OPTimizing Irradiation Through Molecular Assesment of Lymph Node After Primary Systemic Treatment

Study Overview
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Brief Summary
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Breast cancer management integrating surgery, systemic therapy and radiation therapy tends to systemic treatment as the first therapeutic option, continuing afterwards by surgery and radiation therapy with the scope of decreasing the locoregional treatment. This strategy implies doubts about what should be the locoregional treatment, because many patients have remissions and a significant number of them a complete response. The responses are associated with better clinical outcome although there are doubts about they are a surrogate marker of survival. Nodal irradiation after systemic treatment in patients with breast cancer it is under discussion, particularly in the case of patients with initial clinical involvement experiencing complete remission. For this reason, some groups decide irradiation of all nodal regions and others choose no irradiation of the lymph nodes at all. To clarify this discussion the present study is proposed. The One Step Nucleic Amplification (OSNA) is a technique developed by Sysmex Corporation that allows a complete analysis of sentinel nodes and provides a quantification of the tumor marker Cytokeratin 19 (CK19) messenger ribonucleic acid (mRNA) in the sentinel node. The result is expressed by the Tumour Load as number of copies per microliter. This technique has shown its diagnostic ability both without primary systemic treatment and after primary systemic treatment, being more reproducible than conventional processes. In spite of this, fits to mention that the studies of validation used to obtain the European Conformity (CE) mark only included patients without previous systemic treatment to the surgery.

Detailed Description
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Breast cancer management integrating surgery, systemic therapy and radiation therapy tends to systemic treatment as the first therapeutic option, continuing afterwards by surgery and radiation therapy with the scope of decreasing the locoregional treatment. This strategy implies doubts about what should be the locoregional treatment, because many patients have remissions and a significant number of them a complete response. The responses are associated with better clinical outcome although there are doubts about they are a surrogate marker of survival. According to a previous publication, in which the predictors of locoregional recurrence National Surgical Adjuvant Breast and Bowel Project 18 (NSABP18) and National Surgical Adjuvant Breast and Bowel Project 27 (NSABP27) studies are evaluated, both studies designed for viewing the value of neoadjuvant chemotherapy, good results of locoregional control are described, although in many cases radiotherapy was omitted or lymph node were not irradiated. Therefore the need to nodal irradiation begins to be questioned, especially when they are negative after primary systemic treatment, regardless of their previous state. However the clinical guidelines recommend radiotherapy planning according to the previous stage. The problem is the local treatment indication is established based on the indications of irradiation without primary systemic therapy, as showed in retrospective studies, without the existence of randomized studies designed to analyze the role of radiotherapy in these circumstances. In the last American Society of Clinical Oncology (ASCO) preliminary results of a meta-analysis including three large studies of primary systemic treatment were presented. Results show that irradiation improves local control in N1 patients achieving a complete remission, radiotherapy being an independent prognostic factor, in terms of locoregional control; however, they conclude that the optimal selection of patients remains unclear. The controversy remains, because there is no evidence to treat nodes after primary systemic therapy, whether there is a complete remission as if it does not, nor is it known that subgroup of patients may benefit more from local treatments. Long-term studies are needed to analyze this issue, leaving the decision being especially complicated in cases of clinically positive nodes experiencing a complete remission. The problem remains that often is not known exactly has been irradiated since, in many studies, irradiation is indicated at the discretion of the researcher. Given these doubts, European Society conducted a survey to find out what was the attitude about these patients, and the findings shows that 75% of the centers irradiate in the N1 case. The American Society obtained similar results and in Spain 64% of respondents irradiate the lymph nodes. These three publications conclude that studies are needed to determine the importance of irradiation after primary systemic treatment and while waiting for these results, a consensus muts be reached as stated in ASCO 2015 summary. The One Step Nucleic Amplification (OSNA) is a technique developed by Sysmex Corporation that allows a complete analysis of sentinel nodes and provides a quantification of the tumor marker CK19 mRNA in the sentinel node. The result is expressed by the Tumour Load as number of copies per microliter. This technique has shown its diagnostic ability both without primary systemic treatment and after primary systemic treatment, being more reproducible than conventional processes. In spite of this, fits to mention that the studies of validation used to obtain the CE mark only included patients without previous systemic treatment to the surgery. In summary, nodal irradiation after systemic treatment in patients with breast cancer it is under discussion, particularly in the case of patients with initial clinical involvement experiencing complete remission. For this reason, some groups decide irradiation of all nodal regions and others choose no irradiation of the lymph nodes at all. To clarify this discussion the present study is proposed.

Official Title
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OPTimizing Irradiation Through Molecular Assesment of Lymph Node After Primary Systemic Treatment

Conditions
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Breast Cancer

Intervention / Treatment
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* Radiation: Irradiation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Infiltrating carcinoma of the breast. Metastatic lymph nodes (N1) at diagnosis, as determined histologically by Fine Needle Aspiration or Core Needle Biopsy. Primary systemic therapy (including antiestrogen or chemotherapy, and targeted therapies). Tumour surgery: tumorectomy, quadrantectomy or mastectomy. OSNA (ND) or - lymph nodes after primary systemic therapy. Age ≥ 18 years old. Karnofsky Index ≥ 70 %. Signed Informed Consent. Exclusion Criteria: Lymphadenectomy. Bilateral breast cancer. Males. Previous thoracic irradiation therapy. Contraindications of radiotherapy (pregnancy, severe collagen diseases). Other neoplasms. Severe associated comorbidities that, according to the investigator criteria, may interfere with the study evaluations. Lymp nodes OSNA -(L), +, ++ after primary systemic therapy. Sentinel lymph node biopsy previous to the primary systemic therapy. Mammary internal chain affected.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: BA3S<br>Radiotherapy (RT) will be administered, in the breast or thoracic wall, axillary levels I, II and III, and supraclavicular node areas, with optimization of the technique Intentional irradiation of lymph nodes: Patients will receive a total dose of 50 Gy in the whole breast and nodal areas (axillary I, II, III, and supraclavicular) with optimization of the technique, in daily fractions of 2 Gy and 5 fractions/week during 5 weeks. | Radiation: Irradiation<br>* BA3S versus BA2 irradiation of lymphatic node areas, administered using a lineal accelerator, after 3D delimitation of the supraclavicular and axillary levels I, II and III. In both treatment arms, further tumoral bed boost will be allowed according to the investigator criteria, whether dose contribution to the nodal areas can be calculated. Due to its nature, interventions cannot be asked.<br>|
| Experimental: BA2<br>RT will be administered, in the breast or thoracic wall and axillary levels I and II, with optimization of the technique Incidental irradiation of lymph nodes: Patients will receive a total dose of 50 Gy in the whole breast, but not aimed at nodal areas, with optimization of the technique, in daily fractions of 2 Gy and 5 fractions/week during 5 weeks. | Radiation: Irradiation<br>* BA3S versus BA2 irradiation of lymphatic node areas, administered using a lineal accelerator, after 3D delimitation of the supraclavicular and axillary levels I, II and III. In both treatment arms, further tumoral bed boost will be allowed according to the investigator criteria, whether dose contribution to the nodal areas can be calculated. Due to its nature, interventions cannot be asked.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To show the non-inferiority of (BA2) compared to (BA3S), in terms of 5-years diseasefree survival (DFS), including the local, regional and distant disease free survival and excluding second neoplasms | The primary outcome will be the 5-years DFS. DFS is defined as the time from randomization to any breast cancer-related event, including local, regional or distant recurrence, or death from breast cancer. | 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To compare the 5-years incidence of loco-regional tumor recurrence between BA2 and BA3S. | Loco-regional recurrence during the 5-years follow-up, defined as clinical or image-based detection of tumour in treated breast or thoracic wall (local recurrence) or in the ipsilateral axilla or supraclavicular fossa or internal mammary chain (regional recurrence). | 5 Years | 
| To compare the 5-years incidence of distant tumor recurrence between BA2 and BA3S | Distant recurrence rate occurring during the 5-years follow-up, defined as clinical or image-based detection of neoplastic affectation of other organs or tissues different from the treated breast, ipsilateral axilla or supraclavicular fossa or internal mammary chain. | 5 years | 
| To compare the acute and chronic toxicity of the two treatment modalities. | Toxicity, recorded using the Terminology Criteria for Adverse Events v4.0 (CTCAE). | 5 years |