OPTimizing Irradiation Through Molecular Assessment of Lymph Node (OPTIMAL)
NCT ID: NCT02335957
Last Updated: 2022-04-01
Study Results
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Basic Information
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COMPLETED
NA
489 participants
INTERVENTIONAL
2015-04-30
2021-07-31
Brief Summary
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Detailed Description
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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.
Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
NONE
Study Groups
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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.
Irradiation
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.
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.
Irradiation
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.
Interventions
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Irradiation
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.
Eligibility Criteria
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Inclusion Criteria
2. Treated with conservative surgery (tumorectomy or quadrantectomy) without lymphadenectomy.
3. Sentinel lymph node assessed by OSNA, with TTL in the range 250 - 15,000 copies/μL.
4. Age ≥ 18 yrs old.
5. Karnofsky Index ≥ 70 %.
6. Signed Informed Consent.
Exclusion Criteria
2. Bilateral breast cancer.
3. Males.
4. Mastectomy or axillary homolateral lymph node dissection.
5. Previous thoracic irradiation therapy.
6. Systemic neoadjuvant therapy previous to surgery.
7. Contraindications of radiotherapy (pregnancy, severe collagen diseases).
8. Other neoplasms.
9. Severe associated comorbidities that, according to the investigator criteria, may interfere with the study evaluations.
18 Years
FEMALE
No
Sponsors
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Grupo de Investigación Clínica en Oncología Radioterapia
OTHER
Responsible Party
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Esther Prats
ST
Principal Investigators
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Manuel Algara López, Medicine
Role: PRINCIPAL_INVESTIGATOR
Grupo de Investigación Clínica en Oncología Radioterápica (GICOR)
Locations
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Hospital de Perugia
Perugia, , Italy
Hospital Espírito Santo
Evora, , Portugal
Centro Hospitalar De São João
Porto, , Portugal
Hospital Distrital de Santarém
Santarém, , Portugal
Hospital de Cruces
Barakaldo, Bilbao, Spain
Hospital Universitario de Gran Canaria Dr. Negrín
Las Palmas de Gran Canaria, Canary Islands, Spain
Complejo Hospitalario Universitario de Fuenlabrada
Fuenlabrada, Madrid, Spain
Hospital Universitario Puerta de Hierro
Majadahonda, Madrid, Spain
Hospital General Universitario de Santa Lucía
Cartagena, Murcia, Spain
Complejo Hospitalario de Navarra
Pamplona, Navarre, Spain
Fundación Hospital de Jove
Gijón, Principality of Asturias, Spain
Centro Onoclógico de Galicia
A Coruña, , Spain
Complejo Hospitalario Universitario de Albacete
Albacete, , Spain
Hospital Universitario de la Ribera
Alzira, , Spain
Hospital Universitario Infanta Cristina
Badajoz, , Spain
Centro Médico Teknon
Barcelona, , Spain
Clínica Platon
Barcelona, , Spain
Hospital Clínic de Barcelona
Barcelona, , Spain
Hospital del Mar
Barcelona, , Spain
ICO Duran i Reynals
Barcelona, , Spain
Hospital Universitario de Burgos
Burgos, , Spain
Hospital Universitario Puerta del Mar
Cadiz, , Spain
Hospital Provincial de Castellón
Castelló, , Spain
Hospital General Universitario de Ciudad Real
Ciudad Real, , Spain
Hospital de Donostia
Donostia / San Sebastian, , Spain
Hospital Universitario Virgen de las Nieves
Granada, , Spain
Hospital Universitario de León
León, , Spain
Hospital Universitari Arnau de Vilanova
Lleida, , Spain
Hospital Clínico Universitario de San Carlos
Madrid, , Spain
Hospital Fundación Jiménez Díaz
Madrid, , Spain
Hospital Ramon y Cajal
Madrid, , Spain
Hospital Universitario 12 de Octubre
Madrid, , Spain
Hospital Universitario Gregorio Marañón
Madrid, , Spain
Hospital Universitario la Paz
Madrid, , Spain
Hospital General Universitario Virgen de la Arrixaca
Murcia, , Spain
Hospital Universitari Sant Joan de Reus
Reus, , Spain
Hospital Universitario de Salamanca
Salamanca, , Spain
Hospital Clínico Universitario de Santiago
Santiago de Compostela, , Spain
Hospital Virgen de la Macarena
Seville, , Spain
Hospital Virgen del Rocío
Seville, , Spain
Hospital Clinico Universitario de Valencia
Valencia, , Spain
Hospital General Universitario de Valencia
Valencia, , Spain
Hospital Universitari i Politecnic la Fe
Valencia, , Spain
Instituto Valenciano de Oncología (IVO)
Valencia, , Spain
Hospital Clínico Universitario de Valladolid
Valladolid, , Spain
Complejo Hospitalario Universitario de Vigo
Vigo, , Spain
Hospital Universitario de Araba
Vitoria-Gasteiz, , Spain
Hospital Virgen de la Concha
Zamora, , Spain
Hospital Clínico Universitario Lozano Blesa
Zaragoza, , Spain
Hospital Universitario Miguel Servet
Zaragoza, , Spain
Countries
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References
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Kiluk JV, Ly QP, Meade T, Ramos D, Reintgen DS, Dessureault S, Davis M, Shamehdi C, Cox CE. Axillary recurrence rate following negative sentinel node biopsy for invasive breast cancer: long-term follow-up. Ann Surg Oncol. 2011 Dec;18 Suppl 3:S339-42. doi: 10.1245/s10434-009-0704-1. Epub 2009 Sep 24.
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Early Breast Cancer Trialists' Collaborative Group (EBCTCG); Darby S, McGale P, Correa C, Taylor C, Arriagada R, Clarke M, Cutter D, Davies C, Ewertz M, Godwin J, Gray R, Pierce L, Whelan T, Wang Y, Peto R. Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10,801 women in 17 randomised trials. Lancet. 2011 Nov 12;378(9804):1707-16. doi: 10.1016/S0140-6736(11)61629-2. Epub 2011 Oct 19.
Ragaz J, Olivotto IA, Spinelli JJ, Phillips N, Jackson SM, Wilson KS, Knowling MA, Coppin CM, Weir L, Gelmon K, Le N, Durand R, Coldman AJ, Manji M. Locoregional radiation therapy in patients with high-risk breast cancer receiving adjuvant chemotherapy: 20-year results of the British Columbia randomized trial. J Natl Cancer Inst. 2005 Jan 19;97(2):116-26. doi: 10.1093/jnci/djh297.
Overgaard M, Nielsen HM, Overgaard J. Is the benefit of postmastectomy irradiation limited to patients with four or more positive nodes, as recommended in international consensus reports? A subgroup analysis of the DBCG 82 b&c randomized trials. Radiother Oncol. 2007 Mar;82(3):247-53. doi: 10.1016/j.radonc.2007.02.001. Epub 2007 Feb 15.
van Wely BJ, Teerenstra S, Schinagl DA, Aufenacker TJ, de Wilt JH, Strobbe LJ. Systematic review of the effect of external beam radiation therapy to the breast on axillary recurrence after negative sentinel lymph node biopsy. Br J Surg. 2011 Mar;98(3):326-33. doi: 10.1002/bjs.7360. Epub 2010 Nov 30.
Peg V, Espinosa-Bravo M, Vieites B, Vilardell F, Antunez JR, de Salas MS, Delgado-Sanchez JJ, Pinto W, Gozalbo F, Petit A, Sansano I, Del Mar Tellez M, Rubio IT. Intraoperative molecular analysis of total tumor load in sentinel lymph node: a new predictor of axillary status in early breast cancer patients. Breast Cancer Res Treat. 2013 May;139(1):87-93. doi: 10.1007/s10549-013-2524-z. Epub 2013 Apr 11.
Veronesi U, Orecchia R, Zurrida S, Galimberti V, Luini A, Veronesi P, Gatti G, D'Aiuto G, Cataliotti L, Paolucci R, Piccolo P, Massaioli N, Sismondi P, Rulli A, Lo Sardo F, Recalcati A, Terribile D, Acerbi A, Rotmensz N, Maisonneuve P. Avoiding axillary dissection in breast cancer surgery: a randomized trial to assess the role of axillary radiotherapy. Ann Oncol. 2005 Mar;16(3):383-8. doi: 10.1093/annonc/mdi089. Epub 2005 Jan 24.
Martelli G, Boracchi P, De Palo M, Pilotti S, Oriana S, Zucali R, Daidone MG, De Palo G. A randomized trial comparing axillary dissection to no axillary dissection in older patients with T1N0 breast cancer: results after 5 years of follow-up. Ann Surg. 2005 Jul;242(1):1-6; discussion 7-9. doi: 10.1097/01.sla.0000167759.15670.14.
Hwang RF, Gonzalez-Angulo AM, Yi M, Buchholz TA, Meric-Bernstam F, Kuerer HM, Babiera GV, Tereffe W, Liu DD, Hunt KK. Low locoregional failure rates in selected breast cancer patients with tumor-positive sentinel lymph nodes who do not undergo completion axillary dissection. Cancer. 2007 Aug 15;110(4):723-30. doi: 10.1002/cncr.22847.
Bilimoria KY, Bentrem DJ, Hansen NM, Bethke KP, Rademaker AW, Ko CY, Winchester DP, Winchester DJ. Comparison of sentinel lymph node biopsy alone and completion axillary lymph node dissection for node-positive breast cancer. J Clin Oncol. 2009 Jun 20;27(18):2946-53. doi: 10.1200/JCO.2008.19.5750. Epub 2009 Apr 13.
Veronesi U, Viale G, Paganelli G, Zurrida S, Luini A, Galimberti V, Veronesi P, Intra M, Maisonneuve P, Zucca F, Gatti G, Mazzarol G, De Cicco C, Vezzoli D. Sentinel lymph node biopsy in breast cancer: ten-year results of a randomized controlled study. Ann Surg. 2010 Apr;251(4):595-600. doi: 10.1097/SLA.0b013e3181c0e92a.
Caudle AS, Hunt KK, Kuerer HM, Meric-Bernstam F, Lucci A, Bedrosian I, Babiera GV, Hwang RF, Ross MI, Feig BW, Hoffman K, Litton JK, Sahin AA, Yang W, Hortobagyi GN, Buchholz TA, Mittendorf EA. Multidisciplinary considerations in the implementation of the findings from the American College of Surgeons Oncology Group (ACOSOG) Z0011 study: a practice-changing trial. Ann Surg Oncol. 2011 Sep;18(9):2407-12. doi: 10.1245/s10434-011-1593-7. No abstract available.
Giuliano AE, McCall L, Beitsch P, Whitworth PW, Blumencranz P, Leitch AM, Saha S, Hunt KK, Morrow M, Ballman K. Locoregional recurrence after sentinel lymph node dissection with or without axillary dissection in patients with sentinel lymph node metastases: the American College of Surgeons Oncology Group Z0011 randomized trial. Ann Surg. 2010 Sep;252(3):426-32; discussion 432-3. doi: 10.1097/SLA.0b013e3181f08f32.
Giuliano AE, Hunt KK, Ballman KV, Beitsch PD, Whitworth PW, Blumencranz PW, Leitch AM, Saha S, McCall LM, Morrow M. Axillary dissection vs no axillary dissection in women with invasive breast cancer and sentinel node metastasis: a randomized clinical trial. JAMA. 2011 Feb 9;305(6):569-75. doi: 10.1001/jama.2011.90.
Carlson RW, Hudis CA, Pritchard KI; National Comprehensive Cancer Network Breast Cancer Clinical Practice Guidelines in Oncology; American Society of Clinical Oncology Technology Assessment on the Use of Aromatase Inhibitors; St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer. Adjuvant endocrine therapy in hormone receptor-positive postmenopausal breast cancer: evolution of NCCN, ASCO, and St Gallen recommendations. J Natl Compr Canc Netw. 2006 Nov;4(10):971-9. doi: 10.6004/jnccn.2006.0082.
Setton J, Cody H, Tan L, Morrow M, Hudis C, Catalano J, McCormick B, Powell S, Ho A. Radiation field design and regional control in sentinel lymph node-positive breast cancer patients with omission of axillary dissection. Cancer. 2012 Apr 15;118(8):1994-2003. doi: 10.1002/cncr.26504. Epub 2011 Aug 31.
Haffty BG, Hunt KK, Harris JR, Buchholz TA. Positive sentinel nodes without axillary dissection: implications for the radiation oncologist. J Clin Oncol. 2011 Dec 1;29(34):4479-81. doi: 10.1200/JCO.2011.36.1667. Epub 2011 Oct 31. No abstract available.
Bayo E, Herruzo I, Arenas M, Algara M. Consensus on the regional lymph nodes irradiation in breast cancer. Clin Transl Oncol. 2013 Oct;15(10):766-73. doi: 10.1007/s12094-013-1027-z. Epub 2013 Mar 22.
Algara M, Rodriguez E, Martinez-Arcelus FJ, Salinas J, Sanz X, Beato I, Manso A, Soler A, Rodriguez JR, Frias A, Calin A, Juan G, Meireles P, Flaquer A; OPTIMAL investigators. OPTimizing Irradiation through Molecular Assessment of Lymph node (OPTIMAL): a randomized clinical trial. Radiother Oncol. 2022 Nov;176:76-82. doi: 10.1016/j.radonc.2022.09.006. Epub 2022 Sep 19.
Algara Lopez M, Rodriguez Garcia E, Beato Tortajada I, Martinez Arcelus FJ, Salinas Ramos J, Rodriguez Garrido JR, Sanz Latiesas X, Soler Rodriguez A, Juan Rijo G, Flaquer Garcia A. OPTimizing Irradiation through Molecular Assessment of Lymph node (OPTIMAL): a randomized open label trial. Radiat Oncol. 2020 Oct 2;15(1):229. doi: 10.1186/s13014-020-01672-7.
Other Identifiers
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GIC-RAD-2014-02
Identifier Type: -
Identifier Source: org_study_id
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