OPTimizing Irradiation Through Molecular Assesment of Lymph Node After Primary Systemic Treatment

Breast Cancer Clinical Trial

— OPTIMALIIa  

Official title:

OPTimizing Irradiation Through Molecular Assesment of Lymph Node After Primary Systemic Treatment

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03972696
• Other study ID #: GIC-RAD-2016-01
• Status: Terminated
• Phase: N/A
• Start date: January 2017
• Est. completion date: April 30, 2021

Study information

• Verified date: September 2021
• Source: Grupo de Investigación Clínica en Oncología Radioterapia
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Breast cancer management integrating surgery, systemic therapy and radiation therapy tends to systemic treatment as the first therapeutic option, continuing afterwards by surgery and radiation therapy with the scope of decreasing the locoregional treatment. This strategy implies doubts about what should be the locoregional treatment, because many patients have remissions and a significant number of them a complete response. The responses are associated with better clinical outcome although there are doubts about they are a surrogate marker of survival.

Nodal irradiation after systemic treatment in patients with breast cancer it is under discussion, particularly in the case of patients with initial clinical involvement experiencing complete remission. For this reason, some groups decide irradiation of all nodal regions and others choose no irradiation of the lymph nodes at all. To clarify this discussion the present study is proposed.

The "One Step Nucleic Amplification" (OSNA) is a technique developed by Sysmex Corporation that allows a complete analysis of sentinel nodes and provides a quantification of the tumor marker Cytokeratin 19 (CK19) messenger ribonucleic acid (mRNA) in the sentinel node. The result is expressed by the Tumour Load as number of copies per microliter. This technique has shown its diagnostic ability both without primary systemic treatment and after primary systemic treatment, being more reproducible than conventional processes.

In spite of this, fits to mention that the studies of validation used to obtain the European Conformity (CE) mark only included patients without previous systemic treatment to the surgery.

Description:

Breast cancer management integrating surgery, systemic therapy and radiation therapy tends to systemic treatment as the first therapeutic option, continuing afterwards by surgery and radiation therapy with the scope of decreasing the locoregional treatment. This strategy implies doubts about what should be the locoregional treatment, because many patients have remissions and a significant number of them a complete response. The responses are associated with better clinical outcome although there are doubts about they are a surrogate marker of survival.

According to a previous publication, in which the predictors of locoregional recurrence National Surgical Adjuvant Breast and Bowel Project 18 (NSABP18) and National Surgical Adjuvant Breast and Bowel Project 27 (NSABP27) studies are evaluated, both studies designed for viewing the value of neoadjuvant chemotherapy, good results of locoregional control are described, although in many cases radiotherapy was omitted or lymph node were not irradiated.

Therefore the need to nodal irradiation begins to be questioned, especially when they are negative after primary systemic treatment, regardless of their previous state. However the clinical guidelines recommend radiotherapy planning according to the previous stage. The problem is the local treatment indication is established based on the indications of irradiation without primary systemic therapy, as showed in retrospective studies, without the existence of randomized studies designed to analyze the role of radiotherapy in these circumstances. In the last American Society of Clinical Oncology (ASCO) preliminary results of a meta-analysis including three large studies of primary systemic treatment were presented.

Results show that irradiation improves local control in N1 patients achieving a complete remission, radiotherapy being an independent prognostic factor, in terms of locoregional control; however, they conclude that the optimal selection of patients remains unclear. The controversy remains, because there is no evidence to treat nodes after primary systemic therapy, whether there is a complete remission as if it does not, nor is it known that subgroup of patients may benefit more from local treatments. Long-term studies are needed to analyze this issue, leaving the decision being especially complicated in cases of clinically positive nodes experiencing a complete remission. The problem remains that often is not known exactly has been irradiated since, in many studies, irradiation is indicated at the discretion of the researcher.

Given these doubts, European Society conducted a survey to find out what was the attitude about these patients, and the findings shows that 75% of the centers irradiate in the N1 case. The American Society obtained similar results and in Spain 64% of respondents irradiate the lymph nodes. These three publications conclude that studies are needed to determine the importance of irradiation after primary systemic treatment and while waiting for these results, a consensus muts be reached as stated in ASCO 2015 summary.

The "One Step Nucleic Amplification" (OSNA) is a technique developed by Sysmex Corporation that allows a complete analysis of sentinel nodes and provides a quantification of the tumor marker CK19 mRNA in the sentinel node. The result is expressed by the Tumour Load as number of copies per microliter. This technique has shown its diagnostic ability both without primary systemic treatment and after primary systemic treatment, being more reproducible than conventional processes.

In spite of this, fits to mention that the studies of validation used to obtain the CE mark only included patients without previous systemic treatment to the surgery.

In summary, nodal irradiation after systemic treatment in patients with breast cancer it is under discussion, particularly in the case of patients with initial clinical involvement experiencing complete remission. For this reason, some groups decide irradiation of all nodal regions and others choose no irradiation of the lymph nodes at all. To clarify this discussion the present study is proposed.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 32
• Est. completion date: April 30, 2021
• Est. primary completion date: April 30, 2021
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Infiltrating carcinoma of the breast.

• Metastatic lymph nodes (N1) at diagnosis, as determined histologically by Fine Needle Aspiration or Core Needle Biopsy.

• Primary systemic therapy (including antiestrogen or chemotherapy, and targeted therapies).

• Tumour surgery: tumorectomy, quadrantectomy or mastectomy.

• OSNA (ND) or - lymph nodes after primary systemic therapy.

• Age = 18 years old.

• Karnofsky Index = 70 %.

• Signed Informed Consent.

Exclusion Criteria:

• Lymphadenectomy.

• Bilateral breast cancer.

• Males.

• Previous thoracic irradiation therapy.

• Contraindications of radiotherapy (pregnancy, severe collagen diseases).

• Other neoplasms.

• Severe associated comorbidities that, according to the investigator criteria, may interfere with the study evaluations.

• Lymp nodes OSNA -(L), +, ++ after primary systemic therapy.

• Sentinel lymph node biopsy previous to the primary systemic therapy.

• Mammary internal chain affected.

Related Conditions & MeSH terms

• Breast Cancer

Intervention

Radiation:
• Irradiation
BA3S versus BA2 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
Spain	Centro Oncológico de Galicia	A Coruña
Spain	Hospital Infanta Cristina	Badajoz
Spain	ICO Badalona	Badalona
Spain	Hospital Universitario de Cruces	Barakaldo	Bilbao
Spain	Hospital Universitario Santa Lucía	Cartagena
Spain	Hospital Universitario de Donostia	Donostia
Spain	ICO Girona	Girona
Spain	Hospital Universitari Arnau de Vilanova	Lerida
Spain	Hospital Clínico San Carlos	Madrid
Spain	Hospital Universitario Fundación Jiménez Díaz	Madrid
Spain	Hospital Universitario Gregrorio Marañón	Madrid
Spain	Hospital Universitario La Paz	Madrid
Spain	Hospital Universitario Ramón y Cajal	Madrid
Spain	Hospital Universitario Virgen de la Victoria	Málaga
Spain	Hospital Universitario Virgen de la Arrixaca	Murcia
Spain	Hospital Universitario Sant Joan de Reus	Reus	Tarragona
Spain	Hospital Universitario Virgen de la Macarena	Sevilla
Spain	Hospital Universitario Virgen del Rocío	Sevilla
Spain	Hospital General Universitario de Valencia	Valencia
Spain	Hospital Universitario de Araba	Vitoria	Pais Vasco

Sponsors (1)

Lead Sponsor	Collaborator
Grupo de Investigación Clínica en Oncología Radioterapia

Country where clinical trial is conducted

Spain, 

References & Publications (21)

Arenas M, Montero Á, de Las Peñas MD, Algara M. The position and current status of radiation therapy after primary systemic therapy in breast cancer: a national survey-based expert consensus statement. Clin Transl Oncol. 2016 Jun;18(6):582-91. doi: 10.1007/s12094-015-1401-0. Epub 2015 Sep 14. — View Citation

Belkacemi Y, Kaidar-Person O, Poortmans P, Ozsahin M, Valli MC, Russell N, Kunkler I, Hermans J, Kuten A, van Tienhoven G, Westenberg H; Breast Working Party of the EORTC Radiation Oncology Group (ROG). Patterns of practice of regional nodal irradiation in breast cancer: results of the European Organization for Research and Treatment of Cancer (EORTC) NOdal Radiotherapy (NORA) survey. Ann Oncol. 2015 Mar;26(3):529-35. doi: 10.1093/annonc/mdu561. Epub 2014 Dec 5. — View Citation

Bernier J. Post-mastectomy radiotherapy after neodjuvant chemotherapy in breast cancer patients: A review. Crit Rev Oncol Hematol. 2015 Mar;93(3):180-9. doi: 10.1016/j.critrevonc.2014.10.011. Epub 2014 Oct 31. Review. — View Citation

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Di Filippo F, Giannarelli D, Bouteille C, Bernet L, Cano R, Cunnick G, Sapino A. Elaboration of a nomogram to predict non sentinel node status in breast cancer patients with positive sentinel node, intra-operatively assessed with one step nucleic acid amplification method. J Exp Clin Cancer Res. 2015 Nov 4;34:136. doi: 10.1186/s13046-015-0246-2. — View Citation

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Haffty BG, McCall LM, Ballman KV, McLaughlin S, Jagsi R, Ollila DW, Hunt KK, Buchholz TA, Boughey JC. Patterns of Local-Regional Management Following Neoadjuvant Chemotherapy in Breast Cancer: Results From ACOSOG Z1071 (Alliance). Int J Radiat Oncol Biol Phys. 2016 Mar 1;94(3):493-502. doi: 10.1016/j.ijrobp.2015.11.005. Epub 2015 Nov 10. — View Citation

Mamounas EP, Anderson SJ, Dignam JJ, Bear HD, Julian TB, Geyer CE Jr, Taghian A, Wickerham DL, Wolmark N. Predictors of locoregional recurrence after neoadjuvant chemotherapy: results from combined analysis of National Surgical Adjuvant Breast and Bowel Project B-18 and B-27. J Clin Oncol. 2012 Nov 10;30(32):3960-6. doi: 10.1200/JCO.2011.40.8369. Epub 2012 Oct 1. — View Citation

Mamounas EP. Impact of neoadjuvant chemotherapy on locoregional surgical treatment of breast cancer. Ann Surg Oncol. 2015 May;22(5):1425-33. doi: 10.1245/s10434-015-4406-6. Epub 2015 Mar 2. Review. — View Citation

Marks LB, Prosnitz LR. Reducing local therapy in patients responding to preoperative systemic therapy: are we outsmarting ourselves? J Clin Oncol. 2014 Feb 20;32(6):491-3. doi: 10.1200/JCO.2013.51.3523. Epub 2013 Dec 30. — View Citation

Nagar H, Boothe D, Ginter PS, Sison C, Vahdat L, Shin S, Smith M, Chao KS, Nori D, Hayes MK. Disease-free survival according to the use of postmastectomy radiation therapy after neoadjuvant chemotherapy. Clin Breast Cancer. 2015 Apr;15(2):128-34. doi: 10.1016/j.clbc.2014.09.012. Epub 2014 Nov 11. — View Citation

Navarro-Cecilia J, Dueñas-Rodríguez B, Luque-López C, Ramírez-Expósito MJ, Martínez-Ferrol J, Ruíz-Mateas A, Ureña C, Carrera-González MP, Mayas MD, Martínez-Martos JM. Intraoperative sentinel node biopsy by one-step nucleic acid amplification (OSNA) avoids axillary lymphadenectomy in women with breast cancer treated with neoadjuvant chemotherapy. Eur J Surg Oncol. 2013 Aug;39(8):873-9. doi: 10.1016/j.ejso.2013.05.002. Epub 2013 May 25. — View Citation

Noh JM, Park W, Suh CO, Keum KC, Kim YB, Shin KH, Kim K, Chie EK, Ha SW, Kim SS, Ahn SD, Shin HS, Kim JH, Lee HS, Lee NK, Huh SJ, Choi DH. Is elective nodal irradiation beneficial in patients with pathologically negative lymph nodes after neoadjuvant chemotherapy and breast-conserving surgery for clinical stage II-III breast cancer? A multicentre retrospective study (KROG 12-05). Br J Cancer. 2014 Mar 18;110(6):1420-6. doi: 10.1038/bjc.2014.26. Epub 2014 Jan 30. — View Citation

Offersen BV, Boersma LJ, Kirkove C, Hol S, Aznar MC, Biete Sola A, Kirova YM, Pignol JP, Remouchamps V, Verhoeven K, Weltens C, Arenas M, Gabrys D, Kopek N, Krause M, Lundstedt D, Marinko T, Montero A, Yarnold J, Poortmans P. ESTRO consensus guideline on target volume delineation for elective radiation therapy of early stage breast cancer. Radiother Oncol. 2015 Jan;114(1):3-10. doi: 10.1016/j.radonc.2014.11.030. Epub 2015 Jan 24. — View Citation

Rusthoven CG, Rabinovitch RA, Jones BL, Koshy M, Amini A, Yeh N, Jackson MW, Fisher CM. The impact of postmastectomy and regional nodal radiation after neoadjuvant chemotherapy for clinically lymph node-positive breast cancer: a National Cancer Database (NCDB) analysis. Ann Oncol. 2016 May;27(5):818-27. doi: 10.1093/annonc/mdw046. Epub 2016 Feb 9. — View Citation

Shim SJ, Park W, Huh SJ, Choi DH, Shin KH, Lee NK, Suh CO, Keum KC, Kim YB, Ahn SD, Kim SS, Ha SW, Chie EK, Kim K, Shin HS, Kim JH, Lee HS. The role of postmastectomy radiation therapy after neoadjuvant chemotherapy in clinical stage II-III breast cancer patients with pN0: a multicenter, retrospective study (KROG 12-05). Int J Radiat Oncol Biol Phys. 2014 Jan 1;88(1):65-72. doi: 10.1016/j.ijrobp.2013.09.021. Epub 2013 Oct 22. — View Citation

Smith BD. Using chemotherapy response to personalize choices regarding locoregional therapy: a new era in breast cancer treatment? J Clin Oncol. 2012 Nov 10;30(32):3913-5. doi: 10.1200/JCO.2012.44.4539. Epub 2012 Oct 1. — View Citation

Tamaki Y. One-step nucleic acid amplification assay (OSNA) for sentinel lymph node biopsy. Breast Cancer. 2015 May;22(3):230-4. doi: 10.1007/s12282-012-0390-x. Epub 2012 Aug 9. Review. — View Citation

Tsujimoto M, Nakabayashi K, Yoshidome K, Kaneko T, Iwase T, Akiyama F, Kato Y, Tsuda H, Ueda S, Sato K, Tamaki Y, Noguchi S, Kataoka TR, Nakajima H, Komoike Y, Inaji H, Tsugawa K, Suzuki K, Nakamura S, Daitoh M, Otomo Y, Matsuura N. One-step nucleic acid amplification for intraoperative detection of lymph node metastasis in breast cancer patients. Clin Cancer Res. 2007 Aug 15;13(16):4807-16. — View Citation

von Minckwitz G, Untch M, Blohmer JU, Costa SD, Eidtmann H, Fasching PA, Gerber B, Eiermann W, Hilfrich J, Huober J, Jackisch C, Kaufmann M, Konecny GE, Denkert C, Nekljudova V, Mehta K, Loibl S. Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. J Clin Oncol. 2012 May 20;30(15):1796-804. doi: 10.1200/JCO.2011.38.8595. Epub 2012 Apr 16. — View Citation

White J, Mamounas E. Locoregional radiotherapy in patients with breast cancer responding to neoadjuvant chemotherapy: a paradigm for treatment individualization. J Clin Oncol. 2014 Feb 20;32(6):494-5. doi: 10.1200/JCO.2013.53.4974. Epub 2013 Dec 30. — View Citation

* Note: There are 21 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	To show the non-inferiority of (BA2) compared to (BA3S), in terms of 5-years diseasefree survival (DFS), including the local, regional and distant disease free survival and excluding second neoplasms	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	To compare the 5-years incidence of loco-regional tumor recurrence between BA2 and BA3S.	Loco-regional recurrence during the 5-years follow-up, defined as clinical or image-based detection of tumour in treated breast or thoracic wall (local recurrence) or in the ipsilateral axilla or supraclavicular fossa or internal mammary chain (regional recurrence).	5 Years
Secondary	To compare the 5-years incidence of distant tumor recurrence between BA2 and BA3S	Distant recurrence rate occurring during the 5-years follow-up, 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 or internal mammary chain.	5 years
Secondary	To compare the acute and chronic toxicity of the two treatment modalities.	Toxicity, recorded using the Terminology Criteria for Adverse Events v4.0 (CTCAE).	5 years