Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Symptoms and General Pathology

Breast Neoplasms

Neoplasm Metastasis

Breast Diseases

Skin Diseases

Patients in this arm will not receive axillary treatment (axillary lymph node dissection or axillary radiotherapy). Supraclavicular fossa radiotherapy is not allowed when randomised to this arm.

Patients in this arm will receive axillary treatment. Axillary treatment can be axillary lymph node dissection or axillary radiotherapy.

Participants will undergo removal of at least level I and II axillary lymph nodes.

Axillary lymph node dissection

Axillary radiotherapy will be delivered as per the Radiotherapy Trials Quality Assurance (RTTQA) guidelines.

Axillary radiotherapy

Breast or chest wall radiotherapy will be delivered as per the Radiotherapy Trials Quality Assurance (RTTQA) guidelines.

Breast or chest wall radiotherapy

Amit Goyal, MS, MD, FRCS

Claire Murphy

Ludger Barthelmes

Kaiyumars Contractor

Hisham Osman

Eileen Anderson

Sue Down

Brendan Smith

Jalal Kokan

Laura Pettit

Beatrix Elsberger

Anneliese Lawn

Pardeep Arora

Graeme Lumsden

Gareth Irwin

Daniel Henderson

Fiona Hoar

Ricardo Pardo-Garcia

Richard Linforth

Rathinasabapathy Rathinaezhil

Sasirekha Govindarajulu

Inder Kumar

John Benson

Anita Hargreaves

Susan Hignett

Sanjana Masinghe

Emanuele Garreffa

Lynda Wyld

Velin Voynov

Aisling Hennessy

Marjory Maclennan

Tareq Abdullah

Carolyn Bedi

Douglas Ferguson

Sunil Amonkar

Biswajit Ray

Kaustuv Das

Nicholas Holford

Werbena Hamilton-Burke

Kartikae Grover

Hussein Tuffaha

Musa Barkeji

Rishi Parmeshwar

Subodh Seth

Emma MacInnes

Monika Kaushik

Saira Khawaja

Lai Cheng Yew

Debashis Ghosh

Neeraj Garg

Katherine Krupa

Daniel Leff

Ruth James

Anjana Satpathy

Brinda Sethugavalar

Amanda Taylor

Henry Cain

Pankaj Roy

Abdulla Alhasso

Saed Ramzi

Tamara Kiernan

Tahir Masudi

Lee Min Lai

Muhammed Baki

Matei Dordea

Sekhar Marla

Zoe Goldthorpe

Lubna Noor

Duncan Wheatley

Daniel Glassman

Abdul Syed

Konstantinos Zacharioudakis

Shaveta Mehta

Raman Vinayagam

Raghavan Vidya

Caroline Osborne

Bhavani Rengabashyam

The aim of this study is to assess whether, omitting further axillary treatment (ALND and ART) for patients with early stage breast cancer and axillary nodal metastases on needle biopsy, who after NACT have no residual cancer in the lymph nodes on sentinel node biopsy, is non-inferior to axillary treatment in terms of disease free survival (DFS) and results in reduced risk of lymphoedema at 5 years.

Background: The presence of cancer in the axillary lymph nodes on needle biopsy in patients with early stage breast cancer before neoadjuvant chemotherapy (NACT) has been the determinant of the need for axillary treatment (in the form of axillary lymph node dissection (ALND) or axillary radiotherapy (ART)) after completion of NACT. Treatment to the axilla damages lymphatic drainage from the arm and patients can subsequently develop lymphoedema, restricted shoulder movement, pain, numbness, and other sensory problems. As more effective chemotherapy is now available that results in complete eradication of cancer in the axilla in around 40 to 70% of patients, extensive axillary treatment might no longer be necessary in patients with no evidence of residual nodal disease.

Aim: To assess whether, omitting further axillary treatment (ALND and ART) for patients with early stage breast cancer and axillary nodal metastases on needle biopsy, who after NACT have no residual cancer in the lymph nodes on sentinel node biopsy, is non-inferior to axillary treatment in terms of disease free survival (DFS) and results in reduced risk of lymphoedema at 5 years.

Methods:

Study design: A pragmatic, phase 3, open, randomised, multicentre trial and embedded economic evaluation in which participants will be randomised in a 1:1 ratio.

Study population: T1-3N1M0 breast cancer patients aged 18 years or older, with needle biopsy proven nodal metastases, who after NACT have no residual cancer in the lymph nodes on dual tracer sentinel node biopsy and removal of at least 3 lymph nodes (sentinel nodes and marked involved node).

Intervention: All participants will receive human epidermal growth factor receptor 2 (HER2)-targeted treatment, endocrine therapy and radiotherapy to breast or chest wall, if indicated according to local guidelines. Patients in the intervention group will not receive further axillary treatment (ALND or ART), whereas those receiving standard care will receive axillary treatment (ALND or ART) as per local guidelines. Follow-up is annually for at least 5 years.

Outcomes: The co-primary outcomes are disease free survival(DFS) and self-reported lymphoedema defined as 'yes' to the two questions participants will be asked - 'arm heaviness during the past year' and 'arm swelling now' from the Lymphoedema and Breast Cancer Questionnaire at 5 years.

Secondary outcomes: arm function assessed by the QuickDASH (disabilities of the arm, shoulder and hand) questionnaire; health related quality of life assessed using euroqol EQ-5D-5L; axillary recurrence free interval (ARFI); local recurrence; regional (nodal) recurrence; distant metastasis; overall survival; contralateral breast cancer; non-breast malignancy; costs; quality adjusted life years (QALYs) and cost-effectiveness.

Sample size: A sample size of 1900 patients would have the ability to demonstrate a 3.5% non-inferiority margin with a 5% 1-sided significance level and 85% power, allowing for 7% non-collection of primary outcome data assuming a 90% 5-year disease free survival rate in the control arm. It would also be able to detect at least a 5% difference in proportion of patients with lymphoedema with 90% power, a 5% 2-sided significance level and allowing for 25% non-collection of primary outcome data over 5 years.

Analysis plan: All analyses will be carried out on an intention-to-treat basis to preserve randomisation, avoid bias from exclusions and preserve statistical power. Time to event outcomes, including disease free survival and axillary recurrence free interval, will be assessed using Kaplan-Meier curves and compared using Cox proportional hazards models. The proportion of patients experiencing lymphoedema at 5 years will be compared across trial arms using a chi-squared test and a logistic regression model used to adjust for stratification variables. Arm morbidity and health related quality of life will be scored using the appropriate manuals and assessed using a longitudinal mixed model regression analysis if model assumptions valid or a standardised area-under-the-curve analysis. For economic evaluation, incremental cost per QALY gained at 5 years will be estimated.

Timelines for delivery: Total project duration is 120 months based on 6 months for set up; 60 months recruitment period (including an 18 months internal pilot phase); and 54 months for follow up, analysis, writing up and dissemination.

Axillary Management in Breast Cancer Patients With Needle Biopsy Proven Nodal Metastases After Neoadjuvant Chemotherapy

ATNEC - Axillary Management in T1-3N1M0 Breast Cancer Patients With Needle Biopsy Proven Nodal Metastases at Presentation After Neoadjuvant Chemotherapy

DFS calculated as the time from randomisation until the date of first event of either a loco-regional invasive breast cancer relapse, distant relapse, ipsilateral or contralateral new invasive primary breast cancer or death by any cause or the censor date.

Lymphoedema is self-reported based on two items from the validated Lymphoedema and Breast Cancer Questionnaire (arm "swelling now" and arm "heaviness in the past year"). Lymphoedema is defined as 'yes' to both questions.

Arm function will be assessed using shortened version of the Disability of the Arm, Shoulder and Hand (DASH), the 11-item QuickDASH questionnaire. Physical disability is defined as a change from baseline in the QuickDASH score of at least 14 points.

Health related quality of life will be assessed with EQ-5D-5L

Axillary recurrence free interval, calculated from the date of randomisation to the date of axillary recurrence or the censor date.

Overall survival calculated as the time from randomisation until the date of death by any cause or the censor date.

Number of participants with local (breast or chest wall) recurrence

Number of participants with regional (nodal) recurrence

Number of participants with distant metastasis.

Number of participants with contralateral breast cancer.

Number of participants with non-breast cancer

University Hospitals of Derby and Burton NHS Foundation Trust

Consultant Oncoplastic Breast Surgeon & Associate Professor

Antineoplastic Agents

All Drugs and Chemicals

Epirubicin

adjuvant standard CMF given from 1988 to 1996

Adjuvant EC chemotherapy given from 1988 to 1996

High dose epirubicin (HEC) given from 1988 to 1996

Patients will be submitted to extensive cardiac evaluation several years after completion of adjuvant chemotherapy

cardiac MRI

Evandro de Azambuja, MD, PhD

Late Cardiac Evaluation of the Three Arm Belgian Trial A phase III randomized trial involving node-positive early breast cancer patients with a long median follow-up (\~ 15 years)

OBJECTIFS

Primary:

• To compare the incidence of late cardiac events between anthracycline and non-anthracycline chemotherapy given to node-positive breast cancer patients in the Belgian three arm randomized clinical trial

Secondary:

* To compare the late incidence of cardiac events between higher and lower dose anthracycline treated node-positive breast cancer patients;
* To compare anthracyclines (higher and lower doses) and non-anthracycline chemotherapy for:
* left ventricular diastolic function assessed by Echo
* exercise capacity assessed by 6-minute walk test (6MWT)
* cardiac morphology (myocardial inflammation or injury, fibrosis, LVEF) assessed by MRI
* serum cardiac biomarkers (BNP and TNT)
* patient-reported cardiac symptoms
* patient-reported cardiac symptoms assessed by QOL questionnaires are associated with subclinical findings on LVEF assessment
* cognitive function, functional autonomy, and psychological distress

The primary objective of this study is to compare the incidence of cardiac events \[(defined as asymptomatic systolic dysfunction (LVEF \< 50%, asymptomatic NYHA I) or symptomatic heart failure NYHA class II-IV either by Echo and/or by clinical exam (LVEF \< 50% and heart failure symptoms)\] between anthracycline and non-anthracycline chemotherapy treated node-positive breast cancer patients in a long-term follow-up. We will define a binary status for each patient: no cardiac event / one or more cardiac events. Analysis of the primary endpoint will involve a comparison of the CMF-treated patients versus the pooled anthracycline treated patients (EC and HEC). If a significant difference is detected, all paired comparisons will also be performed for the primary endpoint (CMF versus EC, CMF versus HEC, EC versus HEC).

Late Cardiac Evaluation of the Three Arm Belgian Trial Involving Node-positive Early Breast Cancer Patients

Late Cardiac Evaluation of the Three Arm Belgian Trial A Phase III Randomized Trial Involving Node-positive Early Breast Cancer Patients With a Long Median Follow-up (~ 15 Years)

The primary objective of this study is to compare the incidence of cardiac events \[(defined as asymptomatic systolic dysfunction (LVEF \< 50%, asymptomatic NYHA I) or symptomatic heart failure NYHA class II-IV either by Echo and/or by clinical exam (LVEF \< 50% and heart failure symptoms)\] between anthracycline and non-anthracycline chemotherapy. Analysis of the primary endpoint will involve a comparison of the CMF-treated patients versus the pooled anthracycline treated patients (EC and HEC).

* To compare the late incidence of cardiac events between higher and lower dose anthracycline treated node-positive breast cancer patients;
* To compare anthracyclines (higher and lower doses) and non-anthracycline chemotherapy for: LVEF assessed by Echo; exercise capacity assessed by 6-minute walk test; cardiac morphology assessed by MRI; serum cardiac biomarkers; patient-reported cardiac symptoms assessed by QOL questionnaires; cognitive function, functional autonomy, and psychological distress

Centre Hospitalier Universitaire de Tivoli

Clinique Sainte Elisabeth

Centre Hospitalier Jolimont-Lobbes

Réseau Hospitalier Médecine Sociale d'Ath

Hôpital de Braine-l'Alleud

Jules Bordet Institute

Recurrence

Women aged 18-65 years with a newly diagnosed locally advanced or high risk operable breast cancer

Women aged 18-65 years newly diagnosed with LABC/high risk who are willing and able to complete cognitive testing.

Healthy women aged 18-65 years who are willing and able to complete cognitive testing.

Women newly diagnosed locally advanced or high risk breast cancer that qualify for cognitive testing but have a condition related to elevated serum levels of cytokines or other inflammatory markers.

Lori Bernstein, PhD

Bostjan Seruga, MD

Women with breast cancer undergo treatments that decrease the chance of recurrence of cancer, but are associated with several side effects, including declines in memory and attention and other thinking abilities. The causes of these declines are not known. However, we know that (i) people with cancer may have high levels of molecules in the blood (cytokines) that reflect inflammation; (ii) injection of cytokines into animals, and their use to treat some human diseases, can lead to decreased memory and attention; and (iii) in some advanced cancers cytokines predict disease outcome. This longitudinal study evaluates the relation of cytokines to decreased thinking abilities and to disease outcome over time. Results of this study may help develop interventions to prevent or minimize cognitive decline and identify women who are at high risk for recurrence, and such information could be used in treatment decisions and in the development of new treatment options.

SCIENTIFIC ABSTRACT Background: Women with locally advanced breast cancer (LABC), and women with high risk (T2-3/N+4, triple negative) yet operable breast cancer, undergo combined treatment including chemotherapy, surgery, irradiation, and hormonal treatment. These treatments decrease the chance of recurrence of cancer, but are associated with several side effects, including cognitive difficulties. About one third of breast cancer patients treated with chemotherapy report sustained decline in thinking abilities ('chemofog') after treatment. The causes for cognitive declines are not known. However there is recent information that: (i) people with cancer may have high levels of cytokines and other inflammatory molecules in the blood; (ii) injection of cytokines into animals, and their use to treat some human diseases, can lead to problems in memory and other cognitive abilities; (iii) some survivors of breast cancer have very high cytokine levels with no evidence that their cancer is still active and (iv) in some advanced cancers different cytokines and other inflammatory markers have prognostic information for disease outcome. Genetic polymorphisms of neuronal proteins (APOe, BDNF, COMT) are predictive for cognitive decline in non-cancer population). Objective: This longitudinal study will determine whether serum levels of cytokines and other inflammatory markers are related to 1) cognitive dysfunction; and 2) recurrence of disease in women with LABC/High Risk. Method: In 120 women with LABC/High risk relation of cytokines and inflammatory markers to cancer recurrence will be evaluated; blood will be drawn pre-chemotherapy, pre-surgery and then 1 and 2 years after diagnosis. In a subset of 60 women with LABC/high risk, cognitive performance will be evaluated at similar times as blood will be drawn. Similarly, a control group of 60 healthy women will be evaluated for cytokines and cognitive performance. We will also evaluate the predictive role of polymorphisms in genes encoding the neuronal proteins APOe, BDNF, and COMT for cognitive impairment. Data Analysis: The impact of cytokine levels and other inflammatory markers on cognitive performance over time will be evaluated using mixed model regression. Multivariate model will be applied to assess the impact of LABC/high risk and chemotherapy on cognitive functions. Cox proportional-hazard model will evaluate the relationship of cytokines and other blood markers on Time-To-Progression to identify variables that predict reoccurrence. Hypotheses: Cytokines and inflammatory markers are related to cognitive impairment and in disease outcome in women with locally advanced and high risk operable breast cancers. Genetic polymorphisms of neuronal proteins (APOe, BDNF, and COMT) are predictive for increased cognitive decline after diagnoses and treatment of these cancers. Implications: Increased knowledge about the causes of cognitive problems in women with breast cancer should allow development of strategies to prevent or minimize these unpleasant symptoms. Cytokines and other biomarkers might be predictive for disease outcome in women with breast cancer and used in tailoring of adjuvant treatment and as potential targets in development of new therapies.

Using Bio Markers to Predict Disease Recurrence and Cognitive Function in High Risk Breast Ca

Role of Inflammatory Markers in Predicting Disease Recurrency and Cognitive Performance in Women With High Risk and Locally Advanced Breast Cancer

University Health Network, Toronto

Antirheumatic Agents

Anti-Infective Agents

Paclitaxel

Cyclophosphamide

Doxorubicin

Liposomal doxorubicin

Albumin-Bound Paclitaxel

Sorafenib

Tubulin Modulators

Antimitotic Agents

Immunosuppressive Agents

Immunologic Factors

Antineoplastic Agents, Alkylating

Alkylating Agents

Anti-Bacterial Agents

Antibiotics, Antitubercular

Enzyme Inhibitors

Protein Kinase Inhibitors

All patients received doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 (AC) both administered intravenously day 1 every 3 weeks for four cycles, followed by paclitaxel 175 mg/m2 intravenously day 1 every 3 weeks for four cycles or 80 mg/m2 for twelve weeks (physician discretion), combined with sorafenib 400 mg orally twice daily. Sorafenib was held during radiation therapy where indicated and resumed once completed. Sorafenib was continued for a total of 12 months and in combination with adjuvant hormonal therapy where indicated.

Denise Yardley, M.D.

Sorafenib is being looked at in a number of solid tumor settings including breast cancer. This trial is designed as a pilot study to assess the safety and tolerability of a novel oral agent in combination with standard chemotherapy in the treatment of early stage node positive or otherwise high-risk breast cancer. If this should prove to be a tolerable regimen for patients, this would provide rationale for further studies in a larger randomized fashion.

Primary Objectives The primary objective is to assess the safety and tolerability of doxorubicin / cyclophosphamide followed by paclitaxel in combination with sorafenib in patients with early stage node positive or otherwise high-risk breast cancer.

Secondary Objectives The secondary objectives are to assess activity in the form of recurrence-free-interval, distant recurrence-free interval,and overall survival in this pilot study of doxorubicin / cyclophosphamide followed by paclitaxel in combination with sorafenib in patients with early stage node positive or otherwise high-risk breast cancer.

Adjuvant Doxorubicin/Cyclophosphamide and Paclitaxel Plus Sorafenib Breast Cancer

A Pilot Study of Adjuvant Doxorubicin and Cyclophosphamide Followed by Paclitaxel Plus Sorafenib in Women With Node Positive or High-Risk Early Stage Breast Cancer

Bayer

SCRI Development Innovations, LLC

Doxorubicin/Cyclophosphamide Then Paclitaxel/Sorafenib

Doxorubicin 60mg/m2 IV, Cyclophosphamide 600mg/m2 IV every 3 weeks for a total of 12 weeks followed by 12 weeks of paclitaxel (either 175mg/m2 IV every three weeks or 80mg/m2 IV weekly) and sorafenib 400mg twice daily by mouth (up to a maximum of 1 year).

Age Continuous

Sex: Female, Male

United States

Region of Enrollment

John Hainsworth, MD

The Safety and Tolerability of Protocol Treatment, Defined as the Percentage of Patients Experiencing Severe or Life-threatening Side Effects Per CTCAE Version 3.0.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Axillary Management in Breast Cancer Patients With Needle Biopsy Proven Nodal Metastases After Neoadjuvant Chemotherapy	NCT04109079	Breast Cancer Sentinel Lymph ... Neoplasm, Breas...	Axillary lymph ... Axillary radiot... Breast or chest...	18 Years -	University Hospitals of Derby and Burton NHS Foundation Trust
Late Cardiac Evaluation of the Three Arm Belgian Trial Involving Node-positive Early Breast Cancer Patients	NCT01554943	Breast Cancer	cardiac MRI	18 Years - 90 Years	Jules Bordet Institute
Using Bio Markers to Predict Disease Recurrence and Cognitive Function in High Risk Breast Ca	NCT00756132	Locally Advance... Breast Cancer		18 Years - 65 Years	University Health Network, Toronto
Late Cardiac Evaluation of the Three Arm Belgian Trial Involving Node-positive Early Breast Cancer Patients	NCT01554943	Breast Cancer	cardiac MRI	18 Years - 90 Years	Jules Bordet Institute
Adjuvant Doxorubicin/Cyclophosphamide and Paclitaxel Plus Sorafenib Breast Cancer	NCT00544167	Breast Cancer	Doxorubicin Cyclophosphamid... Paclitaxel Sorafenib	18 Years -	SCRI Development Innovations, LLC
Adjuvant Doxorubicin/Cyclophosphamide and Paclitaxel Plus Sorafenib Breast Cancer	NCT00544167	Breast Cancer	Doxorubicin Cyclophosphamid... Paclitaxel Sorafenib	18 Years -	SCRI Development Innovations, LLC

Spots Global Cancer Trial Database for node positive