Oxidative Stress, Anxiety and Depression in Breast Cancer Patients: Impact of Music Therapy

Background Mood alterations, particularly depression, are defined by the National Comprehensive Cancer Network (NCCN) as "multi-factorial unpleasant emotional experiences of psychological (cognitive, behavioral, emotional), social and/or spiritual nature that may interfere with the ability to cope with cancer, its physical symptoms and treatment". A recent meta-analysis showed that 8% to 24% of cancer patients in non-palliative care settings experienced depression. Many factors may contribute to depression in breast cancer patients, including age at diagnosis, cancer stage, surgery, and chemotherapy. Inflammation and oxidative stress are considered possible causing factors for mood disorder in patients with breast cancer, who show an increase in plasma rate of TNF alpha, IL6 and NFKB; alterations in the plasma levels of antioxidant agents, such as glutathione (GSH) and vitamin C, may be found as well. Correlation between mood alterations and oxidative stress is a frequently discussed topic in the scientific literature. Oxidative stress plays a key role in breast cancer development. In patients with different stages of breast cancer it was found a direct correlation between serum total oxidant status (TOS), total antioxidant status (TAS), oxidant stress index (OSI) and cancer progression. In particular, TOS and OSI gradually increase as the disease progresses, while TAS diminishes. Lipoprotein-associated phospholipase A2 (Lp-LPLA2) plays an important role in inflammation, but also in cytokine-induced depression and sickness behavior. Lp-PLA2 could be an important link between lipid homeostasis, inflammatory vascular response and depression. Thus, the analysis of Lp-PLA2 levels associated with LDL in patients with breast cancer, never performed before in the literature, could act as an important system for assessing the inflammatory status of this population. The potential predictive factors of depression during and after radiotherapy (RT) remains largely unexplored or analysed in retrospective studies or with limited numbers of patients. The perception of stigma could have an impact on depressive symptoms in cancer patients. More depressive symptoms, fatigue and stress and higher levels of inflammation markers may be found in patients with a history of childhood trauma. Another factor that has shown a significant association with depression is the role of post-surgical and post-RT aesthetic changes in women with breast cancer, while depressive symptoms were not influenced by RT toxicity. To date, however, prospective studies are needed to identify primary risk factors for depression in patients with breast cancer treated with RT. A proposed mechanism linking radiation therapy and depression is inflammation. Markers of inflammation are increased in patients with depression, and blockage of inflammation mechanisms can also modulate depressive symptoms, in particular "fatigue" in cancer patients. To date only one study has evaluated this relationship, quantifying the expression of IL6 receptors in patients with depression. In general, studies confirmed an improvement in anxiety and depression with the progress of the radiant treatment, and chronic changes occurred only in a percentage of about 10% of the patients. Oxidative stress seems to play also an important role in the aetiology of adverse effects from radiation therapy. Mood alterations, depression in particular, negatively affect both RT, in which the patient's "compliance" plays a fundamental role, and the patient's quality of life. The need for psychological / psychotherapeutic support in cancer patients, and in particular in breast cancer patients, is known and discussed in the literature, and there are many studies about integrative therapeutic approaches. Among the therapeutic approaches for the treatment of depression, analytical receptive music therapy, both as individual or group therapy, has been assessed; it consists in listening to music and in the subsequent verbalization of experiences, emotions and images aroused. A group music therapy intervention has recently proved to be more effective than a control intervention in breast cancer women treated with chemotherapy. The recent "Clinical Practice Guidelines" on the "evidence-based" use of integrative therapies during and after treatment for breast cancer has supported the use of various integrative therapy approaches. Music therapy has been recommended to reduce anxiety and stress, and also in case of depression and mood disorders. It should also be noted that in a recent study, the improvement of symptoms in a group of patients suffering from depression was accompanied by an increase in anti-inflammatory cytokines such as IL4. Objectives The main objective is to evaluate the impact of a group psychotherapy with elements of music therapy, in a population of patients suffering from breast cancer, treated with surgery and undergoing post-operative RT. Selection criteria Subjects Patients diagnosed with early stage invasive breast cancer (pTis-1-2 N0-1 M0), who underwent conservative surgery, and candidates for adjuvant RT. Patients will be identified during the RT visit and assessed according to inclusion and exclusion criteria, detailed elsewhere. The study does not include modifications in the standard surgical and RT process of the healthcare facility. At any time during the study, the patient can withdraw the consent to participate and leave the study. During the entire study period, the patient will be treated according to the standards of Good Clinical Practice (Declaration of Helsinki). Patients who meet the eligibility criteria and who have signed informed consent will be randomized (1:1) into 2 groups: 1. group undergoing group psychotherapy with elements of music therapy (PSY) 2. control group - treatment as usual (TAU). Timing All enrolled patients will be assessed with psychometric assessment and blood sampling (10 ml) at Time T0 (pre-RT), Time T1 (last day of RT), Time T2 (3 months after the end of RT). Procedures The patients will be randomized into two groups: treatment as usual (TAU) group psychotherapy (PSY) Specifically, patients in the TAU group will receive the treatment routinely offered to patients undergoing RT for breast cancer. The radiation therapy treatment will be performed at the SC Radiotherapy of the AOU "Maggiore della Carità" in Novara. The treatment consists in the irradiation of the entire residual breast volume. The irradiation technique will be established according to the current standards of the SC Radiotherapy which include a conformal 3D RT (3D-CRT) or an RT with intensity modulation (IMRT). The treatment will be performed using 6 and 15 MV photon beams produced by a linear accelerator. RT sessions will be performed daily from Monday to Friday for a total of 20-25 sessions. The current protocol provide a total prescribed dose of: 45 Gy, 2.25 Gy/die with boost dose on the neoplastic bed by sequential electron beam or concomitant photon beams or 50 Gy, 2 Gy/die. Every five RT sessions, patients will receive a clinical evaluation by the oncologist radiotherapist. The patients in the PSY group will participate to a short-term group psychotherapy with elements of music therapy; meetings will be 1 / week, for a total of 6 weeks. Beginning of psychotherapy intervention will be 1-2 weeks after recruitment at T0 and will therefore cover the entire duration of the RT cycle. Psychotherapy meetings will take place at the SCDU Psychiatry of the AOU Maggiore della Carità. Obviously, according to ethical reasons, in case a patient in each group (TAU, PSY) at any time, needs a psychiatric visit, psychopharmacological support or individual support, this will be offered according to clinical indications. If these interventions are started before the completion of the protocol, the patient will continue for ethical reasons the intervention started (and in addition the intervention considered necessary by the clinician) and the planned evaluations, but she will be excluded from the analyses on the effectiveness of the proposed intervention, because of the bias of additional treatments. Similarly, according to ethical reasons, if patients at the end of the protocol need additional psychotherapeutic and/or pharmacological support, this will be offered according to clinical conditions that could be different for each patient. This will not imply exclusion from the study protocol. Psychiatric evaluation Depressive symptoms - Beck Depression Inventory (BDI-II); Montgomery-Asberg Depression Rating Scale (MADRS); State-Trait Anxiety Inventory 1 and 2 (STAI Y1, STAI Y2); Resilience Scale for Adults (RSA); Short Form-36 (SF-36). Blood samples Blood samples dosing plasma markers necessary for the study will be gathered in all patients, at the SC Radiotherapy. Samples will then be centrifuged, and serum obtained will be divided into five samples for each detection and stored at -80C, at the Physiology laboratory of the Piemonte Orientale University. The fibrinogen dosage will be included in the BCS® XP system (Siemens Healthcare Diagnostics). Dosage of α and γ of tocopherol, carotenoids, folic acid, vitamin B12 will finally be performed using high resolution liquid chromatography (Agilent 1200 Series). Measurements of the plasma glutathione rate (GSH), lipid peroxidation products (TBARS), IL4, IL6 and TNF alfa will be included in widely used kits. The measurements will be carried out at the Physiology laboratory of the Piemonte Orientale University by Biotechnologists under the supervision of Prof. Elena Grossini. Population Sample size Based on literature data, indicating average anxiety ranges measured with a STAI score from 43.4 to 46.2 and assuming, in the experimental group, a clinically significant reduction of 9 points, 24 patients per group have to be enrolled (alpha: 0.05; Beta: 0.20). In consideration of this data, a sample of 60 total patients is assumed. Statistical analysis A simple randomization in 1:1 ratio will be carried out through a special statistical program. Differences between the 2 groups will be used to assess the impact of the psychotherapy intervention with elements of music therapy. A descriptive statistical analysis and estimate of relative risks will be performed.