Brain metastases (BMs) are associated with a poor prognosis. Standard treatment comprises whole-brain radiation therapy (WBRT). As neo-angiogenesis is crucial in BM growth, combining angiogenesis ...inhibitors such as bevacizumab with radiotherapy is of interest. We aimed to identify the optimal regimen of bevacizumab combined with WBRT for BM for phase II evaluation and provide preliminary efficacy data.
In this multicentre single-arm phase I study with a 3 + 3 dose-escalation design, patients with unresectable BM from solid tumours received three cycles of bevacizumab at escalating doses 5, 10 and 15 mg/kg every 2 weeks at dose levels (DL) 0, 1 and 2, respectively and WBRT (30 Gy/15 fractions/3 weeks) administered from day 15. DL3 consisted of bevacizumab 15 mg/kg with WBRT from day 15 in 30 Gy/10 fractions/2 weeks. Safety was evaluated using NCI-CTCAE version 3. BM response (RECIST 1.1) was assessed by magnetic resonance imaging at 6 weeks and 3 months after WBRT.
Nineteen patients were treated, of whom 13 had breast cancer. There were no DLTs. Grade 1–2 in-field and out-field toxicities occurred for five and nine patients across all DLs, respectively, including three and six patients (including one patient with both, so eight patients overall) of nine patients in DL3. One patient experienced BM progression during treatment (DL0). At the 3-month post-treatment assessment, 10 patients showed a BM response: one of three treated at DL0, one of three at DL1, two of three at DL2 and six of seven at DL3, including one complete response. BM progression occurred in five patients, resulting in two deaths. The remaining patient died from extracranial disease progression.
Bevacizumab combined with WBRT appears to be a tolerable treatment of BM. DL3 warrants further efficacy evaluation based on the favourable safety/efficacy balance.
NCT01332929.
Few data are available on long-term fatigue (LTF) and quality of life (QoL) among epithelial ovarian cancer survivors (EOCS). In this case–control study, we compared LTF, symptoms and several QoL ...domains in EOCS relapse-free ≥3years after first-line treatment and age-matched healthy women.
EOCS were recruited from 25 cooperative GINECO centers in France. Controls were randomly selected from the electoral rolls. All participants completed validated self-reported questionnaires: fatigue (FACIT-F), QoL (FACT-G/O), neurotoxicity (FACT-Ntx), anxiety/depression (HADS), sleep disturbance (ISI), and physical activity (IPAQ). Severe LTF (SLTF) was defined as a FACIT-F score <37/52. Univariate and multivariate logistic regressions were conducted to analyze SLTF and its influencing factors in EOCS.
A total of 318 EOCS and 318 controls were included. EOCS were 63-year-old on average, with FIGO stage I/II (50%), III/IV (48%); 99% had received platinum and taxane chemotherapy, with an average 6-year follow-up. There were no differences between the two groups in socio-demographic characteristics and global QoL. EOCS had poorer FACIT-F scores (40 versus 45, P<0.0001), lower functional well-being scores (18 versus 20, P=0.0002), poorer FACT-O scores (31 versus 34 P<0.0001), and poorer FACT-Ntx scores (35 versus 39, P<0.0001). They also reported more SLTF (26% versus 13%, P=0.0004), poorer sleep quality (63% versus 47%, P=0.0003), and more depression (22% versus 13%, P=0.01). Fewer than 20% of EOCS and controls exercised regularly. In multivariate analyses, EOCS with high levels of depression, neurotoxicity, and sleep disturbance had an increased risk of developing SLTF (P<0.01).
Compared with controls, EOCS presented similar QoL but persistent LTF, EOC-related symptoms, neurotoxicity, depression, and sleep disturbance. Depression, neuropathy, and sleep disturbance are the main conditions associated with severe LTF.
We have previously shown that epithelial ovarian cancer (EOC) and its treatments have negative effects on long-term quality of life (QoL) and fatigue. The present multicenter study investigated the ...main menopausal symptoms and gynecological management of EOC survivors (EOCS).
166 patients with relapse-free ≥3 years after the end of treatment attended a consultation with a gynecologist, including a questionnaire related to vasomotor symptoms (VMS) and sexuality, a clinical examination, a blood sample and an osteodensitometry. QoL, fatigue, insomnia and mood disorders were measured with validated questionnaires and correlated to VMS. VMS and QoL were assessed according to natural menopause (NM) or surgical menopause (SM).
Mean age at the survey was 62 21–83 years and stage III/IV (48%). Mean delay since the end of treatment was 6 years. Fifty-nine patients (36%) had SM. Half of patients reported VMS. Seventy-two percent of EOCS with SM had VMS compared to 41% with NM (P < .001). VMS were not associated with poor global QoL, fatigue, insomnia or mood disorders. Two-thirds of EOCS reported a decrease in libido. Patients with SM showed a greater decrease in libido than NM (P < .02). Fourteen percent of them had osteoporosis and 50% osteopenia. Among the 85 patients with VMS, 80 did not receive HRT after cancer treatment. At the time of the survey, only 7 (4%) patients were receiving hormone replacement therapy (HRT).
VMS and sexual disorders are frequently reported by EOCS, particularly among patients with SM. Most EOCS with menopausal symptoms could benefit from HRT to improve these symptoms.
•≥3 years after treatment, more than half of epithelial ovarian cancer survivors EOCS had vasomotor symptoms.•Two thirds of the EOCS reported a decrease in libido and, 1/3 sexually active EOCS complained of dyspareunia.•EOCS with surgical menopause reported more vasomotor symptoms and sexual disorders than those with natural menopause.•Very few patients received hormone replacement therapy after cancer treatment.
Chemotherapy (CT) remains a backbone treatment of epithelial ovarian cancer (EOC) inducing persistent peripheral neuropathy (CIPN). Using a dedicated patient-reported outcome tool, this study ...investigated persistent CIPN and its pharmacogenetic predictors in a cohort of long-term EOC survivors.
Vivrovaire was a French multicenter cohort of patients with EOC free of disease 3 years after CT completion. Persistent CIPN was assessed using the FACT/GOG-Ntx4 self-questionnaire. The association of homozygous (hom) or heterozygous (het) single nucleotide polymorphisms (SNPs) in selected genes was evaluated.
130 patients were included with a median time from CT completion of 63 35–180 months. The median CIPN score was 37 18–44, with 35 (26.9%) patients reporting severe CIPN (<33). SNPs were identified as follows: CYP2C8 hom, n = 32 (24.6%)/het, n = 99, (76.2%); CYP3A4 hom, n = 0 (0%)/het, n = 8 (6.2%), ERCC1 hom, n = 21 (16.2%)/het, n = 57 (43.8%), and XPC hom, n = 45 (34.6%)/het, n = 66 (50.8%). In univariate analysis, the identification of ≥1 hom SNP was associated with a lower CIPN score (continuous variable; p = 0.045). Patients harboring hom or het CYP2C8_rs1934951 SNP reported more likely severe CIPN (threshold <33) score (OR 2.482; 95% CI 1.126–5.47, p = 0.024). In the multivariate analyses, age, interval from CT completion, type and number of CT courses were not significantly associated with CIPN score (OR 5.165, 95% CI 0.478–55.83, p = 0.176).
Persistent CIPN is common among ovarian cancer long-term survivors. CYP2C8_rs1934951 SNP may be associated with severe residual CIPN in EOC survivors. More studies are warranted to identify predictive factors of CIPN.
•CIPN is a common concern in ovarian cancer survivors.•Using a PRO tool, about 25% of patients report persistent severe CIPN.•CYP2C8_rs1934951 SNP may be associated with a severe long-term CIPN.
Purpose
Oral anticancer therapies have an important place in the therapeutic arsenal, but factors influencing adherence to oral treatment are poorly documented in oncology. The objective of this ...study was to assess the impact of anxio-depressive symptoms and cognitive functioning on oral medication adherence.
Methods
This prospective study included cancer patients initiating a first oral therapy. Before initiation of treatment, an assessment of depression, anxiety, and cognition was performed. Using self-report questionnaires, we collected information on socio-demographic conditions and the non-adherence at 1 (M1) and 3 months (M3) after the beginning of treatment.
Results
Among 129 patients enrolled, median age was 70 years and 81% of patients were treated for metastatic cancer. Before initiating treatment, 16% and 8% of patients presented respectively depression and anxiety symptoms. Global cognitive impairment was observed in 51% of patients. Ten percent of the patients were non-adherent at M1 and 13% at M3. Depression was strongly associated with non-adherence at M1 (
P
= 0.046) and M3 (
P
= 0.014), but not anxiety. Non-adherence was associated with lower working memory (
P
= 0.037) and digit memory (
P
= 0.018) at M1 and short-term memory (
P
= 0.04) at M3. Patients with more than eight co-medications were more often non-adherents (
P
= 0.055).
Conclusions
Non-adherence to oral anticancer therapies was mainly associated to depression. Focusing on depressive symptoms before initiation of oral anticancer therapy could help to identify patient profiles more likely to fail self-management. Working memory, digit memory, and short-term memory also seem to play a role in non-adherence. Further studies should include a more specific population, especially according to age.
Aromatase inhibitors (AIs) are associated with sleep difficulties in breast cancer (BC) patients. Sleep is known to favor memory consolidation through the occurrence of specific oscillations, i.e., ...slow waves (SW) and sleep spindles, allowing a dialogue between prefrontal cortex and the hippocampus. Interestingly, neuroimaging studies in BC patients have consistently shown structural and functional modifications in these two brain regions. With the aim to evaluate sleep oscillations related to memory consolidation during AIs, we collected polysomnography data in BC patients treated (AI+, n = 17) or not (AI-, n = 17) with AIs compared to healthy controls (HC, n = 21). None of the patients had received chemotherapy and radiotherapy was finished since at least 6 months, that limit the confounding effects of other treatments than AIs. Fast and slow spindles were detected during sleep stage 2 at centro-parietal and frontal electrodes respectively. SW were detected at frontal electrodes during stage 3. Here, we show lower frontal SW densities in AI + patients compared to HC. These results concord with previous reports about frontal cortical alterations in cancer following AIs administration. Moreover, AI + patients tended to have lower spindle density at C4 electrode. Regression analyses showed that, in both patient groups, spindle density at C4 electrode explained a large variance of memory performances. Slow spindle characteristics did not differ between groups and sleep oscillations characteristics of AI- patients did not differ significantly from those of both AI + patients and HC. Overall, our results add to the compelling evidence of the systemic effects of AIs previously reported in animals, with deleterious effects on cortical activity during sleep and associated memory consolidation in the current study. There is thus a need to further investigate sleep modifications during AIs administration. Longitudinal studies are needed to confirm these findings and investigation in other cancers on this topic should be conducted.
•Frontal slow wave density is lower during aromatase inhibitors treatment.•Seemly, centro-parietal spindle density tend to be lower.•Spindle density is related to memory performance.•Aromatase inhibitors for breast cancer modify sleep-related memory consolidation.•Current patients' results confirm previous reports in animal models.
Complaints of sleep disturbance are prevalent among breast cancer (BC) patients and are predictors of quality of life. Still, electrophysiological measures of sleep are missing in patients, which ...prevents from understanding the pathophysiological consequences of cancer and its past treatments. Using polysomnography, sleep can be investigated in terms of macro- (e.g. awakenings, sleep stages) and micro- (i.e. cortical activity) structure. We aimed to characterize sleep complaints, and macro- and microstructure in 33 BC survivors untreated by chemotherapy and that had finished radiotherapy since at least 6 months (i.e. out of the acute effects of radiotherapy) compared to 21 healthy controls (HC). Compared to HC, BC patients had a larger number of awakenings (p = 0.008); and lower Delta power (p < 0.001), related to sleep deepening and homeostasis; greater both Alpha (p = 0.002) and Beta power (p < 0.001), related to arousal during deep sleep; and lower Theta power (p = 0.004), related to emotion regulation during dream sleep. Here we show that patients have increased cortical activity related to arousal and lower activity related to sleep homeostasis compared to controls. These results give additional insights in sleep pathophysiology of BC survivors and suggest sleep homeostasis disruption in non-advanced stages of BC.
Background Triple negative breast cancers (TNBC) account for approximately 15% of all breast cancers and are associated with a shorter median survival mainly due to locally advanced tumor and high ...risk of metastasis. The current neoadjuvant treatment for TNBC consists of a regimen of immune checkpoint blocker and chemotherapy (chemo-ICB). Despite the frequent use of this combination for TNBC treatment, moderate results are observed and its clinical benefit in TNBC remains difficult to predict. Patient-derived tumor organoids (PDTO) are 3D in vitro cellular structures obtained from patient's tumor samples. More and more evidence suggest that these models could predict the response of the tumor from which they are derived. PDTO may thus be used as a tool to predict chemo-ICB efficacy in TNBC patients. Method The TRIPLEX study is a single-center observational study conducted to investigate the feasibility of generating PDTO from TNBC and to evaluate their ability to predict clinical response. PDTO will be obtained after the dissociation of biopsies and embedding into extra cellular matrix. PDTO will be cultured in a medium supplemented with growth factors and signal pathway inhibitors. Molecular and histological analyses will be performed on established PDTO lines to validate their phenotypic proximity with the original tumor. Response of PDTO to chemo-ICB will be assessed using co-cultures with autologous immune cells collected from patient blood samples. PDTO response will finally be compared with the response of the patient to evaluate the predictive potential of the model. Discussion This study will allow to assess the feasibility of using PDTO as predictive tools for the evaluation of the response of TNBC patients to treatments. In the event that PDTO could faithfully predict patient response in clinically relevant time frames, a prospective clinical trial could be designed to use PDTO to guide clinical decision. This study will also permit the establishment of a living biobank of TNBC PDTO usable for future innovative strategies evaluation. Trial registration The clinical trial (version 1.2) has been validated by local research ethic committee on December 30.sup.th 2021 and registered at ClinicalTrials.gov with the identifier NCT05404321 on June 3.sup.rd 2022, version 1.2. Keywords: Triple negative breast cancer, Patient-derived tumor organoids, Predictive functional assays, Chemo-immunotherapy
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