Award Title: POSNOC - POsitive Sentinel NOde: adjuvant therapy alone versus adjuvant therapy plus Clearance or axillary radiotherapy: A randomised controlled trial of axillary treatment in women with early stage breast cancer who have metastases in one or two sentinel nodes
Funder: Department of Health and Social Care

Abstract: Women with early breast cancer usually have this removed either by breast conserving surgery (lumpectomy) or removal of the whole breast (mastectomy). During the operation, one or two lymph nodes (glands) are removed from the armpit (axilla) to check if the cancer has spread to them, a procedure called sentinel node biopsy. A quarter of women, have cancer in these nodes. Current practice is to offer these women chemotherapy and/or hormone therapy, plus axillary treatment. Axillary treatment is either further surgery to remove all the remaining nodes from the armpit (axillary node clearance) or axillary radiotherapy. Of patients who have axillary node clearance, less than half have cancer in the remaining glands. Both axillary node clearance and axillary radiotherapy can lead to troublesome long term problems: the most common being arm swelling (lymphoedema), restricted shoulder movement, and sensory changes in the arm and hand. As well as being difficult for the patients, these complications are costly for the NHS. As breast cancer is now detected earlier, and we now have much better and more effective chemotherapy and hormone therapy than in the past, axillary treatment may no longer be necessary. _x000D_
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A recent randomised trial suggested that routine axillary treatment may not be worthwhile. However, this study was not of high enough quality or large enough to provide reliable evidence about the short term and the long term effects (recurrence of cancer). This proposal aims to provide such evidence. _x000D_
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Our study will recruit 1900 women diagnosed with early breast cancer and cancer in their sentinel node biopsy. Patients will be randomised either to adjuvant therapy alone, or to adjuvant therapy plus axillary treatment (axillary lymph node clearance or axillary radiotherapy). Adjuvant therapy is systemic chemotherapy and/or hormone therapy, with radiotherapy to the breast or chest wall if indicated. The main outcome in this trial is recurrence of the cancer within 5 years; other outcomes are complications from the treatment, quality of life, anxiety, spread of cancer to other areas of the body and death. Information about the participants will be collected at clinic visits or over the telephone, and they will also be asked to complete postal questionnaires for the first 3 years.

Lay Abstract: Design: Pragmatic randomised, multicentre, non-inferiority trial._x000D_
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Setting: Hospital breast units, outpatient and inpatient._x000D_
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Target population: Women with operable, core biopsy proven, early stage invasive breast cancer, who have had either breast conserving surgery or mastectomy, and are sentinel node positive(i.e. they have metastasis in the sentinel node). In hospitals where sentinel node histology is checked intra-operatively, at the same time as the breast surgery, women will consent pre-operatively and then randomised intra-operatively if their sentinel nodes are found to be positive._x000D_
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Inclusion criteria_x000D_
Women will be eligible for inclusion only if ALL of the following criteria apply:_x000D_
  • 18 years or older_x000D_
  • Unifocal or multi-focal invasive tumour with lesion not greater than 5 cm in its largest dimension, measured pathologically or for women who are randomised intra-operatively largest tumour diameter on mammogram or ultrasound_x000D_
  • No axillary nodal metastasis on clinical and ultrasound examination_x000D_
  • At sentinel node biopsy have 1 or 2 sentinel nodes with macrometastases (tumour deposit >2.0 mm in largest dimension or defined as macrometastasis on molecular assay) _x000D_
  • Fit for axillary treatment and adjuvant therapy  _x000D_
  • Have given written informed consent _x000D_
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Exclusion criteria_x000D_
Women will be excluded if they have :_x000D_
  • bilateral breast cancer_x000D_
  • more than 2 sentinel node macrometastases or extranodal invasion_x000D_
  • neoadjuvant therapy for breast cancer_x000D_
  • previous axillary surgery on the same body side as the scheduled sentinel node biopsy_x000D_
  • not fit or eligible to receive adjuvant systemic therapy _x000D_
  • previous or concomitant malignancy except_x000D_
     o adequately treated basal or squamous cell carcinoma of the skin or_x000D_
     o adequately treated in situ carcinoma of the cervix or_x000D_
     o adequately treated in situ melanoma _x000D_
     o contra- or ipsilateral in situ breast cancer_x000D_
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Health technologies being assessed: This trial compares adjuvant therapy alone with adjuvant therapy plus axillary treatment(axillary lymph node clearance or axillary radiotherapy). Adjuvant therapy will be based on current guidelines, and will include chemotherapy and/or hormone therapy for all women, and radiotherapy to breast or chest wall if indicated. Human epidermal growth factor receptor 2 (HER2) targeted treatment may be administered when indicated. Axillary and supraclavicular fossa radiotherapy is not allowed when randomised to adjuvant therapy alone. _x000D_
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Study assessments: Baseline data will be collected from the participant's medical notes and questionnaires._x000D_
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Follow-up Assessments_x000D_
Follow-up will be at 6, 12, 24, 36, 48 and 60 months post-randomisation. The 36 and 60 months follow-up will be a clinic visit (doctor or nurse led), however follow-up at other time points may be conducted by a research nurse over the telephone, according to local practice. _x000D_
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Assessments: _x000D_
  1. Follow-up eCRFs will be completed in the clinic or over the telephone to record information on primary and secondary outcomes at 6, 12, 24, 36, 48 and 60 months,_x000D_
  2. Lymphoedema and Breast Cancer Questionnaire (two questions) and QuickDASH questionnaire will be completed in the clinic or over the telephone at 6, 12, 24 and 36 months, _x000D_
  3. Postal questionnaires with up to two reminders, FACT B+4, Spielberger State/Trait Anxiety Inventory and EQ-5D at 3, 6, 12, 24 and 36 months. _x000D_
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Primary Outcome_x000D_
The primary outcome is axillary recurrence at 5 years._x000D_
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Secondary Outcomes_x000D_
Secondary outcomes assessed at 3, 6, 12, 24 and 36 months are:_x000D_
  • Arm morbidity_x000D_
  • Quality of life _x000D_
  • Anxiety _x000D_
  • Economic outcomes_x000D_
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Secondary outcomes assessed at 6, 12, 24, 36, 48 and 60 months are:_x000D_
  • Local (breast or chest wall) recurrence_x000D_
  • Regional (nodal) recurrence _x000D_
  • Distant  metastasis _x000D_
  • Time to axillary recurrence _x000D_
  • Axillary recurrence free survival_x000D_
  • Disease free survival_x000D_
  • Overall survival_x000D_
  • Contralateral breast cancer_x000D_
  • Non-breast malignancy_x000D_
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Sample size: It is estimated that the axillary recurrence rate in the adjuvant therapy plus axillary treatment group at 5 years is 2%. With an absolute non-inferiority margin of 2%, to show that the axillary recurrence rate in the adjuvant therapy alone group at 5 years is not more than 4%, with a one-tailed test for non-inferiority, 1800 patients need to be randomised(with 80% power). Allowing for 5% lost to follow up over the 5 years, gives a sample size of 1900 women. _x000D_
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Project timetables including recruitment rate: Total project duration is 10 years_x000D_
  Set up (6 months): site training and initiation, awareness raising, developing Case Report Forms and database._x000D_
  Feasibility of recruitment (12 months): feasibility assessed based on total recruitment, number of active sites, compliance with the allocated treatment and losses to follow up_x000D_
  Recruitment(33 months): 50 sites recruiting, target recruitment 58 to 63 per month_x000D_
  Follow up(60 months): clinic visits or nurse led follow up and postal questionnaires_x000D_
  Analysis, writing up and dissemination(9 months)._x000D_
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Radiotherapy quality assurance: The sites will be required to adhere to the specific radiotherapy planning and delivery guidelines when treating participants in the study. The NCRI Radiotherapy Trials QA (RTTQA) group will be responsible for implementing and coordinating the Radiotherapy Quality Assurance programme.

Research Activity Codes: 6.1 PHARMACEUTICALS;6.4 SURGERY
Health Categories: CANCER AND NEOPLASMS