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

Breast Cancer Clinical Trial

Official title:

Analisi Dei Marcatori di Stress Ossidativo in Pazienti Affetti da Tumore Della Mammella, Sottoposte a Radioterapia Postoperatoria e Psicoterapia Con Elementi di Musicoterapia

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04446624
• Other study ID #: CE 193/17
• Status: Completed
• Phase: N/A
• Start date: February 1, 2018
• Est. completion date: December 31, 2019

Study information

• Verified date: June 2020
• Source: Università degli Studi del Piemonte Orientale "Amedeo Avogadro"
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Oxidative stress plays an important role in the development of breast cancer, and also of depression which can affect the ability to deal with cancer.

The main objective of this study 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.

Study outcomes will be the following:

1. Effectiveness of the proposed intervention especially on anxiety and depression, as described by changes in psychometric test scores.

2. Changes of oxidative stress and inflammation markers, such as high sensitivity C-reactive protein (hs-PCR), fibrinogen and lipoprotein-associated phospholipase A2 (Lp-LPLA2), GSH, TBARS, IL4, IL6, TNF-α, α and γ tocopherol, carotenoids, folic acid, vitamin B12.

3. Correlation between changes of markers (see point 2) and the clinical/psychometric variables under study.

Methods This is a prospective randomized monocentric study, which will involve 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. Patients who meet the eligibility criteria and who have signed informed consent will be randomized (1:1) as follows: group supportive psychotherapy with elements of music therapy (PSY); control group - treatment as usual (TAU ). Patients will undergo psychometric assessment and blood sampling (10 ml) at T0 (baseline), T1 (last day of RT), T2 (3 months after the end of RT).

Study duration will be one year; during the first 9 months, patients will be recruited and treated, in the following period follow-up evaluations will be completed and data analyses will be conducted.

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 (Bulfone 2009, Rossetti 2017), 24 patients per group have to be enrolled (alpha: 0.05; Beta: 0.20).

Statistical analysis A simple randomization in 1:1 ratio will be carried out. Differences between the 2 groups will be used to assess the impact of psychotherapy intervention with elements of music therapy. A descriptive statistical analysis and estimate of relative risks will be performed.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 60
• Est. completion date: December 31, 2019
• Est. primary completion date: December 31, 2019
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• ECOG 0-1

• Age > 18 years

• Histologically confirmed invasive / intraductal breast cancer

• Conservative breast surgery (quadrantectomy, nodulectomy)

• Free surgical margins

• Pathological stage pTis, pT1-2 pN0-1 M0 (according to the TNM classification)

• Indication for adjuvant RT

• Signature of informed consent

Exclusion Criteria:

• Age < 18 years

• indication to chemotherapy / targeted therapy

• diagnosis of previous major depressive episode

• current comorbidity with abuse of alcohol and / or psychotropic substances

• ongoing psychopharmacological treatment with antidepressants and / or mood stabilizers

• diagnosis of mental retardation, dementia, or other cognitive impairment

• autoimmune / inflammatory diseases / diabetes mellitus

• pregnancy

Related Conditions & MeSH terms

• Anxiety Disorders
• Breast Cancer
• Breast Neoplasms
• Depression
• Depression, Anxiety
• Depressive Disorder
• Oxidative Stress

Intervention

Other:
• Music therapy intervention
Group psychotherapy with music intervention

Locations

Country	Name	City	State
Italy	Department of Translational Medicine, Università del Piemonte Orientale	Novara

Sponsors (1)

Lead Sponsor	Collaborator
Università degli Studi del Piemonte Orientale "Amedeo Avogadro"

Country where clinical trial is conducted

Italy, 

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Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in anxiety from baseline to follow-up	Anxiety is assessed with the State-Trait Anxiety Inventory 1 and 2 (STAI Y1, STAI Y2), a 40-item self-administered test for the assessment of state and trait anxiety. Each item is rated 1 to 4 (1= not at all, 4= severe); no specific cut-off scores exist. The highest the score, the greater is anxiety.	Time T0 (pre-RT); Time T1 (through RT completion, an average of 27 days); Time T2 (3 months after the end of RT)
Primary	Change in depression from baseline to follow-up	Depression is assessed with the Montgomery-Asberg Depression Rating Scale (MADRS and with the Beck Depression Inventory (BDI). The MADRS is a 10-item clinician-rated scale for depressive symptoms detection and severity assessment. Each item is rated on a six-point scale, hence 60 is the maximum total score indicating the maximum severity of depressive symptoms. A score <6 points stands for no depression (normal), 7-19 mild depression, 20-34 moderate depression, = 35 severe depression. The BDI is a 21-item self-administered test for the evaluation of subjective depressive feelings or symptoms. It is rated on a 4-points scale (from 0 to 3 according to severity), with the following cutoff values: 0-9 minimal depression, 10-18 mild depression, 19-29 moderate depression, 30-63 severe depression.	Time T0 (pre-RT); Time T1 (through RT completion, an average of 27 days); Time T2 (3 months after the end of RT)
Primary	Change in Glutathione (GSH) from baseline to follow-up	GSH measurement was performed through the Glutathione Assay Kit (Cayman Chemical, Ann Arbor, MI, USA). For the experiments, each plasma sample was deproteinated and centrifuged at 2000 g for 2 min. Fifty µl of the samples was transferred to a 96-well plate where GSH was detected through a spectrophotometer (VICTOR™ X Multilabel Plate Reader), at excitation/emission wavelengths of 405-414 nm. To ensure accurate GSH quantification (expressed as µM), a reference curve with the GSH Standard was prepared (range of known GSH concentration: 0-16 µM). As regards the performance of the assay, variation coefficient of 3.6% for inter-assay and 1.6% for intra-assay is reported.	Time T0 (pre-RT); Time T1 (through RT completion, an average of 27 days); Time T2 (3 months after the end of RT)
Primary	Change in TBARS from baseline to follow-up	TBARS were determined as malonyldialdeide (MDA) release. MDA measurement was performed by using the TBARS assay Kit (Cayman Chemical). For the experiments, 100 µl of each plasma sample was added to 100 µl of sodium dodecyl sulfate (SDS) solution and 2 ml of the Color Reagent. After centrifugation, 150 µl of each sample was transferred to a 96-well plate where MDA was detected through a spectrophotometer (VICTOR™ X Multilabel Plate Reader), at excitation/emission wavelengths of 530-540 nm. In order to quantify the correct values of TBARS (expressed as µM MDA), a reference standard curve was prepared (range of known TBARS concentration: 0-50 µM). As regards the performance of the assay, intra-coefficient of variation of 5.5% and an inter-coefficient variation of 5.9% is reported.	Time T0 (pre-RT); Time T1 (through RT completion, an average of 27 days); Time T2 (3 months after the end of RT)
Secondary	Change in resilience from baseline to follow-up	Resilience is assessed with the Resilience Scale for Adults (RSA). This is a 33-item self-administered scale evaluating intra- or inter-relational stress preventing factors (positive self-perception, positive future perception, social competence, structured style, family cohesion and social resources). The higher is the total score, the greater is the subject's resilience.	Time T0 (pre-RT); Time T1 (through RT completion, an average of 27 days); Time T2 (3 months after the end of RT)
Secondary	Change in quality of life from baseline to follow-up	Quality of life is assessed with the Short Form-36 (SF-36), a self-administered test assessing health-related quality of life, both from a somatic and psychological standpoint. It assesses several sub-areas: physical activity, role and physical health, physical pain, general health, vitality, social activities, role and emotional state, mental health and health change. Results are expressed in age- calculated percentiles.	Time T0 (pre-RT); Time T1 (through RT completion, an average of 27 days); Time T2 (3 months after the end of RT)
Secondary	Change in Human IL-6 from baseline to follow-up	IL-6 measurement was performed by using the Human IL-6 ELISA kit (Invitrogen Carlsbad, California, USA). For the experiments, 50 µl of each plasma sample and 50 µl of Assay Buffer 1X were added to each well, with 50 µl of Biotin-Conjugate and incubated at room temperature (RT) on microplate shaker for 2 h. After addition of 400 µl Wash Buffer, 100 µl Streptavidin-HRP and 100 µl Substrate Solution, each well was incubated for 10 min at RT in the dark. The enzyme reaction was stopped by adding 100 µl Stop Solution, and IL-6 was detected through a spectrophotometer (VICTOR™ X Multilabel Plate Reader), using a wavelength of 450 nm. In order to quantify the correct value of IL-6 in each sample (expressed as pg/ml), a reference standard curve was prepared (range of IL-6 standard concentration:0-20 pg/mL). As regards the performance of the assay, intra-coefficient of variation of 8.5% and an inter-coefficient variation of 9.8% is reported. The sensitivity of the test is < 1 pg/ml.	Time T0 (pre-RT); Time T1 (through RT completion, an average of 27 days); Time T2 (3 months after the end of RT)
Secondary	Change in Human TNFa from baseline to follow-up	TNFa measurement was performed with the Human TNF alpha ELISA kit (Invitrogen, Carlsbad, California, USA). For the experiments, 50 µl of each plasma sample and 50 µl of Sample Diluent were added to each well, with 50 µl of Biotin-Conjugate and incubated at RT on microplate shaker for 2 h. After addition of 400 µl Wash Buffer, 100 µl Streptavidin-HRP and 100 µl Substrate Solution, each well was incubated for 10 min at RT in the dark. The enzyme reaction was stopped by adding 100 µl of Stop Solution and each well was read immediately. TNFa was detected through a spectrophotometer (VICTOR™ X Multilabel Plate Reader), using a wavelength of 620 nm. To quantify the correct value of in each sample, a reference standard curve was prepared (range of TNFa standard concentration: 0-100 pg/mL). As regards the performance of the assay, intra-coefficient of variation of 3.4% and inter-coefficient variation of 5.2% is reported. The sensitivity of the test is 0.13 pg/ml.	Time T0 (pre-RT); Time T1 (through RT completion, an average of 27 days); Time T2 (3 months after the end of RT)
Secondary	Change in Retinol, a and ? -tocopherol, lycopene and ß carotene from baseline to follow-up	HPLC analysis of retinol, a and ? -tocopherol, lycopene and ß carotene were carried out on Agilent 1200 series HPLC.; 200 ml of each plasma sample was mixed with 300µl of water and 500 µl of ice-cold absolute ethanol and immediately vortexed for 10 s. Two millilitres of ice-cold hexane was added. The mixture was immediately vortexed for 2 minutes and then centrifuged at 3000 g for 1 min and 1 ml of the upper (organic) layer was transferred in a vial, evaporated to dryness under a nitrogen stream and reconstituted with 100 ml of a mixture of acetonitrile/dichloromethane/methanol for HPLC analysis.; Twenty microlitres of this mixture were then injected and the antioxidants were eluted with a mobile phase containing acetonitrile/dichloromethane/methanol, glacial acetic acid (1 g /l) at a constant flow of 1.8 ml/min.; Detection of lipid soluble antioxidants was performed at specific wavelength: retinol (326 nm), ?- and a-tocopherol (292nm), lycopene and ß-carotene (460nm).	Time T0 (pre-RT); Time T1 (through RT completion, an average of 27 days); Time T2 (3 months after the end of RT)
Secondary	Change in Cholesterol and high sensitivity C-reactive Protein from baseline to follow-up	Colesterol and high sensitivity C-reactive Protein (CRP) were analyzed on ADVIA® 1800 Clinical Chemistry Analyzer (Siemens Healthcare Diagnostics), by automated methods and certified kits.; Colesterol (range:0 - 200 mg/dL) High sensitivity C-reactive Protein (range:0 - 1 mg/dL)	Time T0 (pre-RT); Time T1 (through RT completion, an average of 27 days); Time T2 (3 months after the end of RT)