Preclinical data support the activity of celecoxib and fluvastatin in high-grade (HGG) and low-grade gliomas (LGG). A phase I trial (NCT02115074) was designed to evaluate the safety of this ...combination in children with refractory/relapsed HGG and LGG using four dose levels of fluvastatin with a fixed daily dose of celecoxib. A Continual Reassessment Method was used for fluvastatin dose escalation. Dose-limiting toxicities (DLT) were determined on the first treatment cycle. Twenty patients were included. Ten LGG and ten HGG patients received a median of 3.5 treatment cycles. Two DLTs were reported: one grade 3 maculopapular rash (4 mg/kg dose level) and one grade 4 increase of Creatine Phospho-Kinase (6 mg/kg dose level). We identified the dose of 6 mg/kg/day as the recommended phase II dose (RP2D) of fluvastatin with celecoxib. Four patients with LGG continued treatment beyond 12 cycles because of stable disease, including one patient who received 23 treatment cycles. In children with refractory/relapsed glioma, the RP2D of fluvastatin with celecoxib is 6 mg/kg/day. The long-term stable diseases observed in LGG suggest a possible role of the combination in a maintenance setting, given its good tolerance and low cost for children living in low- and middle-income countries.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
After chemotherapy, patients with non-seminomatous germ cell tumors (NSGCTs) with residual masses >1 cm on computed tomography (CT) undergo surgery. However, in approximately 50% of cases, these ...masses only consist of necrosis/fibrosis. We aimed to develop a radiomics score to predict the malignant character of residual masses to avoid surgical overtreatment. Patients with NSGCTs who underwent surgery for residual masses between September 2007 and July 2020 were retrospectively identified from a unicenter database. Residual masses were delineated on post-chemotherapy contrast-enhanced CT scans. Tumor textures were obtained using the free software LifeX. We constructed a radiomics score using a penalized logistic regression model in a training dataset, and evaluated its performance on a test dataset. We included 76 patients, with 149 residual masses; 97 masses were malignant (65%). In the training dataset (
= 99 residual masses), the best model (ELASTIC-NET) led to a radiomics score based on eight texture features. In the test dataset, the area under the curve (AUC), sensibility, and specificity of this model were respectively estimated at 0.82 (95%CI, 0.69-0.95), 90.6% (75.0-98.0), and 61.1% (35.7-82.7). Our radiomics score may help in the prediction of the malignant nature of residual post-chemotherapy masses in NSGCTs before surgery, and thus limit overtreatment. However, these results are insufficient to simply select patients for surgery.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Dose-escalated external beam radiotherapy (RT) is effective in the control of prostate cancer but is associated with a greater incidence of rectal adverse events. We assessed the dosimetric gain and ...safety profile associated with implantation of a new biodegradable rectal spacer balloon.
Patients scheduled for image-guided, intensity-modulated RT for intermediate-risk prostate cancer were prospectively included in the French multicenter BioPro-RCMI-1505 study (NCT02478112). We evaluated the dosimetric gain, implantation feasibility, adverse events (AEs), and prostate-cancer-specific quality of life associated with use of the balloon spacer.
After a scheduled review of the initial recruitment target of 50 patients by the study's independent data monitoring committee (IDMC), a total of 24 patients (including 22 with dosimetry data) were included by a single center between November 2016 and May 2018. The interventional radiologist who implanted the balloons considered that 86% of the procedures were easy. 20 of the 24 patients (83.3%) received IMRT and 4 (16.7%) received volumetric modulated arc therapy (78-80 Gy delivered in 39 fractions). The dosimetric gains associated with spacer implantation were highly significant (p<0.001) for most variables. For the rectum, the median (range) relative gain ranged from 15.4% (-9.2-47.5) for D20cc to 91.4% (36.8-100.0) for V70 Gy (%). 15 patients (62%) experienced an acute grade 1 AE, 8 (33%) experienced a late grade 1 AE, 1 (4.2%) experienced an acute grade 2 AE, and 3 experienced a late grade 2 AE. No grade 3 AEs were reported. Quality of life was good at baseline (except for sexual activity) and did not markedly worsen during RT and up to 24 months afterwards.
The use of a biodegradable rectal spacer balloon is safe, effective and associated with dosimetric gains in modern RT for intermediate-risk prostate cancer.
In most countries, reference chemotherapy for osteosarcoma is MAP regimen (M = high-dose methotrexate, AP = doxorubicin-cisplatinum). In France, the standard preoperative chemotherapy for ...children/adolescents combines M and etoposide-ifosfamide (EI), based on the OS94-trial. We report the safety and efficacy results of patients ≤25 years treated with preoperative M-EI regimen enroled in the French OS2006-study, between 2007 and 2014.
Treatment comprised preoperative chemotherapy with the 7 M-courses and 2 EI-courses, then surgery and postoperative chemotherapy assigned by risk's groups: standard-risk (good histological response without metastases) received 12 M-courses, 3 EI-courses; high-risk (poor histologic response, initial metastases or unresectable primary) received 5 M-courses alternated with 5 AP-courses. 253 patients were randomised to receive (n = 128) or not (n = 125) zoledronate.
409/522 patients enroled in the OS2006 study who received preoperative M-EI were analysed. Median age was 14.3 years (4.7–24.5), with 55 patients aged 18–25 years. Primary tumour location was limb in 383 patients (94%) and 85 (21%) presented metastases. Median chemotherapy duration was 37.4 weeks. 381 (96%) patients underwent surgery, 258 patients (65%) had a good histologic response. 187/324 patients (58%) with localised disease did not receive doxorubicin nor cisplatinum. Toxicity was evaluated in the randomised study: most patients experienced ≥1 severe toxicity (grade IV haematological or grade III/IV extra-haematological). Median follow-up was 4.8 years, and 168 patients had events. Five-year event-free survival was 56% (95% CI, 51–62%) and overall survival 71% (66–76%).
M-EI regimen/strategy was feasible for patient aged ≤25 years with survival rates are comparable to those obtained with MAP regimen.
•Paediatric and young adult methotrexate-based chemotherapy regimen of OS2006 protocol.•Event-free survival and overall survival rates were similar to those with standard Methotrexate-Doxorubicin-Cisplatinum (MAP) regimen used worldwide.•First-line treatment with doxorubicin and cisplatinum was avoided in 58% patients with localised tumours.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
We report here a correlation analysis conducted along with a phase II trial assessing bevacizumab in combination with weekly paclitaxel.
Circulating pro/anti-angiogenic factors were assessed on day 1 ...(D1) and day 8 (D8). The prognostic value for progression-free survival (PFS) was evaluated using a Cox model with biomarkers as continuous variables.
Among the 51 patients enrolled and treated in this trial, biomarker analysis was performed for 42: 18 in Arm A (single-agent) and 24 in Arm B (combination). With a median follow-up of 46 months, PFS was 5.5 versus 5.7 months, respectively (p = 0.75). According to univariate analysis, factors associated with a poor PFS were as follows: visceral angiosarcoma, de novo angiosarcoma, and high PlGF and low VEGF-C baseline values. In multivariate analysis, de novo angiosarcoma (HR = 2.5; p = 0.024) and baseline VEGF-C value (HR = 0.7; p = 0.003) were significant prognostic factors. We observed a significant increase in circulating PlGF (< 0.001) and a decrease in VEGF (< 0.001) during bevacizumab treatment. An increase in FGF was associated with a poor outcome.
De novo angiosarcoma and a low baseline level of VEGF-C were found to be associated with a poor prognosis. Addition of bevacizumab induces major changes in circulating biomarkers (VEGF and PlGF) in a short timeframe without impacting PFS.
Retrospectively registered on EudraCT N° 2009-017020-59 and NCT01303497 (February 24, 2011).
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
To determine the risk factors for acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) after breast cancer.
We conducted a case-control study among women treated for breast cancer between ...1985 and 2001 in French general hospitals, cancer centers, or clinics. We included 182 AML and MDS patients and 534 matched controls. Breast cancer characteristics, type of treatment, and family history of cancer were compared in both groups.
The risk of AML/MDS was increased after topoisomerase-II inhibitor-based chemotherapy (P < 10-16) and was higher for mitoxantrone-based chemotherapy than for anthracycline-based chemotherapy (relative risk RR = 15.6; 95% CI, 7.1 to 34.2; and RR = 2.7; 95% CI, 1.7 to 4.5, respectively). After adjustment for other treatment components, the risk of AML/MDS in patients who received radiotherapy was multiplied by 3.9 (95% CI, 1.4 to 10.8) but was not increased by alkylating agents. Patients receiving granulocyte colony-stimulating factor (G-CSF) support had an increased risk of AML/MDS (RR = 6.3; 95% CI, 1.9 to 21), even when controlling for chemotherapy doses. Similar results were obtained when AML and MDS were considered separately.
This large case-control study demonstrates that the risk of AML/MDS is much higher with mitoxantrone-based chemotherapy than with anthracyclines-based chemotherapy in a population of women recently treated for breast cancer. The risk of AML/MDS associated with mitoxantrone must be kept in mind when using this drug to treat diseases other than breast cancer (eg, prostate cancer or multiple sclerosis). In addition, our study suggests the need to monitor the long-term effects of G-CSF therapy.
PURPOSE EWS-ETS fusion genes are the driving force in Ewing's sarcoma pathogenesis. Because of the variable breakpoint locations in the involved genes, there is heterogeneity in fusion RNA and ...protein architecture. Since previous retrospective studies suggested prognostic differences among patients expressing different EWS-FLI1 fusion types, the impact of fusion RNA architecture on disease progression and relapse was studied prospectively within the Euro-E.W.I.N.G. 99 clinical trial. PATIENTS AND METHODS Among 1,957 patients who registered before January 1, 2007, 703 primary tumors were accessible for the molecular biology study. Fusion type was assessed by polymerase chain reaction on frozen (n = 578) or paraffin-embedded materials (n = 125). The primary end point was the time to disease progression or relapse. Results After exclusion of noninformative patients, 565 patients were entered into the prognostic factor analysis comparing type 1 (n = 296), type 2 (n = 133), nontype 1/nontype 2 EWS-FLI1 (n = 91) and EWS-ERG fusions (n = 45). Median follow-up time was 4.5 years. The distribution of sex, age, tumor volume, tumor site, disease extension, or histologic response did not differ between the four fusion type groups. We did not observe any significant prognostic value of the fusion type on the risk of progression or relapse. The only slight difference was that the risk of progression or relapse associated with nontype 1/nontype 2 EWS-FLI1 fusions was 1.38 (95% CI, 0.96 to 2.0) times higher than risk associated with other fusion types, but it was not significant (P = .10). CONCLUSION In contrast to retrospective studies, the prospective evaluation did not confirm a prognostic benefit for type 1 EWS-FLI1 fusions.
Home hospitalization at the end of life can sometimes be perturbed by unplanned hospital admissions (UHAs, defined as any admission that is not part of a preplanned care procedure), which increase ...the likelihood of death in hospital. The objectives were to describe the occurrence and causes of UHAs in cancer patients receiving end-of-life care at home, and to identify factors associated with UHAs and death in hospital.
A retrospective, single-center study (performed at a regional cancer center in the city of Lille, northern France) of advanced cancer patients discharged to home hospitalization between January 2014 and December 2017. We estimated the incidence of UHA over time using Kaplan-Meier method and Kalbfleish and Prentice method. We investigated factors associated with the risk UHA in cause-specific Cox models. We evaluated factors associated with death in hospital in logistic regressions.
One hundred and forty-two patients were included in the study. Eighty-two patients (57.7 %) experienced one or more UHAs, a high proportion of which occurred within 1 month after discharge to home. Most UHAs were related to physical symptoms and were initiated by the patient's family physician. A post-discharge palliative care consultation was associated with a significantly lower incidence of UHAs. Sixty-five patients (47.8 % of the deaths) died in hospital. In a multivariate analysis, living alone and the presence of one or more children at home were associated with death in hospital.
More than 40 % of cancer patients receiving end of life home hospitalization were not readmitted to hospital, reflecting the effectiveness of this type of palliative care setting. However, over half of the UHAs were due to an acute intercurrent event. Our results suggest that more efforts should be focused on anticipating these events at home - primarily via better upstream coordination between hospital physicians and family physicians.
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The HERBY trial evaluated the benefit of the addition of the antiangiogenic agent Bevacizumab (BEV) to radiotherapy/temozolomide (RT/TMZ) in pediatric patients with newly diagnosed non-brainstem ...high-grade glioma (HGG). The work presented here aims to correlate imaging characteristics and outcome measures with pathologic and molecular data.
Radiological, pathologic, and molecular data were correlated with trial clinical information to retrospectively re-evaluate event-free survival (EFS) and overall survival (OS).
One-hundred thirteen patients were randomized to the RT/TMZ arm (
= 54) or the RT/TMZ+BEV (BEV arm;
= 59). The tumor arose in the cerebral hemispheres in 68 patients (Cerebral group) and a midline location in 45 cases (Midline group). Pathologic diagnosis was available in all cases and molecular data in 86 of 113. H3 K27M histone mutations were present in 23 of 32 Midline cases and H3 G34R/V mutations in 7 of 54 Cerebral cases. Total/near-total resection occurred in 44 of 68 (65%) Cerebral cases but in only 5 of 45 (11%) Midline cases (
< 0.05). Leptomeningeal metastases (27 cases, 13 with subependymal spread) at relapse were more frequent in Midline (17/45) than in Cerebral tumors (10/68,
< 0.05). Mean OS (14.1 months) and EFS (9.0 months) in Midline tumors were significantly lower than mean OS (20.7 months) and EFS (14.9 months) in Cerebral tumors (
< 0.05). Pseudoprogression occurred in 8 of 111 (6.2%) cases.
This study has shown that the poor outcome of midline tumors (compared with cerebral) may be related to (1) lesser surgical resection, (2) H3 K27M histone mutations, and (3) higher leptomeningeal dissemination.
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