET/CT to detect early recurrence. METHODS: Nine patients followed up for glioblastomas who received MRI during 12 months of follow-up were referred for both 68 Ga-PSMA-11 and 18 F-FDOPA PET/CT. The SUV max , lesion-to-striatum ratio, lesion-to-normal parenchyma ratio, and lesion-to-salivary gland ratio were calculated. RESULTS: Good correlation between 18 F-FDOPA and 68 Ga-PSMA PET/CT findings was seen in 5 patients. In 4 patients, the findings of both examinations were consistent with recurrence but were better visualized with the PSMA PET/CT. Examinations of the fifth patient were suggestive of postradiation-related changes and were better analyzed with the PSMA PET/CT, which displayed relatively low uptake compared with DOPA PET/CT. Conversely, 4 patients showed conflicting results: recurrence was not detected on the PSMA PET/CT because of previously introduced bevacizumab treatment; in another patient, both examinations were consistent with recurrence, but there was an uptake mismatch at the suspected lesion sites, and 2 patients presented with inconsistent findings. CONCLUSIONS: Despite a few discrepancies, this study highlights the potential role of 68 Ga-PSMA-11 PET/CT for discriminating postradiation inflammation from recurrence. 68 Ga-PSMA-11 PET/CT has an excellent lesion-to-background ratio, and false-positive and false-negative results could be minimized through implementing certain protocols before performing the examination. More powerful prospective studies are required to validate our results.

Palliative care from the perspective of cancer physicians: a qualitative semistructured interviews study.

OBJECTIVE: Integrated palliative care for populations with cancer is now highly recommended. However, numerous physicians working in cancer care are still reluctant to refer patients to specialist palliative care teams. This study explores their perceptions of palliative care and factors influencing reasons to refer to specialist palliative care. METHODS: We used a qualitative methodology based on semistructured interviews with physicians working in cancer care, in two tertiary hospitals and one comprehensive cancer centre with access to a specialist palliative care team. Forty-six physicians were invited and 18 interviews were performed until data saturation. Participants were mainly men, licensed in cancer care, 37.9 years old on average and had 13 years of professional experience. The length of interviews was on average 34 min (SD=3). Analysis was performed accordingly with the thematic analysis. RESULTS: The data analysis found four themes: symptom management as a trigger, psychosocial support, mediation provided by interventions, and the association with terminal care or death. Palliative care integrated interventions were mainly perceived as holistic approaches that offered symptom management expertise and time. They were valued for helping in consolidating decision-making from a different or external perspective, or an 'outside look'. Several barriers were identified, often due to the confusion between terminal care and palliative care. This was further highlighted by the avoidance of the words 'palliative care', which were associated with death. CONCLUSIONS: National policies for promoting palliative care seemed to have failed in switching oncologists' perception of palliative care, which they still consider as terminal care.

Trabectedin for recurrent WHO grade 2 or 3 meningioma: A randomized phase II study of the EORTC Brain Tumor Group (EORTC-1320-BTG).

BACKGROUND: No systemic treatment has been established for meningioma progressing after local therapies. METHODS: This randomized, multicenter, open-label, phase II study included adult patients with recurrent WHO grade 2 or 3 meningioma. Patients were 2:1 randomly assigned to intravenous trabectedin (1.5 mg/m2 every 3 weeks) or local standard of care (LOC). The primary endpoint was progression-free survival (PFS). Secondary endpoints comprised overall survival (OS), objective radiological response, safety, quality of life (QoL) assessment using the QLQ-C30 and QLQ-BN20 questionnaires, and we performed tissue-based exploratory molecular analyses. RESULTS: Ninety patients were randomized (n = 29 in LOC, n = 61 in trabectedin arm). With 71 events, median PFS was 4.17 months in the LOC and 2.43 months in the trabectedin arm (hazard ratio [HR] = 1.42; 80% CI, 1.00-2.03; P = .294) with a PFS-6 rate of 29.1% (95% CI, 11.9%-48.8%) and 21.1% (95% CI, 11.3%-32.9%), respectively. Median OS was 10.61 months in the LOC and 11.37 months in the trabectedin arm (HR = 0.98; 95% CI, 0.54-1.76; P = .94). Grade ≥3 adverse events occurred in 44.4% of patients in the LOC and 59% of patients in the trabectedin arm. Enrolled patients had impeded global QoL and overall functionality and high fatigue before initiation of systemic therapy. DNA methylation class, performance status, presence of a relevant co-morbidity, steroid use, and right hemisphere involvement at baseline were independently associated with OS. CONCLUSIONS: Trabectedin did not improve PFS and OS and was associated with higher toxicity than LOC treatment in patients with non-benign meningioma. Tumor DNA methylation class is an independent prognostic factor for OS.

Molecular profile to guide personalized medicine in adult patients with primary brain tumors: results from the ProfiLER trial.

Immunohistochemistry and recent molecular technologies progressively guided access to personalized anti-tumoral therapies. We explored the feasibility, efficacy, and the impact of molecular profiling in patients with advanced brain tumors. This multicentric prospective trial ProfiLER enrolled patients with primary brain tumors, who have been pre-treated with at least one line of anti-cancer treatment, and for whom molecular profiles had been achieved using next-generation sequencing and/or comparative genomic hybridization on fresh or archived samples from tumor, relapse, or biopsies. A molecular tumor board weekly analyzed results and proposed molecular-based recommended therapy (MBRT). From February 2013 to December 2015, we enrolled 141 patients with primary brain tumor and analyzed 105 patients for whom tumor genomic profiles had been achieved. Histology mainly identified glioblastoma (N = 46, 44%), low-grade glioma (N = 26, 25%), high-grade glioma (N = 12, 11%), and atypical and anaplastic meningioma (N = 8, 8%). Forty-three (41%) patients presented at least one actionable molecular alteration. Out of 61 alterations identified, the most frequent alterations occurred in CDKN2A (N = 18), EGFR (N = 12), PDGFRa (N = 8), PTEN (N = 8), CDK4 (N = 7), KIT (N = 6), PIK3CA (N = 5), and MDM2 (N = 3). Sixteen (15%) patients could not be proposed for a MBRT due to early death (N = 5), lack of available clinical trials (N = 9), or inappropriate results (N = 2). Only six (6%) of the 27 (26%) patients for whom a MBRT had been proposed finally initiated MBRT (everolimus (N = 3), erlotinib (N = 1), ruxolitinib (N = 1), and sorafenib (N = 1)), but discontinued treatment for toxicity (N = 4) or clinical progression (N = 2). High-throughput sequencing in patients with brain tumors may be routinely performed, especially when macroscopic surgery samples are available; nevertheless delays should be reduced. Criteria for clinical trial enrollment should be reconsidered in patients with brain tumors, and a panel of genes specifically dedicated to neurologic tumors should be developed to help decision-making in clinical practice.

MEVITEM-a phase I/II trial of vismodegib + temozolomide vs temozolomide in patients with recurrent/refractory medulloblastoma with Sonic Hedgehog pathway activation.

BACKGROUND: Vismodegib specifically inhibits Sonic Hedgehog (SHH). We report results of a phase I/II evaluating vismodegib + temozolomide (TMZ) in immunohistochemically defined SHH recurrent/refractory adult medulloblastoma. METHODS: TMZ-naïve patients were randomized 2:1 to receive vismodegib + TMZ (arm A) or TMZ (arm B). Patients previously treated with TMZ were enrolled in an exploratory cohort of vismodegib (arm C). If the safety run showed no excessive toxicity, a Simon's 2-stage phase II design was planned to explore the 6-month progression-free survival (PFS-6). Stage II was to proceed if arm A PFS-6 was ≥3/9 at the end of stage I. RESULTS: A total of 24 patients were included: arm A (10), arm B (5), and arm C (9). Safety analysis showed no excessive toxicity. At the end of stage I, the PFS-6 of arm A was 20% (2/10 patients, 95% unilateral lower confidence limit: 3.7%) and the study was prematurely terminated. The overall response rates (ORR) were 40% (95% CI, 12.2-73.8) and 20% (95% CI, 0.5-71.6) in arm A and B, respectively. In arm C, PFS-6 was 37.5% (95% CI, 8.8-75.5) and ORR was 22.2% (95% CI, 2.8-60.0). Among 11 patients with an expected sensitivity according to new generation sequencing (NGS), 3 had partial response (PR), 4 remained stable disease (SD) while out of 7 potentially resistant patients, 1 had PR and 1 SD. CONCLUSION: The addition of vismodegib to TMZ did not add toxicity but failed to improve PFS-6 in SHH recurrent/refractory medulloblastoma. Prediction of sensitivity to vismodegib needs further refinements.

Skull vault hemangioma mimicking neoplastic lesion on [68Ga]Ga-PSMA-11 PET/CT in a patient with glioblastoma: A case report.

We present the case of a 47-year-old woman treated by radiochimotherapy for a glioblastoma which underwent a [68Ga]Ga-PSMA-11-PET/CT to distinguish postradiation changes from an evolutionary process. This demonstrated a weak homogeneous uptake surrounding the lesion. There was a focal and moderate uptake of a pseudo lytic skull diploe lesion near to the glioblastoma, finally attributed to a calvaria hemangioma. Calvaria hemangiomas are less frequent than vertebral hemangiomas and may demonstrate a modest PSMA uptake that one should keep in mind so as not to misinterpret the examination in patients followed for glioblastomas.

Reduced-dose craniospinal irradiation is feasible for standard-risk adult medulloblastoma patients.

INTRODUCTION: Medulloblastoma is the most common malignant brain tumor in children, but accounts for only 1% of brain cancers in adults. For standard-risk pediatric medulloblastoma, current therapy includes craniospinal irradiation (CSI) at reduced doses (23.4 Gy) associated with chemotherapy. Whereas most same-stage adult patients are still given CSI at 36 Gy, with or without chemotherapy, we report here on our use of reduced-dose CSI associated with chemotherapy for older patients. METHODS: We gathered non-metastatic patients over 18 years old (median age 28 years, range 18-48) with minimal or no residual disease after surgery, no negative histological subtypes, treated between 1996-2018 at the Centre Léon Bérard (Lyon) and the INT (Milano). A series of 54 children with similar tumors treated in Milano was used for comparison. RESULTS: Forty-four adults were considered (median follow-up 101 months): 36 had 23.4 Gy of CSI, and 8 had 30.6 Gy, plus a boost to the posterior fossa/tumor bed; 43 had chemotherapy as all 54 children, who had a median 83-month follow-up. The PFS and OS were 82.2 ± 6.1% and 89 ± 5.2% at 5 years, and 78.5 ± 6.9% and 75.2 ± 7.8% at ten, not significantly different from those of the children. CSI doses higher than 23.4 Gy did not influence PFS. Female adult patients tended to have a better outcome than males. CONCLUSION: The results obtained in our combined series are comparable with, or even better than those obtained after high CSI doses, underscoring the need to reconsider this treatment in adults.

Advanced chordoma treated by first-line molecular targeted therapies: Outcomes and prognostic factors. A retrospective study of the French Sarcoma Group (GSF/GETO) and the Association des Neuro-Oncologues d'Expression Française (ANOCEF).

BACKGROUND: To assess the role of first-line Molecular Targeted Therapies (MTTs) in Advanced chordoma (AC) patients. METHODS: Retrospective study of 80 patients treated between January 2004 and December 2015 at 15 major French Sarcoma or Neurooncology Centres. RESULTS: The sex ratio M/F was 46/34. The median age was 59 (6-86) years. The primary sites were the sacrum (50, 62.5%), mobile spine (12, 15.0%), and skull base (18, 22.5%). Metastases were present in 28 patients (36.0%). The first line of MTTs consisted of imatinib (62, 77.5%), sorafenib (11, 13.7%), erlotinib (5, 6.3%), sunitinib (1, 1.2%) and temsirolimus (1, 1.2%). The reported responses were: partial response (5, 6.3%), stable disease (58, 72.5%), or progressive disease (10, 12.5%). Symptomatic improvement was seen in 28/66 assessable patients (42.4%) and was associated with an objective response occurrence (p = 0.005), imatinib (p = 0.020) or erlotinib use (p = 0.028). The median progression-free survival (PFS) was 9.4°months (95% CI, [6.8-16.1]). Two independent factors of poor prognosis for PFS were identified: a skull-based primary location (HR = 2.5, p = 0.019), and the interval between diagnosis and MTT of <52months (HR = 2.8, p < 0.001). The median overall survival (OS) was 4.4°years (95% CI, [3.8-5.6]). Four independent factors of poor prognosis for OS were identified: the presence of liver metastases (HR = 13.2, p < 0.001), pain requiring opioids (HR = 2.9, p = 0.012), skull-based primary location (HR = 19.7, p < 0.001), and prior radiotherapy (photon alone) (HR = 2.5, p = 0.024). The PFS and OS did not significantly differ between the MTT. CONCLUSIONS: The prognostic factors identified require validation in an independent database but are potently useful to guide treatment decisions and design further clinical trials.

[Adolescent and Young Adults (AYAS) brain tumor national Web conference. On behalf of ANOCEF, GO-AJA and SFCE societies]. / La neuro-oncologie des adolescents et adultes jeunes (AJAS) : place d'une RCP nationale. Au nom de l'ANOCEF, GO-AJA et de la SFCE.

The skills of adult versus pediatric neuro-oncologists are not completely similar though additive. Because the tumors and their protocols are different and the tolerance and expected sequelae are specific. Multidisciplinary meetings including adult and pediatric neuro-oncologists are warranted to share expertise. Since 2008, a weekly national web based conference was held in France. Any patient with the following criteria could be discussed: Adolescent and Young Adults aged between 15 and 25 years, and any adult with a pediatric type pathology, including medulloblastoma, germ cell tumors, embryonic tumors, ependymoma, pilocytic astrocytoma. RESULTS: Attendance during the year 2015 was as follows: 42 meetings were held; the median number of cases discussed at each meeting was 4 (1 to 8); the mean number of attendants was 7 (2 to 12). One hundred and sixty-eight cases concerning 121 patients were discussed. Mean age was 30 years old (7 to 67). Forty-eight percent were discussed at diagnosis. The patients had mostly medulloblastomas (40%), germ cell tumors (11%), ependymomas (11%), pineal tumors (7%) and embryonal tumors (8%). The rate of inclusion in protocols was increased since the opening of this web conference, especially for the germ cell tumor SIOP protocol that is opened without age restriction, and in RSMA standard risk or MEVITEM relapse adult medulloblastoma protocols. CONCLUSION: Multidisciplinary Web conference for AYAs is feasible and increases the inclusion rate in protocols. It should be developed further.

Adjuvant imatinib treatment in gastrointestinal stromal tumor: which risk stratification criteria and for how long? A case report.

Imatinib mesylate is approved for the adjuvant treatment of KIT-positive gastrointestinal stromal tumor (GIST) following surgical resection. However, uncertainty remains in terms of patient eligibility for adjuvant treatment and the optimal duration of treatment. Here, we present two challenging patient cases encountered in clinical practice that highlight the ambiguity in the current recommendations for adjuvant imatinib in GIST and discuss our approaches and rationales for treatment. The first case involves a 36-year-old man with a 7 cm duodenal GIST and possible tumor rupture during surgical resection. This patient's risk of GIST recurrence was either intermediate or high depending on which risk stratification criteria were used. The patient was treated with adjuvant imatinib for 3 years and experienced disease recurrence 14 months after the completion of treatment. Imatinib treatment was reintroduced, and the patient is in partial response 17 months later. The second case involves a 46-year-old woman at high risk of recurrence following surgical resection. Adjuvant treatment with imatinib was initiated. After considering the patient's initial high risk and good side-effect profile, the decision was made to continue adjuvant imatinib treatment for 5 years. As of May 2013, the patient has been receiving continuous imatinib treatment for 52 months, with no sign of progression. These reports exemplify the challenges faced in clinical practice because of uncertainties in optimal risk stratification criteria and duration of treatment. They stress the importance of individualized treatment and shared decision making between the physician and the patient.

[Management of febrile neutropenias in adolescents and young adults: Differences of practice between adult and pediatric units]. / Gestion des aplasies fébriles chez les adolescents et jeunes adultes: différences de pratiques entre secteurs adultes et pédiatriques.

INTRODUCTION: Adolescents and young adults (AYA, 15-25years old) with cancer are treated either in adult or pediatric units. Management of febrile neutropenia (FN) is different between these units. Monitoring rules and indications of hospitalization are often stricter in pediatrics. This study evaluates if these differences influence the occurrence of complications. METHODS: The medical records of AYA patients treated in our institution in the Euro-E-W-I-N-G99 protocol between 01/09/2000 and 31/05/2013 were retrospectively analyzed. We studied febrile neutropenias occurring after VIDE courses, during the induction period. RESULTS: Forty-four patients were included (18 from adult units, 26 from pediatrics). Median age at inclusion was 19.6. After 260 courses of VIDE, we observed a median of 2 FN per adult and 3 per pediatric patient (P=0.2). Hospitalization occurred in median 1.5 time per adult and 3 per pediatric patient (P=0.008). Median cumulated length of stay was 4.5days for adults versus 16 days for pediatric patients (P=0.008). There was no significant difference for survival, number of documented infections, transfusions, dose modifications, chemotherapy delay, need for intensive care, infection after post-induction surgery. CONCLUSION: AYA treated in adult services are less frequently hospitalized for FN with no difference in morbi-mortality. Homogeneous recommendations could be made for these patients, whatever the units they are treated in.

Assessing the multimodal management of advanced solitary fibrous tumors of the pleura in a routine practice setting.

BACKGROUND: Solitary fibrous tumors of the pleura (SFTP) refer as to a heterogeneous group of mesenchymal malignancies with various anatomic and histology features. Upfront surgical resection is the standard approach, but recurrences may be aggressive and difficult to treat. The most widely accepted staging system has been proposed by De Perrot et al. Because SFTPs are rare, evidence to support a role for perioperative chemotherapy is scarce. Likewise, the predictive or prognostic relevance of the De Perrot system may be questioned. METHODS: Multicenter retrospective study of patients with histologically proven SFTP with complete follow-up from surgical diagnostic to tumor recurrence and death. RESULTS: Sixty-eight patients were included. Tumor stage was 0/I for 29 (43%) patients, II for 23 (34%) patients, III for seven (10%) patients, and IV for nine (13%) patients. Postoperative chemotherapy was given to seven patients, mostly with stage III/IV SFTP, mostly consisting of doxorubicin-based regimen. Recurrence rate and median relapse-free survival after surgery were 3%, 52%, 71%, and 80% (p < 0.001), and 107, 70, 29, 11 months (p < 0.001) for stage 0/I, II, III, and IV tumors, respectively. At time of tumor recurrence, 14 patients received exclusive chemotherapy. Highest disease control rates were observed with trabectedin, and gemcitabine-dacarbazine combination. CONCLUSION: Our study confirms the prognostic value of the De Perrot staging system, as well as its possible predictive value for perioperative chemotherapy decision-making, whereas the efficacy of currently available regimens to significantly reduce the risk of tumor recurrence remains questionable. Trabectedin may be of interest for recurrent tumors.

Emerging therapies for soft-tissue sarcomas.

Sarcomas are heterogeneous group of tumors that arise from tissues of mesenchymal origin. Current options for patients with advanced disease are limited, and only 2 drugs have been approved for these diseases over the last decade. Although several drugs are currently under development for soft-tissue sarcoma as a whole, improved understanding of sarcoma biology has led to the emergence of subtype-specific targeted therapy. This article reviews recent clinical data on emerging therapies for soft-tissue sarcoma.

Outcome of patients with advanced solitary fibrous tumors: the Centre Léon Bérard experience.

BACKGROUND: Solitary Fibrous Tumor is a rare type of soft tissue tumor of intermediate malignant potential which may recur or metastasize in 15-20% of cases. Data on the management of patients with advanced SFT is scarce: chemotherapy has been described as ineffective, while recent data suggests that anti-angiogenic therapies may be more efficient. METHODS: We conducted a retrospective study on patients treated for advanced SFT at a single institution: from January 1994 to December 2011, 30 patients were treated in the Centre Léon Bérard for an advanced SFT. RESULTS: Twenty-three patients received cytotoxic chemotherapy as first-line therapy. Best responses were 2 (9%) partial responses, 13 (57%) stable diseases (SD) and 8 (35%) progressive diseases (PD). Median Progression Free Survival (PFS) was 5.2 (95% CI: 3.2-7.1) months and 9 patients were free of progression at 6 months. Ten patients received an anti-angiogenic treatment (sunitinib or pazopanib) as a 2nd, 3rd or 4th line. Best responses were 5 SD and 5 PD; median PFS was 5.1 months (95% CI 0.7-9.6). Four patients (36%) were progression-free for more than 6 months. Two patients receiving pazopanib were without progression at 6 and 8 months and two patients receiving sunitinib were free of progression at 30 months. CONCLUSION: Response rate with standard chemotherapy was low and PFS appear similar between cytotoxic chemotherapy and anti-angiogenic agents.