Postmastectomy radiotherapy in high-risk breast cancer patients given adjuvant systemic therapy. A 30-year long-term report from the Danish breast cancer cooperative group DBCG 82bc trial.

BACKGROUND: Between 1982 and 1990 the Danish Breast Cancer Cooperative Group (DBCG) conducted a randomized trial in high-risk pre- and postmenopausal (<70 years) breast cancer patients comparing mastectomy plus adjuvant systemic therapy alone versus the same treatment plus postoperative irradiation. AIM: To present a comprehensive analysis of the complete DBCG 82bc study with a 30-year long-term follow-up of the cancer therapeutic effect and survival, together with an additional focus on the potential long-term life-threatening morbidity related to cardiac irradiation and/or the risk of secondary cancer induction. METHODS: A total of 3083 patients with pathological stage II and stage III breast cancer were after mastectomy randomly assigned to receive adjuvant systemic therapy and postoperative irradiation to the chestwall and regional lymph nodes (1538 pts), or adjuvant systemic therapy alone (1545 pts). Pre- and menopausal patients (DBCG 82b) received 8-9 cycles of CMF with an interval of 4 weeks, whereas postmenopausal patients (DBCG 82c) received tamoxifen 30 mg daily for one year. The median follow-up time was 34 years. The primary endpoints were loco-regional recurrence (LRR) and overall mortality, and the secondary endpoints were distant metastasis, breast cancer mortality, and irradiation related late morbidity. RESULTS: Overall the 30-year cumulative incidence of loco-regional recurrence was 9% in irradiated patients versus 37% in non-irradiated patients who received adjuvant systemic therapy alone (HR: 0.21 [95% cfl 0.18-0.26]). Distant metastasis probability at 30 years was 49% in irradiated patients compared to 60% in non-irradiated (HR: 0.77 [0.70-0.84]). Consequently, these figures resulted in a reduced breast cancer mortality: 56% vs 67% (HR: 0.75 [0.69-0.82], and overall mortality (81% vs 86% at 30 years (p < 0.0001), HR: 0.83 [0.77-0.90] in favor of irradiation. Radiotherapy did not result in any significant excess death of other courses, such as ischemic heart disease, HR: 0.82 [0.58-1.18]; nor secondary lung cancer HR: 1.44 [0.92-2.24], or other non-cancer related death HR: 1.15 [0.92-1.45]. CONCLUSION: The study definitely demonstrate that optimal long-term treatment benefit of high-risk breast cancer can only be achieved if both loco-regional and systemic tumor control are aimed for. Therefore, radiotherapy has an important role in the multidisciplinary treatment of breast cancer. The PMRT treatment did not result in excess ischemic heart damage, nor in other non-breast cancer related death.

Internet-delivered Mindfulness-Based Cognitive Therapy for anxiety and depression in cancer survivors: Predictors of treatment response.

BACKGROUND: The present study investigates possible predictors of treatment response in an Internet-delivered Mindfulness-Based Cognitive Therapy (iMBCT) intervention with therapist support. This iMBCT program, a fully online delivered intervention with asynchronous therapist support, has previously been shown to be efficacious in reducing symptoms of anxiety and depression in women treated for breast cancer and men treated for prostate cancer. METHODS: Eighty-two breast- and prostate cancer survivors experiencing psychological distress received 8 weeks of therapist-guided iMBCT. Primary outcomes were improvement in anxiety and depression scores from baseline to post-treatment and from baseline to six-months follow-up. Clinical predictors included levels of depression and anxiety at the time of screening and at baseline, as well as time since diagnosis. Demographic predictors included age and educational level. Therapy-related predictors included working alliance, self-compassion, and five facets of mindfulness. Mixed Linear Models were employed to test the prediction effects over time. RESULTS: Higher levels of baseline depression were associated with increased treatment response in anxiety at post-treatment, and lower levels of self-compassion were associated with increased treatment response in depression at post-treatment. None of the proposed predictors significantly predicted treatment response at six-months follow-up. CONCLUSION: The findings suggest that iMBCT can be provided for cancer survivors regardless of their age, educational level, and time since diagnosis (up to five years) and that therapeutic alliance is not crucial for treatment response. We did not identify characteristics predicting treatment response, although many factors were tested. Still, other characteristics may be predictors, and given the relatively small sample size and a large number of statistical tests, the results should be interpreted with caution.

Internet-delivered mindfulness-based cognitive therapy for anxiety and depression in cancer survivors: A randomized controlled trial.

OBJECTIVE: Internet-delivered interventions may alleviate distress in cancer survivors with limited access to psychological face-to-face treatment. In collaboration with a group of cancer survivors, we developed and tested the efficacy of a therapist-assisted internet-delivered mindfulness-based cognitive therapy (iMBCT) program for anxiety and depression in cancer survivors. METHODS: A total of 1282 cancer survivors were screened for anxiety and depression during their routine oncology follow-up; eligible breast (n = 137) and prostate cancer (n = 13) survivors were randomized to iMBCT or care-as-usual (CAU) wait-list. Primary outcomes of anxiety and depression were assessed at baseline, 5 weeks, 10 weeks (post intervention), and 6 months. RESULTS: Significant effects were found for both anxiety (Cohen's d = 0.45; P = .017) and depressive symptoms (d = 0.42; P = .024) post intervention. The effects were maintained at follow-up for anxiety (d = 0.40; P = .029), but not for depressive symptoms (d = 0.28; P = .131). CONCLUSIONS: Our preliminary findings suggest iMBCT to be a helpful intervention for cancer survivors suffering from symptoms of anxiety. Further studies on the efficacy for symptoms of depression are needed.

Molecular and cellular adaptations to exercise training in skeletal muscle from cancer patients treated with chemotherapy.

BACKGROUND: A growing body of evidence suggests that exercise training has beneficial effects in cancer patients. The aim of the present study was to investigate the molecular basis underlying these beneficial effects in skeletal muscle from cancer patients. METHODS: We investigated expression of selected proteins involved in cellular processes known to orchestrate adaptation to exercise training by western blot. Skeletal muscle biopsies were sampled from ten cancer patients before and after 4-7 weeks of ongoing chemotherapy, and subsequently after 10 weeks of continued chemotherapy in combination with exercise training. Biopsies from ten healthy matched subjects served as reference. RESULTS: The expression of the insulin-regulated glucose transporter, GLUT4, increased during chemotherapy and continued to increase during exercise training. A similar trend was observed for ACC, a key enzyme in the biosynthesis and oxidation of fatty acids, but we did not observe any changes in other regulators of substrate metabolism (AMPK and PDH) or mitochondrial proteins (Cyt-C, COX-IV, SDHA, and VDAC). Markers of proteasomal proteolysis (MURF1 and ATROGIN-1) decreased during chemotherapy, but did not change further during chemotherapy combined with exercise training. A similar pattern was observed for autophagy-related proteins such as ATG5, p62, and pULK1 Ser757, but not ULK1 and LC3BII/LC3BI. Phosphorylation of FOXO3a at Ser318/321 did not change during chemotherapy, but decreased during exercise training. This could suggest that FOXO3a-mediated transcriptional regulation of MURF1 and ATROGIN-1 serves as a mechanism by which exercise training maintains proteolytic systems in skeletal muscle in cancer patients. Phosphorylation of proteins that regulate protein synthesis (mTOR at Ser2448 and 4EBP1 at Thr37/46) increased during chemotherapy and leveled off during exercise training. Finally, chemotherapy tended to increase the number of satellite cells in type 1 fibers, without any further change during chemotherapy and exercise training. Conversely, the number of satellite cells in type 2 fibers did not change during chemotherapy, but increased during chemotherapy combined with exercise training. CONCLUSIONS: Molecular signaling cascades involved in exercise training are disturbed during cancer and chemotherapy, and exercise training may prevent further disruption of these pathways. TRIAL REGISTRATION: The study was approved by the local Scientific Ethics Committee of the Central Denmark Region (Project ID: M-2014-15-14; date of approval: 01/27/2014) and the Danish Data Protection Agency (case number 2007-58-0010; date of approval: 01/28/2015). The trial was registered at http//www.clinicaltrials.gov (registration number: NCT02192216; date of registration 07/17-2014).

The 'Cancer Home-Life Intervention': A randomised controlled trial evaluating the efficacy of an occupational therapy-based intervention in people with advanced cancer.

BACKGROUND: People with advanced cancer face difficulties with their everyday activities at home that may reduce their health-related quality of life. To address these difficulties, we developed the 'Cancer Home-Life Intervention'. AIM: To evaluate the efficacy of the 'Cancer Home Life-Intervention' compared with usual care with regard to patients' performance of, and participation in, everyday activities, and their health-related quality of life. DESIGN AND INTERVENTION: A randomised controlled trial ( ClinicalTrials.gov NCT02356627). The 'Cancer Home-Life Intervention' is a brief, tailored, occupational therapy-based and adaptive programme for people with advanced cancer targeting the performance of their prioritised everyday activities. SETTING/PARTICIPANTS: Home-living adults diagnosed with advanced cancer experiencing functional limitations were recruited from two Danish hospitals. They were assessed at baseline, and at 6 and 12 weeks of follow-up. The primary outcome was activities of daily living motor ability. Secondary outcomes were activities of daily living process ability, difficulty performing prioritised everyday activities, participation restrictions and health-related quality of life. RESULTS: A total of 242 participants were randomised either to the intervention group ( n = 121) or the control group ( n = 121). No effect was found on the primary outcome (between-group mean change: -0.04 logits (95% confidence interval: -0.23 to 0.15); p = 0.69). Nor was any effect on the secondary outcomes observed. CONCLUSION: In most cases, the 'Cancer Home-Life Intervention' was delivered through only one home visit and one follow-up telephone contact, which not was effective in maintaining or improving participants' everyday activities and health-related quality of life. Future research should pay even more attention to intervention development and feasibility testing.

Adjuvant Cyclophosphamide and Docetaxel With or Without Epirubicin for Early TOP2A-Normal Breast Cancer: DBCG 07-READ, an Open-Label, Phase III, Randomized Trial.

Purpose Administration of anthracycline and taxane therapy in the adjuvant setting is considered a standard for breast cancer. We evaluated a non-anthracycline-based regimen in TOP2A-normal patients. Patients and Methods In this multicenter, open-label, phase III trial, 2,012 women with early TOP2A-normal breast cancer and at least one high-risk factor were randomly assigned to receive six cycles of docetaxel (75 mg/m2) and cyclophosphamide (600 mg/m2) every 3 weeks (DC) or three cycles of epirubicin (90 mg/m2) and cyclophosphamide (600 mg/m2) followed by three cycles of docetaxel (100 mg/m2; EC-D). The primary end point was disease-free survival (DFS) after a median of 5 years of follow-up. Secondary end points were patient-reported toxicity, overall survival (OS), and distant disease-free survival. Results At a median estimated potential follow-up of 69 months, 5-year DFS was 87.9% (95% CI, 85.6% to 89.8%) in the EC-D arm and 88.3% (95% CI, 86.1% to 90.1%) in the DC arm. There was no significant difference in the risk of DFS events (hazard ratio [HR], 1.00; 95% CI, 0.78 to 1.28; P = 1.00), distant disease-free survival (HR, 1.12; 95% CI, 0.86 to 1.47; P = .40), or mortality (HR, 1.15; 95% CI, 0.83 to 1.59; P = .41) in the intent-to-treat analysis. A significant interaction between menopausal status and treatment group was observed for DFS ( P = .04) but not for OS ( P = .07). Patients with grade 3 tumors derived most benefit from DC, and patients with grade 1 to 2 tumors derived most benefit from EC-D (DFS: interaction P = .02; and OS: interaction P = .03). Patients receiving EC-D reported significantly more stomatitis, myalgia or arthralgia, vomiting, nausea, fatigue, and peripheral neuropathy, whereas edema was more frequent after DC. Conclusion This study provides evidence to support no overall outcome benefit from adjuvant anthracyclines in patients with early TOP2A-normal breast cancer.

Efficacy of Mindfulness-Based Cognitive Therapy on Late Post-Treatment Pain in Women Treated for Primary Breast Cancer: A Randomized Controlled Trial.

PURPOSE: To assess the efficacy of mindfulness-based cognitive therapy (MBCT) for late post-treatment pain in women treated for primary breast cancer. METHODS: A randomized wait list-controlled trial was conducted with 129 women treated for breast cancer reporting post-treatment pain (score ≥ 3 on pain intensity or pain burden assessed with 10-point numeric rating scales). Participants were randomly assigned to a manualized 8-week MBCT program or a wait-list control group. Pain was the primary outcome and was assessed with the Short Form McGill Pain Questionnaire 2 (SF-MPQ-2), the Present Pain Intensity subscale (the McGill Pain Questionnaire), and perceived pain intensity and pain burden (numeric rating scales). Secondary outcomes were quality of life (World Health Organization-5 Well-Being Index), psychological distress (the Hospital Depression and Anxiety Scale), and self-reported use of pain medication. All outcome measures were assessed at baseline, postintervention, and 3-month and 6-month follow-up. Treatment effects were evaluated with mixed linear models. RESULTS: Statistically significant time × group interactions were found for pain intensity (d = 0.61; P = .002), the Present Pain Intensity subscale (d = 0.26; P = .026), the SF-MPQ-2 neuropathic pain subscale (d = 0.24; P = .036), and SF-MPQ-2 total scores (d = 0.23; P = .036). Only pain intensity remained statistically significant after correction for multiple comparisons. Statistically significant effects were also observed for quality of life (d = 0.42; P = .028) and nonprescription pain medication use (d = 0.40; P = .038). None of the remaining outcomes reached statistical significance. CONCLUSION: MBCT showed a statistically significant, robust, and durable effect on pain intensity, indicating that MBCT may be an efficacious pain rehabilitation strategy for women treated for breast cancer. In addition, the effect on neuropathic pain, a pain type reported by women treated for breast cancer, further suggests the potential of MBCT but should be considered preliminary.

Effect of obesity on prognosis after early-stage breast cancer.

PURPOSE: This study was performed to characterize the impact of obesity on the risk of breast cancer recurrence and death as a result of breast cancer or other causes in relation to adjuvant treatment. PATIENTS AND METHODS: Information on body mass index (BMI) at diagnosis was available for 18,967 (35%) of 53,816 women treated for early-stage breast cancer in Denmark between 1977 and 2006 with complete follow-up for first events (locoregional recurrences and distant metastases) up to 10 years and for death up to 30 years. Information was available on prognostic factors and adjuvant treatment for all patients. Univariate analyses were used to compare the associations of known prognostic factors and risks of recurrence or death according to BMI categories. Cox proportional hazards regression models were used to assess the influence of BMI after adjusting for other factors. RESULTS: Patients with a BMI of 30 kg/m(2) or more were older and had more advanced disease at diagnosis compared with patients with a BMI below 25 kg/m(2) (P < .001). When data were adjusted for disease characteristics, the risk of developing distant metastases after 10 years was significantly increased by 46%, and the risk of dying as a result of breast cancer after 30 years was significantly increased by 38% for patients with a BMI of 30 kg/m(2) or more. BMI had no influence on the risk of locoregional recurrences. Both chemotherapy and endocrine therapy seemed to be less effective after 10 or more years for patients with BMIs greater than 30 kg/m(2). CONCLUSION: Obesity is an independent prognostic factor for developing distant metastases and for death as a result of breast cancer; the effects of adjuvant therapy seem to be lost more rapidly in patients with breast cancer and obesity.