Evaluating patient-reported symptoms and late adverse effects following completion of first-line chemotherapy for ovarian cancer using the MOST (Measure of Ovarian Symptoms and Treatment concerns).

OBJECTIVES: Knowledge on the course of symptoms patients with ovarian cancer experience is limited. We documented the prevalence and trajectories of symptoms after first-line chemotherapy using the Measure of Ovarian Symptoms and Treatment concerns (MOST). METHODS: A total of 726 patients who received platinum-based chemotherapy for ovarian cancer were asked to complete the MOST every 3 months, beginning 6 months post-diagnosis and continuing for up to 4 years. We used descriptive statistics to examine temporal changes in MOST-S26 index scores for disease or treatment-related (MOST-DorT), neurotoxicity (MOST-NTx), abdominal (MOST-Abdo), and psychological (MOST-Psych) symptoms, and wellbeing (MOST-Wellbeing) and selected individual symptoms. We used group-based trajectory models to identify groups with persistently poor symptoms. RESULTS: The median MOST-Abdo, MOST-DorT and MOST-Wellbeing score were worst at chemotherapy-end but improved and stabilised by 1, 3 and 12 months after treatment, respectively. The median MOST-NTx score peaked at 1 month after treatment before improving, while the median MOST-Psych score did not change substantially over time. Long-term moderate-to-severe fatigue (32%), trouble sleeping (31%), sore hands and feet (21%), pins and needles (20%) and anxiety (18%) were common. Trajectory models revealed groups of patients with persistent symptoms had MOST-DorT scores above 30 and MOST-NTx scores above 40 at treatment-end. CONCLUSIONS: Although many patients report improvements in symptoms by 3 months after first-line chemotherapy for ovarian cancer, patients who score > 30/100 on MOST-S26-DorT or > 40/100 on MOST-S26-NTx at the end of chemotherapy are likely to have persistent symptoms. The MOST could triage this at-risk subset for early intervention.

Cognitive Functions under Anti-HER2 Targeted Therapy in Cancer Patients: A Scoping Review.

Pharmacological therapy targeting the HER2 protein is one of the major breakthroughs in the treatment of cancer patients overexpressing HER2 who have increased survival rates. Despite improved survival, it is important to determine the less frequent adverse effects in order to tailor treatments more personalized to the patients' features. The possible impact of cancer treatments on cognitive functions is huge, and the effects of anti-HER 2 therapies on this issue have not been reviewed and are the objective of this study. Analysis of PubMed, Scopus, Cochrane library and Web of Science databases revealed six studies performed in breast and serous uterine cancer patients analyzing cognitive function under chemotherapy regimens including anti-HER2 drugs. Four of these studies reported small to significant worsening of cognitive function following chemotherapy regimens containing trastuzumab (the most widely used anti-HER2 drug). In neoadjuvant settings, and in breast cancer patients, treatment with the new anti-HER-2 drug trastuzumab emtansine seems to induce less cognitive impairment than therapeutic regimens containing chemotherapy and trastuzumab. Acute administration of trastuzumab induced cognitive impairment in gastric cancer mice models, confirming its ability to alter cognitive function in patients. More studies analyzing the impact of anti-HER2 therapy on cognitive function are necessary at preclinical and clinical levels in order to personalize pharmacological treatment and offer cancer patients a better quality of life.

Caffeic acid phenethyl ester counteracts doxorubicin-induced chemobrain in Sprague-Dawley rats: Emphasis on the modulation of oxidative stress and neuroinflammation.

Chemotherapy-induced cognitive dysfunction (chemobrain) is one of the major complaints for cancer patients treated with chemotherapy such as Doxorubicin (DOX). The induction of oxidative stress and neuroinflammation were identified as major contributors to such adverse effect. Caffeic acid phenethyl ester (CAPE) is a natural polyphenolic compound, that exhibits unique context-dependent antioxidant activity. It exhibits pro-oxidant effects in cancer cells, while it is a potent antioxidant and cytoprotective in normal cells. The present study was designed to investigate the potential neuroprotective effects of CAPE against DOX-induced cognitive impairment. Chemobrain was induced in Sprague Dawley rats via systemic DOX administration once per week for 4 weeks (2 mg/kg/week, i.p.). CAPE was administered at 10 or 20 µmol/kg/day, i.p., 5 days per week for 4 weeks. Morris water maze (MWM) and passive avoidance tests were used to assess learning and memory functions. Oxidative stress was evaluated via the colorimetric determination of GSH and MDA levels in both hippocampal and prefrontal cortex brain regions. However, inflammatory markers, acetylcholine levels, and neuronal cell apoptosis were assessed in the same brain areas using immunoassays including either ELISA, western blotting or immunohistochemistry. DOX produced significant impairment in learning and memory as indicated by the data generated from MWM and step-through passive avoidance tests. Additionally DOX-triggered oxidative stress as evidenced from the reduction in GSH levels and increased lipid peroxidation. Treatment with DOX resulted in neuroinflammation as indicated by the increase in NF-kB (p65) nuclear translocation in addition to boosting the levels of pro-inflammatory mediators (COX-II/TNF-α) along with the increased levels of glial fibrillary acid protein (GFAP) in the tested tissues. Moreover, DOX reduced acetylcholine levels and augmented neuronal cell apoptosis as supported by the increased active caspase-3 levels. Co-treatment with CAPE significantly counteracted DOX-induced behavioral and molecular abnormalities in rat brain tissues. Our results provide the first preclinical evidence for CAPE promising neuroprotective activity against DOX-induced neurodegeneration and memory deficits.

Abrogating doxorubicin-induced chemobrain by immunomodulators IFN-beta 1a or infliximab: Insights to neuroimmune mechanistic hallmarks.

Chemobrain is a well-established clinical syndrome that impairs patient's daily function, in particular attentiveness, coordination and multi-tasking. Thus, it interferes with patient's quality of life. The putative pharmacological intervention against chemobrain relies on understanding the molecular mechanisms underlying it. This study aimed to examine the potential neuroprotective effects of two immunomodulators: Interferon-ß-1a (IFN-ß-1a), as well as Tumor necrosis function-alpha (TNF-α) inhibitor; Infliximab in doxorubicin (DOX)-induced chemobrain in rats. Besides, the current study targets investigating the possible molecular mechanisms in terms of neuromodulation and interference with different death routes controlling neural homeostasis. Herein, the two immunomodulators IFN-ß-1a at a dose of 300,000 units; s.c.three times per week, or Infliximab at a dose of 5 mg/kg/week; i.p. once per week were examined against DOX (2 mg/kg/w, i.p.) once per week for 4 consecutive weeks in rats.The consequent behavioral tests and markers for cognitive impairment, oxidative stress, neuroinflammation, apoptosis and neurobiological abnormalities were further evaluated. Briefly, IFN-ß-1a or Infliximab significantly protected against DOX-induced chemobrain. IFN-ß-1a or Infliximab ameliorated DOX-induced hippocampal histopathological neurodegenerative changes, halted DOX-induced cognitive impairment, abrogated DOX-induced mitochondrial oxidative, inflammatory and apoptotic stress, mitigated DOX-induced autophagic dysfunction and finally upregulated the mitophagic machineries. In conclusion, these findings suggest that either IFN-ß-1a or Infliximab offers neuroprotection against DOX-induced chemobrain which could be explained by their antioxidant, anti-inflammatory, pro-autophagic, pro-mitophagic and antiapoptotic effects. Future clinical studies are recommended to personalize either use of IFN-ß-1a or infliximab to ameliorate DOX-induced chemobrain.

Doxorubicin chemotherapy-induced "chemo-brain": Meta-analysis.

Doxorubicin is a leading chemotherapeutic halting cellular replication and inducing p53-dependent apoptosis in cancerous tissue. Like many chemotherapies, doxorubicin damages healthy tissue throughout the body through cellular mechanisms independent of its chemotherapeutic action. Although cognitive impairment is commonly recorded in patients after chemotherapy, the occurrence of doxorubicin-induced "chemo-brain" is debated, as doxorubicin cannot cross the blood-brain barrier. However, the potential of indirect doxorubicin neurotoxicity remains, providing a foundation for doxorubicin-mediated chemo-brain. We present the first meta-analysis of defined cognitive performance of doxorubicin-treated patients. A search of PubMed and MedLine collected 494 studies, 14 of which met analysis criteria. Performance of 511 doxorubicin-treated women with breast cancer was compared to that of 306 healthy controls across measures of defined cognitive modalities. Treated patients experience significant impairment in global cognition compared to controls (g= -0.41, P < 0.001), with select impairment in executive function (g = -0.25, P < 0.0001), language (g = -0.30, P < 0.0001), memory (g = -0.12, P < 0.01) and processing speed (g = -0.28, P < 0.01). Within memory, short-term verbal memory is most significantly affected (g = -0.21, P < 0.01). Impairment in select cognitive modalities (executive function, language, memory, short-term verbal memory, processing speed) is prevalent in doxorubicin-treated patients, with some cognitive functions remaining intact (attention, motor function, visuospatial abilities). This information can guide the development of future interventions to improve quality-of-life (QOL) and doxorubicin-derived therapies that target cytotoxicity to cancerous tissue, avoiding healthy tissue damage, which is mediated by seemingly independent mechanisms.

Heterogeneous Response of Chemotherapy-Related Cognitive Decline in Patients with Breast Cancer: A Prospective Study.

OBJECTIVE: A significant proportion of adjuvant-treated breast cancer patients experience cognitive decline, challenging the person's ability to return to normal activities after treatment. However, not every patient experiences cognitive problems, and even in patients with impairments, determining clinically important cognitive decline remains challenging. Our objective was to explore differences in neuropsychological performance following adjuvant chemotherapy (CT) in patients with breast cancer. METHOD: We conducted a prospective observational study in an Oncology Breast Clinic and assessed neuropsychological performance before and after adjuvant CT and in non-CT-treated women with breast cancer and healthy controls (HCs). Standardised between-group differences and regression-based change scores were calculated. RESULTS: CT-treated patients (n = 66) performed significantly different from non-CT-treated patients (n = 39) and HCs (n = 56). There was a significant effect on verbal fluency (p = .0013). CT performed significantly worse than non-CT and HC [effect size (ES) = .89, p < .001 and ES = .61, p ≤ .001, respectively] and from HCs with regard to proactive interference (ES = .62, p ≤ .001). Regression-based scores revealed more severe cognitive decline in the CT-treated group [24.24% (16/66)] than in the non-CT-treated group [15.20% (6/39)] and HC group [7.14% (4/56)]. Patients who underwent CT and showed cognitive decline were less educated and older, with significantly lower baseline scores. CONCLUSIONS: CT-treated patients showed more vulnerability on cognitive control and monitoring than non-CT-treated breast cancer patients and HCs. Older patients with less education and lower baseline cognitive performance represent a group at risk for cognitive decline following CT. Identification of patients at risk for decline could improve targeted support and rehabilitation.