Publications by authors named "Tesfaye Madebo"

6 Publications

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High-dose versus standard-dose twice-daily thoracic radiotherapy for patients with limited stage small-cell lung cancer: an open-label, randomised, phase 2 trial.

Lancet Oncol 2021 03;22(3):321-331

Department of Clinical and Molecular Medicine, NTNU, Norwegian University of Science and Technology, Trondheim, Norway; Department of Oncology, St Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.

Background: Concurrent chemoradiotherapy is standard treatment for limited stage small-cell lung cancer (SCLC). Twice-daily thoracic radiotherapy of 45 Gy in 30 fractions is considered to be the most effective schedule. The aim of this study was to investigate whether high-dose, twice-daily thoracic radiotherapy of 60 Gy in 40 fractions improves survival.

Methods: This open-label, randomised, phase 2 trial was done at 22 public hospitals in Norway, Denmark, and Sweden. Patients aged 18 years and older with treatment-naive confirmed limited stage SCLC, Eastern Cooperative Oncology Group (ECOG) performance status 0-2, and measurable disease according to the Response Evaluation Criteria in Solid Tumors version 1.1 were eligible. All participants received four courses of intravenous cisplatin 75 mg/m or carboplatin (area under the curve 5-6 mg/mL × min, Calvert's formula) on day 1 and intravenous etoposide 100 mg/m on days 1-3 every 3 weeks. Participants were randomly assigned (1:1) in permuted blocks (sized between 4 and 10) stratifying for ECOG performance status, disease stage, and presence of pleural effusion to receive thoracic radiotherapy of 45 Gy in 30 fractions or 60 Gy in 40 fractions to the primary lung tumour and PET-CT positive lymph node metastases starting 20-28 days after the first chemotherapy course. Patients in both groups received two fractions per day, ten fractions per week. Responders were offered prophylactic cranial irradiation of 25-30 Gy. The primary endpoint, 2-year overall survival, was assessed after all patients had been followed up for a minimum of 2 years. All randomly assigned patients were included in the efficacy analyses, patients commencing thoracic radiotherapy were included in the safety analyses. Follow-up is ongoing. This trial is registered at ClinicalTrials.gov, NCT02041845.

Findings: Between July 8, 2014, and June 6, 2018, 176 patients were enrolled, 170 of whom were randomly assigned to 60 Gy (n=89) or 45 Gy (n=81). Median follow-up for the primary analysis was 49 months (IQR 38-56). At 2 years, 66 (74·2% [95% CI 63·8-82·9]) patients in the 60 Gy group were alive, compared with 39 (48·1% [36·9-59·5]) patients in the 45 Gy group (odds ratio 3·09 [95% CI 1·62-5·89]; p=0·0005). The most common grade 3-4 adverse events were neutropenia (72 [81%] of 89 patients in the 60 Gy group vs 62 [81%] of 77 patients in the 45 Gy group), neutropenic infections (24 [27%] vs 30 [39%]), thrombocytopenia (21 [24%] vs 19 [25%]), anaemia (14 [16%] vs 15 [20%]), and oesophagitis (19 [21%] vs 14 [18%]). There were 55 serious adverse events in 38 patients in the 60 Gy group and 56 serious adverse events in 44 patients in the 45 Gy group. There were three treatment-related deaths in each group (one neutropenic fever, one aortic dissection, and one pneumonitis in the 60 Gy group; one thrombocytic bleeding, one cerebral infarction, and one myocardial infarction in the 45 Gy group).

Interpretation: The higher radiotherapy dose of 60 Gy resulted in a substantial survival improvement compared with 45 Gy, without increased toxicity, suggesting that twice-daily thoracic radiotherapy of 60 Gy is an alternative to existing schedules.

Funding: The Norwegian Cancer Society, The Liaison Committee for Education, Research and Innovation in Central Norway, the Nordic Cancer Union, and the Norwegian University of Science and Technology.
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http://dx.doi.org/10.1016/S1470-2045(20)30742-7DOI Listing
March 2021

Randomized phase III trial comparing switch-maintenance pemetrexed with observation followed by pemetrexed at progression in advanced NSCLC.

Acta Oncol 2020 Sep 16;59(9):1051-1057. Epub 2020 Jun 16.

Department of Clinical and Molecular Medicine, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.

Two phase III trials show that maintenance pemetrexed therapy after platinum-doublet chemotherapy prolongs overall survival (OS) and progression free survival (PFS) in advanced non-squamous non-small-cell lung cancer (NSCLC). However, few patients in the control arms received pemetrexed at progression in these trials, performance status (PS) two patients were ineligible and few of the participants were elderly. Thus, we designed this study comparing immediate switchmaintenance pemetrexed therapy with pemetrexed at progression after platinum-doublet chemotherapy. Patients with stage IIIB/IV non-squamous NSCLC, ≥18 years, PS 0-2, and non-progression after four courses of carboplatin/vinorelbine were randomized to receive immediate maintenance pemetrexed therapy or observation followed by pemetrexed at progression. The primary endpoint was OS, secondary endpoints were PFS, toxicity and health related quality of life (HRQoL). 105 patients were randomized between May 2014 and September 2017. Median age was 67 years, 36% were >70 years, 9% had PS 2, 91% stage IV and 47% were women. In the observation arm, 73% received pemetrexed at progression. Patients in the maintenance arm had a numerically longer OS (median 12.0 vs. 10.0 months;  = .10) and a statistically significant longer PFS (median 3.1 vs. 1.9 months;  < .01). In multivariable analyses adjusting for baseline characteristics, there was a trend toward improved OS (HR 0.65, 95% CI 0.42-1.01);  = .05), and a significantly improved PFS (HR 0.53, 95% CI 0.35-0.80;  < .01). There were no significant differences in toxicity or HRQoL between the treatment arms. There was a trend toward prolonged OS and significantly longer PFS from switch maintenance pemetrexed therapy when 73% of patients in the control arm received pemetrexed at progression. NCT02004184.
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http://dx.doi.org/10.1080/0284186X.2020.1778179DOI Listing
September 2020

Treatment completion for latent tuberculosis infection in Norway: a prospective cohort study.

BMC Infect Dis 2018 Nov 19;18(1):587. Epub 2018 Nov 19.

Department of Vaccine Preventable Diseases, Norwegian Institute of Public Health, Oslo, Norway.

Background: Successful treatment of latent tuberculosis infection (LTBI) is essential to reduce tuberculosis (TB) incidence rates in low-burden countries. This study measures treatment completion and determinants of non-completion of LTBI treatment in Norway in 2016.

Methods: This prospective cohort study included all individuals notified with LTBI treatment to the Norwegian Surveillance System for Infectious Diseases (MSIS) in 2016. We obtained data from MSIS and from a standardized form that was sent to health care providers at the time of patient notification to MSIS. We determined completion rates. Pearson's chi squared test was used to study associations between pairs of categorical variables and separate crude and multivariable logistic regression models were used to identify factors associated with treatment completion and adverse drug effects.

Results: We obtained information on treatment completion from 719 of the 726 individuals notified for LTBI treatment in 2016. Overall, 91% completed treatment. Treatment completion was highest in the foreign-born group [foreign-born, n = 562 (92%) vs Norwegian-born, n = 115 (85%), p = 0.007]. Treatment completion did not differ significantly between prescribed regimens (p = 0.124). Adverse events were the most common reason for incomplete treatment. We found no significant differences in adverse events when comparing weekly rifapentine (3RPH) with three months daily isoniazid and rifampicin (3RH). However, there were significantly fewer adverse events with 3RPH compared to other regimens (p = 0.037). Age over 35 years was significantly associated with adverse events irrespective of regimen (p = 0.024), whereas immunosuppression was not significantly associated with adverse events after adjusting for other variables (p = 0.306). Treatment under direct observation had a significant effect on treatment completion for foreign-born (multivariate Wald p-value = 0.017), but not for Norwegian-born (multivariate Wald p-value = 0.408) individuals.

Conclusions: We report a very high treatment completion rate, especially among individuals from countries with high TB incidence. The follow-up from tuberculosis-coordinators and the frequent use of directly observed treatment probably contributes to this. Few severe adverse events were reported, even with increased age and in individuals that are more susceptible. While these results are promising, issues of cost-effectiveness and targeting treatment to individuals at highest risk of TB are important components of public health impact.
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http://dx.doi.org/10.1186/s12879-018-3468-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6245849PMC
November 2018

Pulmonary function tests - an easy selection method for respiratory-gated radiotherapy in patients with left-sided breast cancer.

Acta Oncol 2015 Jul 31;54(7):1025-31. Epub 2014 Dec 31.

Department of Hematology and Oncology, Stavanger University Hospital , Stavanger , Norway.

Purpose: The purpose of this study was to establish a feasible and convenient method for selection of the subset of patients with left-sided breast cancer for whom respiratory-gated radiotherapy (RT) would be necessary to meet the national recommendation regarding radiation dose to the heart.

Material And Methods: The volume of heart receiving a dose equal to or higher than 25 Gy (V25Gy), the mean heart dose (Dmean) and total lung volume (TLV-CT) were obtained from treatment plans based on computer tomography (CT) series recorded during free breathing (FB), and the correlation between dose to the heart and TLV-CT was studied. Second, the correlation between TLV-CT and TLV defined from three pulmonary function tests (PFTs); spirometry, gas diffusion and plethysmograhy, was evaluated.

Results: Dose to the heart (V25Gy and Dmean) decreased with increasing TLV-CT. Pearson's correlation coefficient (r) for TLV-CT versus V25Gy and Dmean was equal (r = -0.809, p < 0.01) for patients planned for tangential breast RT only, and r = -0.853 and -0.861 (p < 0.01) for patients planned for loco-regional RT. Regression analysis showed good correlation between TLV-CT and TLV calculated from pulmonary function tests (R(2) ≥ 0.717, p < 0.01).

Conclusion: TLV defined by routine pulmonary function tests can be used to identify the subset of left-sided breast cancer patients who require respiratory-gated RT.
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http://dx.doi.org/10.3109/0284186X.2014.990107DOI Listing
July 2015

Traditional Chinese medicine herbal treatment may have a relevant impact on the prognosis of patients with stage IV adenocarcinoma of the lung treated with platinum-based chemotherapy or combined targeted therapy and chemotherapy.

Integr Cancer Ther 2011 Jun 8;10(2):127-37. Epub 2010 Dec 8.

Department of Medical Oncology, Longhua Hospital, Shanghai, China.

Background: Targeted therapy (TT), chemotherapy, and traditional Chinese medicine herbal treatment (TCM) can improve the prognosis of advanced pulmonary adenocarcinoma patients. Their independent prognostic value is unknown.

Objective: To study whether TCM improves survival in stage IV pulmonary adenocarcinoma patients with platinum-based chemotherapy (PBT), or combined PBT and second-line TT.

Methods: Retrospective analysis of 133 fully ambulant clinical outpatients treated with PBT alone or PBT with/without second-line TT, with/without TCM. Univariate (Kaplan-Meier) and multivariable (Cox model) survival analysis were performed, using disease-specific mortality as an endpoint.

Results: Gender (P = .002), TT (P < .0001), and TCM (P < .0001) had univariate prognostic value but not age, radiotherapy, or TCM syndrome differentiation (P > .10). TCM herbal treatment (P < .0001) and TT (P = .03) had multivariable independent prognostic value. TCM-treated patients (n = 103, PBT+TT+TCM+ = 62; PBT+TT-TCM+ =41) had 88% 1-year overall survival rate with median survival time (MST) of 27 months, contrasting 27% 1-year overall survival and MST of 5.0 months for non-TCM-treated (n = 30) patients. Patients with chemotherapy/TT/TCM (PBT+TT+TCM+, n = 62), TCM without TT (PBT+TT-TCM+, n = 41), or chemotherapy only (PBT+TT-TCM-, n = 30), had 1-year survival rates of 94%, 78%, and 27% respectively; for these 3 groups, respectively, MST was not reached (MST of 30.9 months), 22.6, and 5.0 months (P < .0001).

Conclusions: TCM herbal treatment may improve survival of stage IV pulmonary adenocarcinoma patients treated with chemotherapy without or with second-line TT. This warrants formal phase 1 and 2 trials and ultimately properly designed prospective clinical validation trials with adequate methodology developed for data collection.
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http://dx.doi.org/10.1177/1534735410387599DOI Listing
June 2011

Circulating antioxidants and lipid peroxidation products in untreated tuberculosis patients in Ethiopia.

Am J Clin Nutr 2003 Jul;78(1):117-22

Center for International Health, University of Bergen, Bergen, Norway.

Background: Knowledge of the antioxidant profile and its relation to lipid peroxidation in tuberculosis patients with or without accompanying HIV infection is scarce, particularly in developing countries.

Objective: The objective was to further investigate the interaction between HIV, tuberculosis, and antioxidants and their relations with markers of oxidative stress in a large population of Ethiopians.

Design: In a cross-sectional study, we evaluated antioxidants and markers of oxidative stress in Ethiopian tuberculosis patients with (n = 25) and without (n = 100) HIV infection and in Ethiopian (n = 45) and Norwegian (n = 25) healthy control subjects.

Results: Concentrations of the antioxidant vitamins C and E and of vitamin A were significantly lower in tuberculosis patients than in healthy Ethiopians. Tuberculosis patients also had significantly lower thiol concentrations, particularly of the reduced forms. Tuberculosis patients, particularly those who were co-infected with HIV, had higher malondialdehyde concentrations than did control subjects. High malondialdehyde concentrations were associated with clinical severity as measured by the Karnofsky Performance Status Index and anthropometric scores. Ethiopian control subjects had lower concentrations of vitamin E and higher concentrations of malondialdehyde than did Norwegian control subjects.

Conclusions: Our findings further support a link between oxidative stress, tuberculosis, and HIV infection. However, whether antioxidant supplementation will improve tuberculosis outcome or is of importance for its prevention should be further examined in future prospective studies.
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http://dx.doi.org/10.1093/ajcn/78.1.117DOI Listing
July 2003