OPTimizing Irradiation Through Molecular Assessment of Lymph Node (OPTIMAL)

Study Overview
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Brief Summary
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The main purpose of this study is to show the non-inferiority of the incidental irradiation, as compared to intentional irradiation of the axillary nodes, in terms of 5-years disease-free survival (DFS) of early stage breast cancer patients with limited affectation of sentinel node assessed by OSNA (250 to 15,000 copies/uL), treated with breast-conservative surgery without axillary lymphadenectomy.

Detailed Description
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Since long, the standard loco-regional treatment of the early-stage breast cancer is breast conservative surgery (tumorectomy) followed by a selective biopsy of the sentinel lymph node and, if positive, lymphadenectomy of axillary levels I and II. Complementary irradiation of the breast and ganglionar areas has shown to reduce disease-specific mortality. Therefore, adjuvant radiotherapy of the whole breast is currently indicated after conservative surgery. The recommendation to irradiate axillary lymph nodes is clear in patients with more than three affected nodes. The standard volumes to irradiate after lymphadenectomy include supraclavicular and level III axillary regions, while axillary levels I and II, and the internal breast lymph node chain, are reserved for cases of cumbersome axillary affectation, patients who have not undergone lymphadenectomy or it was insufficient, or affectation of the internal breast lymph node chain. However, when only 1 to 3 nodes are affected, there is no unanimity on the recommendation of radiotherapy, despite some studies have shown that irradiation improves survival. In addition, the National Cancer Institute of Canada trial (NCIC-CTGMA20), high risk patients with negative lymph nodes and patients with positive lymph nodes (most of them with 1 to 3 affected nodes) showed that local irradiation with or without regional lymph node irradiation improved disease-free survival, as well as loco-regional and distant disease control. Moreover, a systematic review including more than 20,000 patients from 45 studies concludes that the irradiation of the breast reduced the loco-regional relapse, even in patients without affected lymph nodes. One Step Nucleic Acid Amplification (OSNA) is a technique developed by Sysmex Corporation that allows a readily and complete analysis of sentinel lymph nodes during surgery. OSNA provides a quantification of the Cytokeratin 19 (CK19) tumour cell marker in the messenger ribonucleic acid (mRNA) of the sentinel node, the result being expressed as total tumour load (TTL), which is a discrete number of copies per microliter. This technique has shown ability to discriminate macrometastasis, micrometastasis or negativity, and to predict affectation of non-sentinel lymph nodes. According to previous results, a TTL < 15,000 is associated with a 85% probability of non-affectation of (non-sentinel) axillar lymph nodes. The therapeutic value of the axillary lymphadenectomy has been questioned since long, and the recent publication of the Z0011 study proposes solely a selective biopsy of the sentinel lymph node. This has impacted clinical practice guidelines as prestigious as those of the National Comprehensive Cancer Network; however, irradiation is always considered in these cases. In summary, the amount of nodal volumes to irradiate in early stages of breast cancer is under discussion, particularly in the case of patients not submitted to axillar lymphadenectomy despite affectation of sentinel lymph nodes. In most cases, the irradiation of the breast implies incidental irradiation of the axillary level I, and in some cases the level II. For this reason, some groups have decided not to irradiate these axillary regions intentionally, while others advocate irradiating these regions intentionally.

Official Title
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OPTimizing Irradiation Through Molecular Assessment of Lymph Node (OPTIMAL)

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, ductal carcinoma of the breast. Treated with conservative surgery (tumorectomy or quadrantectomy) without lymphadenectomy. Sentinel lymph node assessed by OSNA, with TTL in the range 250 - 15,000 copies/μL. Age ≥ 18 yrs old. Karnofsky Index ≥ 70 %. Signed Informed Consent. Exclusion Criteria: Other types of breast cancer different from infiltrating ductal carcinoma. Bilateral breast cancer. Males. Mastectomy or axillary homolateral lymph node dissection. Previous thoracic irradiation therapy. Systemic neoadjuvant therapy previous to surgery. Contraindications of radiotherapy (pregnancy, severe collagen diseases). Other neoplasms. Severe associated comorbidities that, according to the investigator criteria, may interfere with the study evaluations.

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 |
| --- | --- |
| Other: Intentional irradiation of lymph nodes<br>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>* Intentional versus incidental 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: Incidental irradiation of lymph nodes<br>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>* Intentional versus incidental 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 |
| --- | --- | --- |
| Disease Free Survival | 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 |
| --- | --- | --- |
| Time to loco-regional recurrence up 5-years | Loco-regional recurrence during the 5-years follow-up, defined as clinical or image-based detection of tumour in treated breast (local recurrence) or in the ipsilateral axilla or supraclavicular fossa (regional recurrence). | 5 years | 
| Time to distant recurrence up 5-years | Distant recurrence occuring during the 5-years follow-up, defined as 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. | 5 years | 
| Number of patients with acute toxicity, defined as any adverse event appearing up to one month after finalization of radiotherapy. | Acute toxicity, assessed by a selected subset of the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) | 7 years | 
| Number of patients with chronic toxicity, defined as any adverse event appearing during follow-up, up to 5 years. | Chronic toxicity , assessed by a selected subset of the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) | 7 years | 
| Total irradiation dose (Gy) received in axillary levels I, II and III, supraclavicular fossa, and internal mammary chain volumes, at the end of radiotherapy. | Total dose (Gy) received in axillary levels I, II,and II, supraclavicular, and internal mammary chain volumes. | 2 years |