Algara López et al. Radiat Oncol (2020) 15:229 https://doi.org/10.1186/s13014-020-01672-7 STUDY PROTOCOL Open Access OPTimizing Irradiation through Molecular Assessment of Lymph node (OPTIMAL): a randomized open label trial Manuel Algara López1* , Elvira Rodríguez García2, Inmaculada Beato Tortajada3, Francisco José Martínez Arcelus4, Juan Salinas Ramos5, José Reyes Rodríguez garrido6, Xavier Sanz Latiesas7, Ana Soler Rodríguez8, Germán Juan Rijo9 and Amanda Flaquer García10 Abstract Background: Conservative surgery followed by breast and nodal irradiation is the standard loco-regional early breast cancer (BC) treatment for patients with four or more involved lymph nodes. However, the treatment strategy when fewer nodes are involved remains unclear, especially when lymphadenectomy has not been performed. Sensitive nodal status assessment molecular techniques as the One-Step Nucleic Acid Amplification (OSNA) assay can contrib- ute to the definition and standardization of the treatment strategy. Therefore, the OPTIMAL study aims to demonstrate the feasibility of incidental irradiation of axillary nodes in patients with early-stage BC and limited involvement of the SLN. Methods: BC patients who underwent conservative surgery and whose SLN total tumour load assessed with OSNA ranged between 250–15,000 copies/µL will be eligible. Patients will be randomized to receive irradiation on the breast, tumour bed, axillary and supraclavicular lymph node areas (intentional arm) or only on the breast and tumour bed (incidental arm). All areas, including the internal mammary chain, will be contoured. The mean, median, D5% and D95% doses received in all volumes will be calculated. The primary endpoint is the non-inferiority of the incidental irradiation of axillary nodes compared to the intentional irradiation in terms of 5-year disease free survival. Secondary endpoints comprise the comparison of acute and chronic toxicity and loco-regional and distant disease recurrence rates. Discussion: Standardizing the treatment and diagnosis of BC patients with few nodes affected is crucial due to the lack of consensus. Hence, the quantitative score for the metastatic burden of SLN provided by OSNA can contribute by improving the discrimination of which BC patients with limited nodal involvement can benefit from incidental radiation as an adjuvant treatment strategy. Trial registration: ClinicalTrial.gov, NCT02335957; https​://clini​caltr​ials.gov/ct2/show/NCT02​33595​7 Keywords: Breast cancer, Conserving surgery, OSNA, Nodal irradiation, Incidental dose Background It has been shown that breast and nodal irradiation reduce mortality and disease recurrence in breast cancer *Correspondence: malgara@parcdesalutmar.cat 1 (BC) patients [1]. Therefore, there is evidence supporting Radiation Oncology Department, Del Mar Hospital, Autonomous University of Barcelona, Hospital del Mar Medical Research Institute, the use of adjuvant radiotherapy after conservative sur- Passeig Maritim, 25, 08003 Barcelona, Spain gery. Since nodal irradiation increases survival rates, it Full list of author information is available at the end of the article is recommended in patients with four or more involved © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat​iveco​mmons​.org/licen​ses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creat​iveco​ mmons​.org/publi​cdoma​in/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Algara López et al. Radiat Oncol (2020) 15:229 Page 2 of 9 lymph nodes (LN) [2], as well as in patients with other mRNA expression of the tumour marker cytokeratin 19 types of locally advanced tumours with LN involvement (CK19) [20]. The OSNA assay not only provides auto- [3]. A randomized clinical trial carried out by the Brit- mated and complete intraoperative analyses of the SLN ish Columbia Cancer Agency, showed that the 20-year but also standardized and reliable results for SLN meta- disease-free survival (DFS) of patients subjected to the static status. The total tumour load (TTL), defined as the combination of chemotherapy and radiation was 13% sum of the CK19 mRNA copies from all positive SLNs higher than that of the patients who were treated with of the patient, entails a quantitative score that integrates chemotherapy alone [4]. Similar results were achieved both the metastatic burden and the number of involved in the DBCG 82 b&c trial showing a difference of 10% SLN. The TTL score was proved to be an independent in the 15-year overall survival rate between the treat- predictor factor of the axillary nodal status, where only ment combination and chemotherapy alone (39% vs. 14.7% of patients with TTL beneath 15.000 copies/µl 29%, respectively) [5]. Furthermore, a study funded by had other positive non-SLN [21]. Recently, the PLUTTO the Canadian Cancer Society concluded that adjuvant study results also proved its impact on the prognosis of radiation treatment of limited LN-positive patients (0–3 BC patients [22]. involved nodes) led to a decrease in disease recurrence Therefore, the OPTIMAL study (OPTimizing Irra- [6]. However, there is no consensus on the recommenda- diation through Molecular Assessment of Lymph node) tion of radiotherapy when the nodal involvement ranges aims to demonstrate the non-inferiority of incidental between 1 and 3 LN [7]. irradiation of axillary nodes in comparison to inten- Furthermore, this situation became even more unclear tional irradiation in terms of the 5-year DFS of patients since Giuliano et al. demonstrated no significant ben- with early-stage BC and limited involvement of the SLN efit in loco-regional control with completion of axillary according to the OSNA quantitative score. lymph node dissection (ALND) in comparison to no ALND in patients with 1–2 involved LN [8, 9]. On the other hand, AMAROS [10] and OTOASOR [11] trials Methods/design demonstrated that nodal irradiation should be regarded Study design as the recommended treatment for patients with few The OPTIMAL study is an open-label multicentre and involved LN, instead of ALND. In line with their results, international trial (NCT02335957) conducted in over 40 the Canadian trial NCIC-CTG MA20 [6] showed that sites in Spain, Portugal, and Italy. Eligible patients will be local irradiation combined with regional irradiation randomized with a 1:1 allocation ratio to receive irradia- improved the DFS as well as the loco-regional and dis- tion on breast, tumour bed, axillary and supraclavicular tant control of the disease in high-risk patients with neg- lymph node areas (intentional arm) or only on breast and ative and with positive LN, mostly with 1 to 3 involved tumour bed (incidental arm), as depicted in Fig. 1. Rand- LN, while Poortmans et al. [12] demonstrated that the omization by blocking within centres to minimize imbal- irradiation of the regional nodes in patients with limited ance of treatments among centres will be performed axillary disease results in an increase of the DFS. Darby using the online randomization software RANDI2 (www. et al. [13] reported that, after breast-conserving surgery, dkfz.de; Heidelberg University) embedded in the elec- the application of radiotherapy to the breast reduced tronic case record form (eCRF). All patients will have to mortality and the disease recurrence by half. Finally, a provide their Informed Consent prior to the inclusion in systematic review, which included more than 20,000 the study. patients from 45 studies, concluded that breast irradia- tion reduced the loco-regional relapse even in patients without LN involvement [14]. Later on, the meta-analysis Eligibility criteria conducted by Budach et al. [15, 16] concluded that addi- Inclusion criteria tional regional radiation to the internal mammary and medial supraclavicular LN improved overall and disease- • Older than 18 years old free survival rates in stage I-III BC patients. • Female invasive ductal breast cancer patients The uncertainty about the proper radiation therapy • T1–T2 tumour stage entails the need for a method that standardizes the choice • Previous treatment with breast-conserving surgery of treatment and complements the limited diagnostic without axillary lymphadenectomy information [17–19], such as nodal involvement assess- • OSNA assayed SLN with a TTL within the 250– ment. The OSNA (One-Step Nucleic Acid Amplification) 15,000 copies/µL range assay provides a quantitative value of the metastatic bur- • Karnofsky Performance scale Index ≥ 70% den of the sentinel lymph node (SLN) by measuring the • Written and signed Informed Consent Algara López et al. Radiat Oncol (2020) 15:229 Page 3 of 9 Fig. 1 OPTIMAL-I study design. BC breast cancer, CK19 cytokeratin 19, mRNA messenger ribonucleic acid, SLN sentinel lymph node, TTL total tumour load Algara López et al. Radiat Oncol (2020) 15:229 Page 4 of 9 Exclusion criteria the deep fascia, excluding the muscle and underly- ing ribs. The posterior margin should not extend • Invasive lobular carcinoma and other histologic beyond the deep fascia or the edges of the visible/ subtypes palpable breast in medial and lateral directions. • Bilateral breast cancer • Tumour bed The delineation of the tumour bed is • Male breast cancer patients only mandatory for patients who require a boost. It • Patients who underwent a mastectomy or ipsilat- is strongly recommended to delimit the medial, lat- eral dissection of axillary LN eral, superior, inferior, anterior and posterior margins • Having received previous thoracic irradiation of the surgical cavity at the time of the surgery, with • Systemic neoadjuvant therapy prior to surgery clips or gold seeds. In the absence of implanted fidu- • Contraindications to radiotherapy such as preg- cial markers, the tumour bed may be localised if there nancy or serious collagen disease. is a well-defined seroma, considering visible changes • Other neoplasms and or any associated sever in the computed tomography (CT) or by means of comorbidities that may interfere with the study support from previous mammograms or magnetic resonance imaging. This volume shall be defined by drawing around the implanted markers and changes Endpoints in the surrounding tissue architecture. Primary endpoint • Supraclavicular In the incidental arm, nodes will be The primary endpoint is the non-inferiority of inciden- contoured as part of the procedure whereas, in the tal irradiation of axillary nodes in contrast to inten- control group, this will be hidden so as not to influ- tional irradiation, in terms of the 5-year DFS of patients ence the dosimetric planning. The limits will be cra- diagnosed with early-stage breast cancer with limited nial edge (thyroid cartilage); caudal edge (clavicle involvement of the SLN treated with breast-conserva- head); medial edge (1 cm lateral to the lateral wall of tive surgery without axillary lymphadenectomy. the trachea excluding the thyroid); lateral edge (acro- mioclavicular joint); anterior edge (the sternocleido- Secondary endpoints mastoid muscle and the clavicle); posterior edge (the The secondary endpoints established were the following: trapezius muscle). • Axilla level III In the incidental arm, nodes will be • Loco-regional tumour recurrence in the two treat- contoured as part of the procedure whereas, in the ment arms within the 5-year follow-up period. control group, this will be hidden to not influence • Distant tumour recurrence in the two treatment the dosimetric planning. The limits will be the cra- arms within the 5-year follow-up period. nial edge (5 mm cranial to the axillary vessels); caudal • Acute toxicity induced by either the incidental or edge (1 cm caudal to the axillary vessels); medial edge intentional radiation treatment. (the ribcage); lateral edge (the res major muscle); • Chronic toxicity induced by either the incidental or anterior edge (the pectoralis major muscle); posterior intentional radiation treatment. edge (chest wall and intercostal muscles). • Total irradiation dose (Gy) received in axillary lev- • Axilla level II In the incidental arm, nodes will be els I-III, supraclavicular fossa, and internal mam- contoured as part of the procedure whereas, in the mary chain volumes. control group, this will be hidden to not influence the dosimetric planning. The limits will be the cra- nial edge (5 mm cranial to the axillary vessels); caudal edge (caudal edge of pectoralis minor muscle); medial Radiation procedure edge (the medial border of the pectoralis minor mus- Volume contouring cle); lateral edge (the lateral border of the pectoralis All node areas from axillary levels I-III, the supracla- minor muscle); anterior edge (the anterior surface of vicular fossa and the internal mammary chain must the pectoralis minor muscle); posterior edge (chest be contoured in all patients regardless of the assigned wall and intercostal muscles). arm following the guidelines of the Radiation Therapy • Axilla level I In the incidental arm, nodes will be con- Oncology Group [23]. The Clinical Target Volumes toured as part of the procedure whereas, in the con- (CTV) will be delimited as stated below: trol group, this will be hidden to not influence the dosimetric planning. The limits will be the cranial • Breast The CTV includes the whole breast’s soft tis- edge (1 cm below caput humeri); caudal edge (free sues ranging from 5 mm below the skin surface to edge of pectoralis major muscle); medial edge (the Algara López et al. Radiat Oncol (2020) 15:229 Page 5 of 9 lateral border of the pectoralis minor muscle); lateral tor rotation and shield with multileaf collimator is edge (the medial edge of the dorsolateral muscle); allowed. anterior edge (the plane defined by the anterior sur- • Tumour bed Photons or electrons are allowed. Mini- face of the pectoralis major and minor lateral dorsal); tangential photon fields or single electron field (also posterior edge (the anterior surface of the subscapu- mixed energies) can be utilised. The use of boluses laris muscle). can be considered if needed. Simultaneous integrated • Internal mammary chain Nodes will be contoured boost brachytherapy or intraoperative irradiation in both arms and will be hidden to not influence the is also allowed if the dose contribution to the nodal dosimetric planning. The limits will be the cranial areas can be calculated. The bolus can be used. The edge (cranial edge of rib 1); caudal edge: (cranial edge dose and fractionation choice is left at the discretion of rib 5); medial edge (the edge of the sternum); lat- of the treating physician. eral edge (5 mm lateral of internal mammary vessels • Node areas In the control group, the treatment plan- or 2 cm from the edge of the sternum); anterior edge ning must be optimized to ensure that the nodal (dorsal surface of m. pectoralis major, dorsal surface areas receive the prescribed dose (except for the of the sternum); posterior edge (pleura). internal mammary chain), minimizing the dose at the • Organs at risk The delineation of ipsilateral lung organs at risk. High tangent, AP/PA, conformational and heart is mandatory for the calculation of dose- 3D and IMRT techniques are allowed. In the experi- volume histograms. The ipsilateral lung must be mental group, treatment planning for nodal areas is outlined as a single structure, and care should be not performed. The internal mammary chain will not taken not to include any airways; the CT must cover be irradiated intentionally in any case. the entire lung volume. The heart must be outlined as a single structure to the extent of the pericardial An unplanned gap of up 3 days is acceptable. Longer sac; the major blood vessels (superior and inferior) non-planned interruptions should be compensated by are excluded and the superior extent may be simpli- hyperfractionation of the daily normal dose. fied by identifying the vessels superior to the heart. Contralateral breast, contralateral lung, oesophagus, caput humeri, thyroid and spinal cord may be deline- Dose prescription ated according to institutional protocols. All doses prescribed will follow the International Com- mission on Radiation Units and Measurements guide- Enlarging all volumes by adding a 5–10 mm margin in lines. A minimum of 95% of the volume must receive at all directions to create the planning treatment volume least 95% of the prescribed dose. Less than 5% of the vol- (PTV) is recommended. ume may receive a dose of 105% and less than 2% should receive a dose of 107%, with a maximum overall dose of 110%. The dose in the breast must be 50.0 Gy by 25 Treatment planning fractions of 2.0 Gy in 5 weeks or through hypofraction- The treatment planning must be carried out on a 3D sys- ated schedules as 40.05 Gy in 15 fractions of 2.67 Gy for tem with tissue heterogeneity correction and matrix res- 3 weeks. In the tumour bed, the schedule and total dose olution of 2.5 mm. Techniques in the supine position are are left to the centre’s criteria. In node areas, the inten- allowed and the prone position is not allowed. tional irradiation to the breast and tumour bed will be calculated. Limiting doses for the organs at risk must be: • Breast Tangent beam pair arrangement to encom- (1) ipsilateral lung: V20 less than 25%; and (2) heart: V20 pass the whole breast is recommended, intending to less than 10% and V40 less than 5%. minimize the total dose in the ipsilateral lung and heart. The treatment plan can be optimized with any dose compensation system, (virtual edges, mechani- Radiotherapy verification cal wedges, automatic wedges, field-in-field IMRT Verification methods will be conducted in both arms. and steep and shoot or sliding windows IMRT). Treatment verification is required at the first treatment The treatment will be performed with photons of 6 fraction and allowed on the three first fractions. The MV–15 MV. The isocenter will be located within the verification must be performed using electronic portal breast PTV in the experimental group and may be images of the treatment beam; either with MV or kV. located outside the PTV if the single isocenter tech- Orthogonal images or cone-beam images can be used on nique is being used in the control group. To minimize the verification of the isocentre. Weekly control will be irradiated ipsilateral lung and heart volumes, collima- performed, and systematic daily control is also allowed. Algara López et al. Radiat Oncol (2020) 15:229 Page 6 of 9 Table 1 Schedule of visits and assessments (dots) that will be performed during the 5-year follow-up period Post-intervention (year) 1 2 3 4 5 ● Post-intervention (month) 1 3 6 9 12 18 24 30 36 42 48 54 60 ● ● ● ● ● ● ● ● ● ● ● ● ● Acute toxicity ● ● ● ● ● Physical exam ● ● ● ● ● ● ● ● ● ● ● ● ● Image evaluation of local recurrence Survival and disease recurrence Chronic toxicity (Continuous recording) Co-medication, (adjuvant) (Continuous recording) Follow‑up Criteria for Adverse Events v4.0 (CTCAE) [24] criteria. Patients will be followed for up to 5 years after the Specific follow-up outcomes will be assessed and regis- intervention according to the visit schedule detailed in tered during the visits scheduled as stated in Table 1. Table 1. In each visit, a physical examination and recur- rence assessment will be performed. An image assess- ment will be requested every year after the intervention. Sample size estimation Reasons for discontinuing follow-up must be reported. A total of 1.400 patients must be recruited to show the non-inferiority of the experimental arm (incidental irra- Data collection and analysis diation) with an 80% of statistical power when we assume Data collection a 5-year recurrence rate of 15% in the control arm (inten- nica®, LLC). The demographic and clinical data requested The study data will be recorded in an eCRF (OpenCli- tional irradiation) [8], a 5% non-inferiority margin, a yearly dropout rate of 5%, and a fixed sample design. is depicted in Table 2. Acute and chronic toxicity will Despite the short follow-up period, the large number be recorded according to the Common Terminology of patients to be included in the study will preserve the Table 2 Data collected in the electronic case record form Panel in eCRF Data recorded Informed consent Date I/E criteria Yes; not Demographic data Age at inclusion; Menstrual State Comorbidities If yes: specify Cancer Histology and Receptors, SLN OSNA Tumour grade; Tumour size (maximum diameter); P53 (%); Ki67 (%); Lymphovascular infiltration; Ductal Ca in situ; % Estrogenic receptors; % Progesterone receptors; HER2 receptor status; OSNA TTL of SLN Previous medication (Adjuvant therapy) Drug; Start date; Stop date Type of surgery Tumour surgery; date; Margins Randomization Treatment randomly allocated; Randomization date Radiotherapy intervention Patient completed the allocated treatment (If no: main reason); Start date; End date; Treatment gaps (If yes, reason); Dose per volume (Mean; Median; D95; D5; Volume) in the breast, tumour bed, supraclavicular and axillary levels I-III, and Internal mammary chain Co-medication Drug; Start date; Stop date Survival and disease recurrence Date of follow-up visit (If not performed, reason); Local recurrence; Regional recurrence (If yes: nodal level); Distant recurrence (If yes: organ); Vital status (if dead: date and cause) Image evaluation of local recurrence Technique; Local recurrence (if yes: Maximum diameter) Physical ­examinationa Palpable breast tumour (if yes: size, skin infiltration, inflammatory carcinoma, satellite lesions); Palpable axillary nodes (if yes: size); Palpable supraclavicular nodes (if yes: size); Node staging Acute and chronic toxicity CTCAE term; Grade; Start date; Stop date; Status (recovered w/o sequels; death) eCRF electronic case record form, OSNA One-Step Nucleic Acid Amplification, TTL total tumour load, SLN sentinel lymph node, CTCAE Common Terminology Criteria for Adverse Events a Physical examination is conducted at follow-up visits. It is also addressed at baseline and radiotherapy sessions to confirm the compliance of eligible criteria. If suspicious LNs are detected, the patient will discontinue the study Algara López et al. Radiat Oncol (2020) 15:229 Page 7 of 9 statistical significance of the survival rates and will be the axillary levels I and II are being irradiated. Accord- enough to evaluate differences in the toxicity rates. ingly, more than 70% of patients who had not under- gone lymphadenectomy received LN radiation and even Statistical analysis 19% received unallowed supraclavicular irradiation in Two sets of patients will be analysed: the intention- the study conducted by Giuliano et al. [26]. In line with to-treat (ITT) group, which includes all randomized previous research, a recent larger meta-analysis reported patients, to describe the baseline clinic-pathological that expanding the radiation field to the axillary and patients’ characteristics; and the per-protocol subset, supraclavicular nodes after ALND reduces locoregional which includes patients who finish the intervention treat- recurrences without an improvement on the overall and ment as planned with all dosimetry data completed, for cancer-specific survival [27]. Thus, patients’ survival the endpoint. A descriptive analysis will be carried out would be improved due to the inclusion of the internal reporting absolute and relative frequencies for all vari- mammary chain in the radiation plan. Consequently, elu- ables recorded and stratified by treatment group. Two cidating the effect of node radiation by means incidental analyses of the primary endpoint (disease-free survival or intentional doses in early BC is needed. rate) will be conducted. The confirmatory analyses will Thus, the OPTIMAL trial was designed to outline an be carried out using a non-inferiority long-rank test in evidence-based strategy for the treatment of BC patients the ITT set of patients, which includes all randomized with limited nodal involvement by determining the non- patients regardless of whether the treatment or follow- inferiority of incidental radiation of the axillary nodes up are accomplished. A secondary explanatory analysis in comparison with intentional radiation. The ESTRO will be conducted in the per-protocol subgroup, which (European Society for Radiotherapy and Oncology) will include patients who will have finished the inter- meeting in Assisi stated the importance of further inves- vention treatment with all dosimetry data completed, tigations on regional lymph node treatment and high- by an adjusted Cox regression model using the covari- lighted the design and expected results of the OPTIMAL, ates: centre, age at inclusion, tumour size, hormone SENOMAC, and POSNOC studies, all of them focused receptor status, Her2 receptor status, and OSNA results. on the treatment of patients with limited axillary disease With regards to the secondary endpoints: the outcomes [28]. of loco-regional and distant recurrence will be analysed Final results from the INSEMA and SOUND trials using the Cox approach, this time in the ITT set. Acute [29, 30], which mainly questioned the use of no-ALND toxicity will be analysed by a chi-squared test comparing instead of SLN biopsy procedures in early BC, may also frequencies in both treatment groups. Chronic toxicity contribute to better outline treatment strategies in early will be analysed by using Kaplan Meier curves and com- BC. Nonetheless, even though patients with limited paring them by a standard log-rank test. Interim analy- LN involvement (1–3 macrometastases) are consid- ses are planned when 85 events and 169 events will be ered in these studies, whole-breast radiation therapy is reached. conducted. In the OPTIMAL trial, the SLN status and the limited Current status of the trial LN involvement is determined according to the OSNA From February 2015 to February 2020, a total of 451 quantitative molecular assay [20]. At the time of the patients have been recruited (224 in the intentional arm study design, few studies with regards to OSNA perfor- and 227 in the incidental arm). Currently, acute toxic- mance had been reported. Nowadays, its contribution to ity events have been reported in 319 cases. A total of 48 the improvement of BC patient staging and prognosis has chronic toxicity and 13 recurrence events have been also been widely reported [31]. In fact, LN assessment with informed. OSNA assay and the evaluation of the TTL as a quan- titative score of the metastatic burden of the patients is Discussion recommended for the management of BC patients in the Nowadays, early BC patients with 2 or fewer involved LN SESPM (Spanish Society of Senology and Breast Pathol- undergo nodal irradiation instead of lymphadenectomy ogy) and the NICE (National Institute for Health and although it is unclear whether these patients require Care Excellence) guidelines [32–34]. This technique pro- local-specific treatment. This uncertainty arises from vides quick and standardized results at in-house diagnos- that current studies do not clearly describe the radiation tic laboratories, which prompts the patient’s diagnosis volumes used as adjuvant treatment. Furthermore, some and treatment tailoring since central laboratories are not physicians advocate that the breast of these patients required for a reliable LN assessment. should be treated with high or modified tangents [25]. In conclusion, due to the lack of consensus on the Therefore, although it is not stated as LN irradiation, proper therapeutic strategy of BC patients with few Algara López et al. Radiat Oncol (2020) 15:229 Page 8 of 9 involved LNs standardizing the treatment and diagno- Ethics approval and consent to participate The study will be conducted in accordance with the Declaration of Hel- sis is crucial. Hence, the quantitative score for meta- sinki—Ethical Principles for Medical Research Involving of Human Subjects static burden provided by OSNA assay can contribute by and guidelines for Good Clinical Practice. The Spanish Agency of Medicines improving the discrimination of the BC patients with a and Medical Devices evaluated and classified the study. The study has been approved by the Institution Research Board of each centre. limited nodal involvement who can benefit from inciden- tal radiation as an adjuvant treatment strategy. Consent for publication Not applicable. Abbreviations Competing interests ALND: Axillary lymph node dissection; AP/PA: Anterior-posterior/posterior- Dr. Algara has received consulting honoraria from Sysmex and Aristo and anterior; BC: Breast cancer; CK19: Cytokeratin 19; CTCAE: Common Terminol- speaking honoraria from Siemens and Roche; the rest of authors declare that ogy Criteria for Adverse Events; DFS: Disease-free survival; eCRF: Electronic they have no competing interests. case report form; ESTRO: European Society for Radiotherapy and Oncology; ITT: Intention-to-treat; LN: Lymph node; mRNA: Messenger ribonucleic acid; Author details 1 NICE: National Institute for Health and Care Excellence; OSNA: One-Step Radiation Oncology Department, Del Mar Hospital, Autonomous University Nucleic Acid Amplification; SESPM: Spanish Society of Senology and Breast of Barcelona, Hospital del Mar Medical Research Institute, Passeig Maritim, 25, Pathology; SLN: Sentinel lymph node; TTL: Total tumour load. 08003 Barcelona, Spain. 2 Radiation Oncology Department, Virgen del Rocío University Hospital, Seville, Spain. 3 Radiation Oncology Department, Castellón Acknowledgements Provincial Hospital, Castellón de La Plana, Spain. 4 Radiation Oncology Depart- Thanks to all collaborators of the OPTIMAL study group and all patients who ment, La Fe Polytechnic University Hospital La Fe, Valencia, Spain. 5 Radiation participated in the OPTIMAL study. Aurea Manso, Radiation Oncology, Hospital Oncology Department, Santa Lucia General University Hospital, Cartagena, La Paz, Madrid; Andere Frías, Radiation Oncology, Cruces University Hospital, Spain. 6 Radiation Oncology Department, University Hospital of Leon, León, Bilbao; Ezequiel González, Radiation Oncology, University Clinical Hospital of Spain. 7 Radiation Oncology Department, Del Mar Hospital, Pompeu Fabra Santiago de Compostela; Ana Calín, Radiation Oncology, University General University, Hospital del Mar Medical Research Institute, Barcelona, Spain. 8 Gregorio Marañón, Madrid; Inmaculada Díaz, Radiation Oncology, Oncology Radiation Oncology Department, De La Ribera Hospital, Alzira, Spain. 9 Centre of Galicia, A Coruña; Elena Guimón, Radiation Oncology, Donostia Uni- Radiation Oncology Department, Cabueñes University Hospital, Gijón, Spain. 10 versity Hospital; Antonio José Lozano, Radiation Oncology, University Clinical Araba Txagorritxu University Hospital, Vitoria, Spain. 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Locoregional radiation therapy in patients with high-risk breast cancer Authors’ contributions receiving adjuvant chemotherapy: 20-year results of the British Columbia Study design, manuscript conception and writing: MA and XS. Every author randomized trial. J Natl Cancer Inst. 2005;97:116–26. reviewed the manuscript and substantially contributed to the current patient 5. Overgaard M, Nielsen HM, Overgaard J. Is the benefit of postmastectomy recruitment. All authors read and approved the final manuscript. irradiation limited to patients with four or more positive nodes, as recom- mended in international consensus reports? A subgroup analysis of the Funding DBCG 82 b&c randomized trials. Radiother Oncol. 2007;82:247–53. The sponsor GICOR (Grupo de Investigación Clínica en Oncología Radi- 6. 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