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

March 20, 2022 updated by: Esther Prats, Grupo de Investigación Clínica en Oncología Radioterapia
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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

489

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Italy
      • Perugia, Italy
        • Hospital de Perugia
  • Portugal
      • Porto, Portugal
        • Centro Hospitalar de São João
      • Santarém, Portugal
        • Hospital Distrital de Santarém
      • Évora, Portugal
        • Hospital Espirito Santo
  • Spain
      • A Coruña, Spain
        • Centro Onoclógico de Galicia
      • Albacete, Spain
        • Complejo Hospitalario Universitario de Albacete
      • Alzira, Spain
        • Hospital Universitario de La Ribera
      • Badajoz, Spain
        • Hospital Universitario Infanta Cristina
      • Barcelona, Spain
        • Hospital Clinic de Barcelona
      • Barcelona, Spain
        • Hospital del Mar
      • Barcelona, Spain
        • Centro Medico Teknon
      • Barcelona, Spain
        • Clínica Platon
      • Barcelona, Spain
        • ICO Duran i Reynals
      • Burgos, Spain
        • Hospital Universitario de Burgos
      • Cadiz, Spain
        • Hospital Universitario Puerta Del Mar
      • Castelló, Spain
        • Hospital Provincial de Castellon
      • Ciudad Real, Spain
        • Hospital General Universitario de Ciudad Real
      • Donostia, Spain
        • Hospital de Donostia
      • Granada, Spain
        • Hospital Universitario Virgen de las Nieves
      • Lerida, Spain
        • Hospital Universitari Arnau de Vilanova
      • León, Spain
        • Hospital Universitario de Leon
      • Madrid, Spain
        • Hospital Ramon y Cajal
      • Madrid, Spain
        • Hospital Universitario 12 de Octubre
      • Madrid, Spain
        • Hospital Universitario La Paz
      • Madrid, Spain
        • Hospital Universitario Gregorio Maranon
      • Madrid, Spain
        • Hospital Fundación Jiménez Diaz
      • Madrid, Spain
        • Hospital Clínico Universitario de San Carlos
      • Murcia, Spain
        • Hospital General Universitario Virgen de la Arrixaca
      • Reus, Spain
        • Hospital Universitari Sant Joan de Reus
      • Salamanca, Spain
        • Hospital Universitario de Salamanca
      • Santiago de Compostela, Spain
        • Hospital Clinico Universitario de Santiago
      • Sevilla, Spain
        • Hospital Virgen Del Rocio
      • Sevilla, Spain
        • Hospital Virgen de la Macarena
      • Valencia, Spain
        • Hospital Clinico Universitario de Valencia
      • Valencia, Spain
        • Hospital Universitari i Politècnic La Fe
      • Valencia, Spain
        • Hospital General Universitario de Valencia
      • Valencia, Spain
        • Instituto Valenciano de Oncologia (IVO)
      • Valladolid, Spain
        • Hospital Clinico Universitario de Valladolid
      • Vigo, Spain
        • Complejo Hospitalario Universitario de Vigo
      • Vitoria, Spain
        • Hospital Universitario de Araba
      • Zamora, Spain
        • Hospital Virgen de la Concha
      • Zaragoza, Spain
        • Hospital Universitario Miguel Servet
      • Zaragoza, Spain
        • Hospital Clinico Universitario Lozano Blesa
    • Asturias
      • Gijón, Asturias, Spain
        • Fundación Hospital de Jove
    • Bilbao
      • Barakaldo, Bilbao, Spain
        • Hospital de Cruces
    • Canarias
      • Palmas de Gran Canaria, Canarias, Spain
        • Hospital Universitario de Gran Canaria Dr. Negrin
    • Madrid
      • Fuenlabrada, Madrid, Spain
        • Complejo Hospitalario Universitario de Fuenlabrada
      • Majadahonda, Madrid, Spain
        • Hospital Universitario Puerta de Hierro
    • Murcia
      • Cartagena, Murcia, Spain
        • Hospital General Universitario de Santa Lucia
    • Navarra
      • Pamplona, Navarra, Spain
        • Complejo Hospitalario de Navarra

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Female

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Other: 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.
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.
Experimental: 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.
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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Disease Free Survival
Time Frame: 5 years
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
Time Frame: 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
Time Frame: 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.
Time Frame: 7 years
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.
Time Frame: 7 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.
Time Frame: 2 years
Total dose (Gy) received in axillary levels I, II,and II, supraclavicular, and internal mammary chain volumes.
2 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Grupo de Investigación Clínica en Oncología Radioterapia

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

April 1, 2015

Primary Completion (Actual)

July 1, 2021

Study Completion (Actual)

July 1, 2021

Study Registration Dates

First Submitted

December 23, 2014

First Submitted That Met QC Criteria

January 7, 2015

First Posted (Estimate)

January 12, 2015

Study Record Updates

Last Update Posted (Actual)

April 1, 2022

Last Update Submitted That Met QC Criteria

March 20, 2022

Last Verified

March 1, 2022

More Information

Terms related to this study

Other Study ID Numbers

  • GIC-RAD-2014-02

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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