OPTimizing Irradiation through Molecular Assessment of Lymph node (OPTIMAL): a randomized clinical trial.

BACKGROUND AND PURPOSE: In breast cancer (BC) patients, the involvement of four or more lymph nodes (LN) is an indication of regional irradiation. The optimal treatment strategy remains unclear when fewer nodes are involved and lymphadenectomy is not performed. We designed a clinical trial to show the non-inferiority of Incidental (INC) compared to intentional (INT) irradiation of axillary nodes in patients with early-stage BC and low burden LN involvement. MATERIALS AND METHODS: BC patients, cN0 (n = 487) undergoing breast conservation surgery and sentinel node biopsy, with total tumor load assessed by OSNA (One-Step Nucleic Acid Amplification) of 250-15,000 copies mRNA CK19/µL in sentinel LN were randomized to receive INC or INT nodal irradiation. The primary endpoint was 5-year disease-free survival (DFS). Secondary endpoints were locoregional recurrence (LRR), distant recurrence (DR), and acute and chronic toxicity (CT). RESULTS: Five-years DFS were 93.7% (INC) and 93.8% (INT) (difference 0.1% [one-sided 95% CI < 5.7%]; non-inferiority p = 0.075). Cumulative Incidences of LRR were 3.5% (INC) and 3.4% (INT) (difference of 0.1% [<4.8%]; p = 0.021), and 5% (INC) and 3.5% (INT) (difference 1.4% [<6.0%]; non-inferiority p = 0.101) for DR. CT was more Incident with INT (26.9%) than with INC (19.2%), though the difference was not statistically significant (HR 1.39 [95% CI: 0.92, 2.10]; p = 0.11). CONCLUSION: Intentional does not outperform incidental irradiation by more than 5.7% in terms of 5-year DFS, 4.8% for LRR, and 6% for DR. REGISTRATION NUMBER: ClinicalTrials.gov Identifier: NCT02335957.

OPTimizing Irradiation through Molecular Assessment of Lymph node (OPTIMAL): a randomized open label trial.

BACKGROUND: Conservative surgery followed by breast and nodal irradiation is the standard loco-regional early breast cancer (BC) treatment for patients with four or more involved lymph nodes. However, the treatment strategy when fewer nodes are involved remains unclear, especially when lymphadenectomy has not been performed. Sensitive nodal status assessment molecular techniques as the One-Step Nucleic Acid Amplification (OSNA) assay can contribute to the definition and standardization of the treatment strategy. Therefore, the OPTIMAL study aims to demonstrate the feasibility of incidental irradiation of axillary nodes in patients with early-stage BC and limited involvement of the SLN. METHODS: BC patients who underwent conservative surgery and whose SLN total tumour load assessed with OSNA ranged between 250-15,000 copies/µL will be eligible. Patients will be randomized to receive irradiation on the breast, tumour bed, axillary and supraclavicular lymph node areas (intentional arm) or only on the breast and tumour bed (incidental arm). All areas, including the internal mammary chain, will be contoured. The mean, median, D5% and D95% doses received in all volumes will be calculated. The primary endpoint is the non-inferiority of the incidental irradiation of axillary nodes compared to the intentional irradiation in terms of 5-year disease free survival. Secondary endpoints comprise the comparison of acute and chronic toxicity and loco-regional and distant disease recurrence rates. DISCUSSION: Standardizing the treatment and diagnosis of BC patients with few nodes affected is crucial due to the lack of consensus. Hence, the quantitative score for the metastatic burden of SLN provided by OSNA can contribute by improving the discrimination of which BC patients with limited nodal involvement can benefit from incidental radiation as an adjuvant treatment strategy. TRIAL REGISTRATION: ClinicalTrial.gov, NCT02335957; https://clinicaltrials.gov/ct2/show/NCT02335957.

Irradiación de áreas ganglionares en pacientes sin linfadenectomía axilar / Axillary radiation in patients without axillary lymphadenectomy

La biopsia selectiva del ganglio centinela (BSGC) es actualmente una propuesta estándar para la estadificación de la axila en pacientes con cáncer de mama con una clara tendencia a minimizar la cirugía axilar incluso en presencia de ganglio centinela (GC) positivo. En caso de GC negativo la BSGC ha reemplazado a la linfadenectomía axilar (LA) demostrando equivalente supervivencia, mientras que los más sólidos consensos (American Society of Clinical Oncology) y, hasta fechas recientes, las guías de la National Comprehensive Cancer Network recomendaban completar la LA cuando se identifican metástasis en el GC. Esto da como resultado un excelente control locorregional y proporciona información que permite tomar decisiones sobre tratamientos adyuvantes tanto al oncólogo médico como al oncólogo radioterápico. No obstante, en los últimos tiempos múltiples estudios han debatido el valor terapéutico de la linfadenectomía quirúrgica, cobrando especial relevancia a raíz de la publicación del ensayo del American College of Surgeons Oncology Group (ACOSOG) Z0011, en el que se cuestiona el valor de esta actitud terapéutica y se propone únicamente una BSGC, omitiéndose la LA, en pacientes seleccionadas con uno o 2 GC positivos. La evidencia científica nos dice que la radioterapia puede jugar un papel fundamental en el control de la enfermedad axilar y, a fecha de hoy, no sabemos si la baja tasa de recidiva a este nivel, en los estudios mencionados, puede estar influida por la irradiación de la mama y axila inferior. Serían necesarios estudios con un diseño apropiado para contestar esta pregunta. En ausencia de más datos, nuestra propuesta es la irradiación axilar valorando individualmente los factores de riesgo de recidiva locorregional(AU)

Sentinel lymph node biopsy (SLNB) is currently a standard approach for staging of the axilla in patients with breast cancer, with a clear tendency to minimize surgery even in the presence of a positive axillary sentinel lymph node (SLN). The strongest consensus (American Society of Clinical Oncology) and, until recently, the National Comprehensive Cancer Network guidelines used to recommend complete axillary lymphadenectomy when metastases were identified in the SLN. However, SLNB has replaced axillary lymphadenectomy in SLN-negative patients and has demonstrated equivalent survival. This approach results in excellent locoregional control and provides information that allows both the medical oncologist and the radiation oncologist to take decisions about adjuvant treatments. Many recent studies, however, have debated the therapeutic value of surgical lymphadenectomy. This debate has become particularly important after the publication of the trial of the American College of Surgeons Oncology Group (ACOSOG) Z0011, which questions the value of this therapeutic approach and proposes SLNB alone, without lymphadenectomy, in selected patients with one or 2 positive SLN. The scientific evidence indicates that radiotherapy may play a major role in the control of axillary disease and, to date, it is not known whether the low recurrence rate in the axilla reported in the above-mentioned studies may have been influenced by radiation of the breast and lower axilla. To answer this question, new and appropriately designed trials are needed. In the absence of more data, we propose the use of axillary radiation, but with assessment of the risk factors for locoregional recurrence in each patient(AU)