Clinical trial NCT02335957: OPTimizing Irradiation Through Molecular Assessment of Lymph Node (OPTIMAL)
Official title: OPTimizing Irradiation Through Molecular Assessment of Lymph Node (OPTIMAL)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Breast Cancer
Lead sponsor: Grupo de Investigación Clínica en Oncología Radioterapia
Sponsor class: OTHER
First posted: 2015-01-12
Enrollment: 489
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: Inclusion Criteria:

1. Infiltrating, ductal carcinoma of the breast.
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:

1. Other types of breast cancer different from infiltrating ductal carcinoma.
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.

Primary outcomes:
measure: Disease Free Survival
timeFrame: 5 years
Secondary outcomes:
measure: Time to loco-regional recurrence up 5-years
timeFrame: 5 years
measure: Time to distant recurrence up 5-years
timeFrame: 5 years
measure: Number of patients with acute toxicity, defined as any adverse event appearing up to one month after finalization of radiotherapy.
timeFrame: 7 years
measure: Number of patients with chronic toxicity, defined as any adverse event appearing during follow-up, up to 5 years.
timeFrame: 7 years
measure: Total irradiation dose (Gy) received in axillary levels I, II and III, supraclavicular fossa, and internal mammary chain volumes, at the end of radiotherapy.
timeFrame: 2 years
Other outcomes:
Locations:
city: Perugia
country: Italy
facility: Hospital de Perugia
city: Porto
country: Portugal
facility: Centro Hospitalar De São João
city: Santarém
country: Portugal
facility: Hospital Distrital de Santarém
city: Évora
country: Portugal
facility: Hospital Espírito Santo
city: Gijón
country: Spain
facility: Fundación Hospital de Jove
state: Asturias
city: Barakaldo
country: Spain
facility: Hospital de Cruces
state: Bilbao
city: Palmas de Gran Canaria
country: Spain
facility: Hospital Universitario de Gran Canaria Dr. Negrín
state: Canarias
city: Fuenlabrada
country: Spain
facility: Complejo Hospitalario Universitario de Fuenlabrada
state: Madrid
city: Majadahonda
country: Spain
facility: Hospital Universitario Puerta de Hierro
state: Madrid
city: Cartagena
country: Spain
facility: Hospital General Universitario de Santa Lucía
state: Murcia
city: Pamplona
country: Spain
facility: Complejo Hospitalario de Navarra
state: Navarra
city: A Coruña
country: Spain
facility: Centro Onoclógico de Galicia
city: Albacete
country: Spain
facility: Complejo Hospitalario Universitario de Albacete
city: Alzira
country: Spain
facility: Hospital Universitario de la Ribera
city: Badajoz
country: Spain
facility: Hospital Universitario Infanta Cristina
city: Barcelona
country: Spain
facility: Centro Médico Teknon
city: Barcelona
country: Spain
facility: Clínica Platon
city: Barcelona
country: Spain
facility: Hospital Clínic de Barcelona
city: Barcelona
country: Spain
facility: Hospital del Mar
city: Barcelona
country: Spain
facility: ICO Duran i Reynals
city: Burgos
country: Spain
facility: Hospital Universitario de Burgos
city: Cadiz
country: Spain
facility: Hospital Universitario Puerta del Mar
city: Castelló
country: Spain
facility: Hospital Provincial de Castellón
city: Ciudad Real
country: Spain
facility: Hospital General Universitario de Ciudad Real
city: Donostia
country: Spain
facility: Hospital de Donostia
city: Granada
country: Spain
facility: Hospital Universitario Virgen de las Nieves
city: Lerida
country: Spain
facility: Hospital Universitari Arnau de Vilanova
city: León
country: Spain
facility: Hospital Universitario de León
city: Madrid
country: Spain
facility: Hospital Clínico Universitario de San Carlos
city: Madrid
country: Spain
facility: Hospital Fundación Jiménez Díaz
city: Madrid
country: Spain
facility: Hospital Ramon y Cajal
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Madrid
country: Spain
facility: Hospital Universitario Gregorio Marañón
city: Madrid
country: Spain
facility: Hospital Universitario la Paz
city: Murcia
country: Spain
facility: Hospital General Universitario Virgen de la Arrixaca
city: Reus
country: Spain
facility: Hospital Universitari Sant Joan de Reus
city: Salamanca
country: Spain
facility: Hospital Universitario de Salamanca
city: Santiago de Compostela
country: Spain
facility: Hospital Clínico Universitario de Santiago
city: Sevilla
country: Spain
facility: Hospital Virgen de la Macarena
city: Sevilla
country: Spain
facility: Hospital Virgen del Rocío
city: Valencia
country: Spain
facility: Hospital Clinico Universitario de Valencia
city: Valencia
country: Spain
facility: Hospital General Universitario de Valencia
city: Valencia
country: Spain
facility: Hospital Universitari i Politecnic la Fe
city: Valencia
country: Spain
facility: Instituto Valenciano de Oncología (IVO)
city: Valladolid
country: Spain
facility: Hospital Clínico Universitario de Valladolid
city: Vigo
country: Spain
facility: Complejo Hospitalario Universitario de Vigo
city: Vitoria
country: Spain
facility: Hospital Universitario de Araba
city: Zamora
country: Spain
facility: Hospital Virgen de la Concha
city: Zaragoza
country: Spain
facility: Hospital Clínico Universitario Lozano Blesa
city: Zaragoza
country: Spain
facility: Hospital Universitario Miguel Servet
Study officials:
affiliation: Grupo de Investigación Clínica en Oncología Radioterápica (GICOR)
name: Manuel Algara López, Medicine
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: Clarke M, Collins R, Darby S, Davies C, Elphinstone P, Evans V, Godwin J, Gray R, Hicks C, James S, MacKinnon E, McGale P, McHugh T, Peto R, Taylor C, Wang Y; Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005 Dec 17;366(9503):2087-106. doi: 10.1016/S0140-6736(05)67887-7.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.