OPTimizing Irradiation Through Molecular Assessment of Lymph Node (OPTIMAL)

Breast Cancer Clinical Trial

— OPTIMAL  

Official title:

OPTimizing Irradiation Through Molecular Assessment of Lymph Node (OPTIMAL)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02335957
• Other study ID #: GIC-RAD-2014-02
• Status: Completed
• Phase: N/A
• Start date: April 2015
• Est. completion date: July 2021

Study information

• Verified date: March 2022
• Source: Grupo de Investigación Clínica en Oncología Radioterapia
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 489
• Est. completion date: July 2021
• Est. primary completion date: July 2021
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Breast Cancer

Intervention

Radiation:
• 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.

Locations

Country	Name	City	State
Italy	Hospital de Perugia	Perugia
Portugal	Hospital Espírito Santo	Évora
Portugal	Centro Hospitalar De São João	Porto
Portugal	Hospital Distrital de Santarém	Santarém
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	Hospital de Cruces	Barakaldo	Bilbao
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 General Universitario de Santa Lucía	Cartagena	Murcia
Spain	Hospital Provincial de Castellón	Castelló
Spain	Hospital General Universitario de Ciudad Real	Ciudad Real
Spain	Hospital de Donostia	Donostia
Spain	Complejo Hospitalario Universitario de Fuenlabrada	Fuenlabrada	Madrid
Spain	Fundación Hospital de Jove	Gijón	Asturias
Spain	Hospital Universitario Virgen de las Nieves	Granada
Spain	Hospital Universitario de León	León
Spain	Hospital Universitari Arnau de Vilanova	Lerida
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 Universitario Puerta de Hierro	Majadahonda	Madrid
Spain	Hospital General Universitario Virgen de la Arrixaca	Murcia
Spain	Hospital Universitario de Gran Canaria Dr. Negrín	Palmas de Gran Canaria	Canarias
Spain	Complejo Hospitalario de Navarra	Pamplona	Navarra
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	Sevilla
Spain	Hospital Virgen del Rocío	Sevilla
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
Spain	Hospital Virgen de la Concha	Zamora
Spain	Hospital Clínico Universitario Lozano Blesa	Zaragoza
Spain	Hospital Universitario Miguel Servet	Zaragoza

Sponsors (1)

Lead Sponsor	Collaborator
Grupo de Investigación Clínica en Oncología Radioterapia

Countries where clinical trial is conducted

Italy,  Portugal,  Spain, 

References & Publications (19)

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. Review. — View 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. — View 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. Review. — View 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. — View 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. Review. — View 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. Review. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. Epub 2007 Feb 15. — View Citation

Peg V, Espinosa-Bravo M, Vieites B, Vilardell F, Antúnez JR, de Salas MS, Delgado-Sánchez JJ, Pinto W, Gozalbo F, Petit A, Sansano I, Del Mar Téllez 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. — View 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. — View 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. — View 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. Review. — View 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. Epub 2005 Jan 24. — View 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. — View Citation

* Note: There are 19 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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