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Radiation therapy after sentinel lymph node biopsy for early stage breast cancer using a magnetic tracer: Results of a single institutional prospective study of tolerance
Cancer/Radiothérapie 23 (2019) 23–27
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ScienceDirect www.sciencedirect.com
Original article
Radiation therapy after sentinel lymph node biopsy for early stage breast cancer using a magnetic tracer: Results of a single institutional prospective study of tolerance Tolérance de la radiothérapie après utilisation d’un traceur ferromagnétique pour la détection du ganglion sentinelle chez des patients opérés d’emblée pour un cancer du sein : résultats d’une étude prospective monocentrique L. Bazire a,∗ , S. Alran b,c , S. El Bamrani b , L. Gaujal b,d , A. Vincent-Salomon e , A. Tardivon f , Y.M. Kirova a a
Department of radiation oncology, institut Curie, 25, rue d’Ulm, 75005 Paris, France Department of surgery, institut Curie, 25, rue d’Ulm, 75005 Paris, France Department of surgery, hôpital Saint-Joseph, 185, rue Raymond-Losserand, 75014 Paris, France d Department of surgery, hôpital Delafontaine, 2, rue du docteur Delafontaine, BP 279, 93205 Saint-Denis cedex, France e Department of pathology, institut Curie, 25, rue d’Ulm, 75005 Paris, France f Department of radiology, institut Curie, 25, rue d’Ulm, 75005 Paris, France b c
a r t i c l e
i n f o
Article history: Received 21 January 2018 Received in revised form 11 March 2018 Accepted 22 March 2018 Keywords: Breast cancer Sentinel lymph node biopsy Super paramagnetic iron oxide Magnetic tracer Breast radiation therapy
a b s t r a c t Purpose. – . The aim of the study was, through a single institutional analysis of a large population of breast cancer patients, to assess the feasibility of and the tolerance to radiotherapy after the use of magnetic detection method for sentinel lymph node biopsy. Material and methods. – The super paramagnetic iron oxide particles database was collected prospectively and identified 520 cases from October 2013 to December 2016 at our institution. All of them received super paramagnetic iron oxide particles injection 20 minutes before the surgical procedure and some of them received also isotope technique. Injection site for super paramagnetic iron oxide particles and isotope was periareolar. Among them, 288 patients received adjuvant radiotherapy. In our study, we evaluated the tolerance of postoperative radiotherapy. Results. – The median age of the patients was 64 years. The median follow-up period was 16 months (range: 1–42 months). Double detection of sentinel lymph node was done in the first 30 patients (10.4%). The sentinel lymph node identification rate was 99.7% (287 out of 288). There were 34 axillary lymph node dissections, of which 58.8% were realized straightaway. The total radiation dose was 50 Gy EQD2 (range: 28.5–66 Gy). Regarding the occurrence of radiodermatitis, 95.8% of patients had grade 0–2 radiodermatitis and 1% had grade 3. During follow-up, 19.4% of patients developed grade 1–2 post-therapeutic fibrosis (of which 92.9% grade 1). Conclusion. – The results of this large-scale study show that the radiotherapy after sentinel lymph node biopsy using super paramagnetic iron oxide particles is feasible, and that no increase of the toxicity was observed. ´ e´ franc¸aise de radiotherapie ´ © 2018 Societ oncologique (SFRO). Published by Elsevier Masson SAS. All rights reserved.
r é s u m é Mots clés : Cancer du sein Ganglion sentinelle
Objectif de l’étude. – Évaluer la faisabilité et la tolérance de la radiothérapie après utilisation d’un traceur ferromagnétique pour la détection du ganglion sentinelle chez des patientes opérées d’emblée pour un cancer du sein.
∗ Corresponding author. E-mail address: [email protected] (L. Bazire). https://doi.org/10.1016/j.canrad.2018.03.008 ´ e´ franc¸aise de radiotherapie ´ 1278-3218/© 2018 Societ oncologique (SFRO). Published by Elsevier Masson SAS. All rights reserved.
24 Radio-isotope Traceur ferromagnétique Radiothérapie
L. Bazire et al. / Cancer/Radiothérapie 23 (2019) 23–27
Matériel et méthodes. – Une base de données d’utilisation d’un traceur ferromagnétique a été collectée prospectivement et a identifié 520 cas d’octobre 2013 à décembre 2016 dans notre établissement. Tous les patients ont rec¸u une injection de traceur ferromagnétique 20 minutes avant l’intervention chirurgicale et certains d’entre eux ont également rec¸u une injection d’isotope. Le site d’injection était périaréolaire. Parmi eux, 288 ont rec¸u une radiothérapie adjuvante. Dans notre étude, nous avons évalué la tolérance de la radiothérapie postopératoire. Résultats. – . L’âge médian des patients était de 64 ans. La période de suivi médian était de 16 mois (1–42). Une double détection du ganglion sentinelle a été réalisée chez les 30 premiers patients (10,4 %). Le taux d’identification du ganglion sentinelle était de 99,7 % (287/288). Il y avait 34 curages axillaires (dont 58,8 % ont été réalisés en situation peropératoire). La dose totale de radiothérapie était de 50 Gy en EQD2 (équivalence 2 Gy) (28,5–66). En ce qui concerne la survenue d’une radiodermite, 95,8 % des patients étaient atteints d’une radiodermite de grade 0–2 et 1 % d’une grade 3. Pendant le suivi, 19,4 % des patients ont été atteints d’une fibrose post-thérapeutique de grade 1-2 (dont 92,9 % de grade 1). Conclusion. – Cette large étude a montré que la radiothérapie après utilisation d’un traceur ferromagnétique pour détecter le ganglion sentinelle était faisable, sans augmentation de la toxicité. ´ e´ franc¸aise de radiotherapie ´ oncologique (SFRO). Publie´ par Elsevier Masson SAS. Tous © 2018 Societ ´ ´ droits reserv es.
1. Introduction Since 1990s, the use of sentinel lymph node biopsy is an appropriate alternative to axillary lymph node dissection for the management of early breast cancer with clinically negative axillary node [1]. The most widely used technique is the isotopic method. It uses a lymphophilic radioactive tracer, technetium-99 (99m Tc), injected into the breast [2]. The sentinel node is identified by a scintigraphy and the surgeon uses a hand-held gamma probe to locate it. This is a cumbersome technique, exposing to radioactivity and requiring access to a nuclear medicine unit. This technique may be combined with the colorimetric method that uses a patent blue dye, but this exposes the patient to the risk of an anaphylactic reaction [3]. Therefore, it is interesting to develop safer and/or easier techniques for detecting sentinel lymph node and to make a realistic assessment of the tolerance, including adjuvant radiotherapy. The aim of the study was, through a single institutional analysis of a large population of patients with breast cancer, to assess the feasibility of and the tolerance to radiotherapy after the use of magnetic detection method for sentinel lymph node biopsy. 2. Materiel and methods 2.1. Magnetic technique Twenty minutes before the surgical procedure, 2 mL of ® Sienna + , a super paramagnetic iron oxide particles tracer was ® injected in the peri-areolar area. The SentiMag hand-held magnetic sensor (magnetometer) was then used to detect the magnetic tracer spread in the lymphatic system. This enabled the surgeon to detect and excise the magnetic sentinel lymph node(s) that require ® histological analysis. The SentiMag probe emits first an alternating magnetic field that is absorbed by the tracer particles. The particles respond in emitting a magnetic field which is detected by the sensor and this guides the surgeon to the location of axillary lymph nodes. The surgeon identified the sentinel lymph nodes via both visual and audio cues, i.e. respectively, brown stain of the lymph node(s) ® and increased frequency on the SentiMag display. For the first 30 patients, double detection was implemented with the isotopic method. Then, only the magnetic procedure was performed. 2.2. Study design Axillary node lymph status was preoperatively studied by physical examination, ultrasound scan and, if necessary, node needle
aspiration cytology or true cut core biopsy. The sentinel lymph node biopsy indication was selected, based on a negative axillary lymph node status of preoperative patients. The super paramagnetic iron oxide particles database was collected prospectively and 520 cases were identified from October 2013 to December 2016 at our institution. A total of 364 histologically verified, consecutive early-stage breast cancer patients (cT0-T2N0) were operated without any neoadjuvant treatment. Among them, 288 patients received adjuvant radiotherapy (Fig. 1). Breast or chest wall radiotherapy was indicated in the presence of invasive breast carcinoma (lobular or ductal) after conservative surgery or mastectomy, respectively. After the conservative surgery, high-energy photons to the whole breast were delivered either by a normofractionated regimen (50 Grays (Gy) over 5 to 6 weeks, five fractions per week, 25 fractions) or by a hypofractionated regimen. There were three hypofractionated regimens, 40 Gy in 15 fractions over 3 weeks, 41.6 Gy in 13 fractions over 5 weeks or 28.5 Gy in five fractions over 5 weeks, using previously described techniques [4–6]. According to institutional indication (age less than 60 years or Elston–Ellis grade III, presence of vascular emboli, absence of hormone receptor expression, local lymph node involvement or tumour size at least 20 mm), a sequential boost (10 to 16 Gy in five to eight fractions) or simultaneous integrated boost (63 Gy in 28 fractions) was delivered to the tumour bed. After mastectomy, electrons to the chest wall were delivered at a dose of 50 Gy over 5 to 6 weeks (five fractions per week, 25 fractions), as previously published [7]. In case of positive sentinel lymph node biopsy (with or without axillary lymph node dissection), a normofractionated regimen was delivered (46 to 48 Gy in 23 to 24 fractions to the supraclavicular and axillary lymph nodes and a photon/electron mix to internal mammary lymph nodes). Patients were placed in the standard supine or isocentric lateral supine positions depending on anatomical and/or dosimetric constraints [8,9]. Delineation of lymph node areas was based on atlases published in the literature [10–13]. The recommendations of the International Commission on Radiation Units and Measurements (ICRU) reports 29, 50 and 62 were complied with [13]. An information sheet explaining radiotherapy, treatment procedures, the possible risks and the telephone number to be contacted in an emergency was given to each patient before starting treatment. Patients were also provided with oral and written information about skin care before and during radiotherapy. A local moisturizer (cream, lotion or oil) before starting radiotherapy and one lukewarm shower per day with neutral pH soap were recommended. Inversely, baths, swimming pools, excessive perspiration, prolonged exposure to sunlight, the use of razors, and the
L. Bazire et al. / Cancer/Radiothérapie 23 (2019) 23–27
25
Fig. 1. Single institutional prospective study of tolerance of radiation therapy for early stage breast cancer after sentinel lymph node biopsy using a magnetic tracer: study flow-chart. SPIO: super paramagnetic iron oxide particles.
application of deodorants, Cologne or perfume were not recommended. We have described patient, tumour and surgery characteristics, and then the tolerance of the adjuvant radiotherapy. During and after completion of adjuvant treatment, patients underwent routine yearly follow-up in which toxicity (specifically radiodermatitis and fibrosis) was assessed according to Common Terminology Criteria for Adverse Events, version 4.0 (CTCAE v4.0). 3. Results Patients and treatments characteristics have been summarized in Tables 1 and 2. Out of 288 patients enrolled, there were 287 women (99.7%), the median age was 64 years (range 30–93) and the median body-mass index was 23.9 kg/m2 (range: 16.3–40.5 kg/m2 ). The median follow-up was 16 months (range: 1–42 months). All patients had preoperative mammography with or without ultrasound scan and 65 (22.6%) had preoperative magnetic resonance imaging. Two hundred and fifty-seven patients (89.2%) had breast conservative surgery (of whom five had a total mastectomy in a second time) and 31 patients had right away a total mastectomy. Of the patients who had conservative surgery, 46 (16%) had oncoplastic surgery. Seventy-two patients (25%) received adjuvant chemotherapy, based on the combination of 5-fluorouacil, epirubicin and cyclophosphamide, and taxanes (docetaxel or paclitaxel) or adriamycin and cyclophosphamide. Double detection of sentinel lymph node was done for the first 30 patients (10.4%). The sentinel lymph node identification rate was 99.7% (287/288). There were 34 axillary lymph node dissection (of which 58.8% were performed during the breast surgery). After surgery, 35 patients (12.2%) had histologically proven axillary lymph node involvement. Invasive carcinoma histologic subtype represented 89.2% of the population study. Sixty percent of the first 30 patients had pigmentation related to super paramagnetic iron oxide particles injection. Then, a deeper injection into the breast
Table 1 Single institutional prospective study of tolerance of radiation therapy for early stage breast cancer after sentinel lymph node biopsy using a magnetic tracer: patient characteristics (n = 288). Median age [range] Gender Female Male Median body mass index [range] Postoperative lymph node status pN0 pN0i+ pN1mi pN ≥ 1 Tumour size [range] Tumour stage (TNM staging) pTis pT1 pT2 pT3 NA Carcinoma histologic subtype Invasive ductal carcinoma Invasive lobular carcinoma Ductal carcinoma in situ Mixed Other Hormone receptor expression Estrogen receptor Progesterone receptor HER2 expression Ki67 < 20% ≥ 20% NA Grade (invasive tumour) I II III NA
64 years [30–93] 287 1 23.9 kg/m2 [16.3–40.5] 228 (79.2%) 8 (2.8%) 17 (5.9%) 35 (12.2%) 16.1 mm [2.5–150] 6 (2.1%) 226 (78.5%) 48 (16.6%) 6 (%) 2 (0.7%) 195 (67.7%) 54 (18.8%) 7 (2.4%) 8 (2.8%) 24 (8.3%) 263 (91.3%) 221 (76.7%) 17 (5.9%) 185 (64.2%) 86 (29.9%) 17 (5.9%) 68 (23.6%) 156 (54.2%) 53 (18.4%) 11 (3.8%)
TNM: Tumour, node, metastasis; HER2: Human epidermal growth factor receptor-2.
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L. Bazire et al. / Cancer/Radiothérapie 23 (2019) 23–27
Table 2 Single institutional prospective study of tolerance of radiation therapy for early stage breast cancer after sentinel lymph node biopsy using a magnetic tracer: treatment characteristics (n = 288). Surgery Breast conservative Mastectomy Breast conservative then mastectomy Sentinel node detection technique Magnetic Magnetic and isotopic Adjuvant systemic treatment Chemotherapy Hormonal therapy
252 (87.5%) 31 (10.8%) 5 (1.7%) 288 (100%) 30 (10.4%) 72 (25.0%) 238 (82.6%)
method (with or without blue dye) as the standard one [19]. Out of the 160 patients studied, the identification rate was 95.0% with the standard technique and 94.4% with the magnetic technique. Like® wise, the Central-European SentiMag prospective clinical study provides that magnetic tracer was performing to localize sentinel lymph node in 150 patients [20]. The detection rates per patient for 99m Tc and magnetic method were 97.3% (146 out of 150) and 98.0% (147 out of 150), respectively. Finally, a meta-analysis confirmed that the magnetic technique was non-inferior for sentinel lymph node detection when compared to standard tracers [21]. However, it is difficult to make any comparison because no other study has assessed the tolerance of radiotherapy in this context. Furthermore some questions remain unanswered: the moment of the disappearance of residual pigmentation related to the sentinel lymph node biopsy, as well as the feasibility of mammograms and MRI images in the follow-up period. Finally, some patients should not receive magnetic tracers, such as patients with genetic features requiring MRI in the follow-up period or patients planned for sparing skin mastectomy who should also avoid the residual pigmentation due to the magnetic technique. 5. Conclusion This large-scale study has shown that the radiotherapy after sentinel lymph node biopsy using super paramagnetic iron oxide particles is feasible, and that no increase of the toxicity was observed. But a longer follow-up period is needed to document the long-term toxicity, as well as the moment of disappearance of the residual pigmentation.
Fig. 2. 3-months super paramagnetic iron oxide particles residual pigmentation in a patient with early stage breast cancer after sentinel lymph node biopsy using a periareolar injection of the tracer.
Disclosure of interest The authors declare that they have no competing interest.
and a decrease in concentration of the tracer allowed to significantly reduce the risk of pigmentation. The total radiation dose was 50 Gy EQD2 (range: 28.5–66 Gy). Regarding the occurrence of radiodermatitis, 95.8% of patients had grade 0-2 radiodermatitis and 1% had grade 3. No grade 4 or above were observed. During the follow-up period, 19.4% of patients developed grade 1-2 posttherapeutic fibrosis (of which 92.9% grade 1). No grade 3 or above were observed. In only 27.8% of cases (n = 80) the moment of the residual pigmentation disappearance was documented and it was between 6 and 9 months after the surgery (Fig. 2). For the other patients, this information was missing in the patients’ records. 4. Discussion This is the largest series ever published in the literature dealing with the issue of the tolerance of radiotherapy after the use of magnetic tracer for sentinel lymph node detection in breast cancer in a single institutional study. Through this study, we have confirmed the previously published preliminary results from our institution reporting that the radiotherapy after sentinel lymph node biopsy using magnetic tracer is feasible and that there was no increased toxicity [14,15]. The super paramagnetic iron oxide particles technique had an excellent tolerance profile, without any increase in toxicity, especially radio induced by comparison with the usual techniques (isotopic and colorimetric methods) [16,17]. In addition, no anaphylactic reaction was observed with iron oxide particles in this study. Several studies evaluated the feasibility and noninferiority of the magnetic method. Shiozawa et al. published the first study combining the standard and isotopic methods [18]. The detection rates of the blue dye and magnetic methods were 80% (24 out of 30) and 77% (23 out of 30), respectively. The SentiMAG Multicentre Trial also compared detection rates using the radioisotope
References [1] Lyman GH, Giuliano AE, Somerfield MR, Benson AB, Bodurka DC, Burstein HJ, et al. American Society of Clinical Oncology guideline recommendations for sentinel lymph node biopsy in early-stage breast cancer. J Clin Oncol 2005;23:7703–20. [2] Veronesi U, Paganelli G, Galimberti V, Viale G, Zurrida S, Bedoni M, et al. Sentinel-node biopsy to avoid axillary dissection in breast cancer with clinically negative lymph-nodes. Lancet 1997;349:1864–7. [3] Giuliano AE, Kirgan DM, Guenther JM, Morton DL. Lymphatic mapping and sentinel lymphadenectomy for breast cancer. Ann Surg 1994;220:391–8. [4] Trialists’ Group START., Bentzen SM, Agrawal RK, Aird EGA, Barrett JM, BarrettLee PJ, et al. The UK Standardisation of Breast Radiotherapy (START) Trial A of radiotherapy hypofractionation for treatment of early breast cancer: a randomised trial. Lancet Oncol 2008;9:331–41. [5] Trialists’ Group START, Bentzen SM, Agrawal RK, Aird EGA, Barrett JM, BarrettLee PJ, et al. The UK Standardisation of Breast Radiotherapy (START) Trial B of radiotherapy hypofractionation for treatment of early breast cancer: a randomised trial. Lancet 2008;371:1098–107. [6] Kirova YM, Campana F, Savignoni A, Laki F, Muresan M, Dendale R, et al. Breast-conserving treatment in the elderly: long-term results of adjuvant hypofractionated and normofractionated radiotherapy. Int J Radiat Oncol Biol Phys 2009;75:76–81. [7] Kirova YM, Campana F, Fournier-Bidoz N, Stilhart A, Dendale R, Bollet MA, et al. Postmastectomy electron beam chest wall irradiation in women with breast cancer: a clinical step toward conformal electron therapy. Int J Radiat Oncol Biol Phys 2007;69:1139–44. [8] Fournier-Bidoz N, Kirova YM, Campana F, Dendale R, Fourquet A. Simplified field-in-field technique for a large-scale implementation in breast radiation treatment. Med Dosim 2012;37:131–7. [9] Kirova YM, Hijal T, Campana F, Fournier-Bidoz N, Stilhart A, Dendale R, et al. Whole breast radiotherapy in the lateral decubitus position: a dosimetric and clinical solution to decrease the doses to the organs at risk (OAR). Radiother Oncol 2014;110:477–81. [10] Offersen BV, Boersma LJ, Kirkove C, Hol S, Aznar MC, Biete Sola A, et al. ESTRO consensus guideline on target volume delineation for elective radiation therapy of early stage breast cancer. Radiother Oncol 2015;114:3–10. [11] Kirova YM, Castro Pena P, Dendale R, Servois V, Bollet MA, Fournier-Bidoz N, et al. Simplified rules for everyday delineation of lymph node areas for breast cancer radiotherapy. Br J Radiol 2010;83:683–6.
L. Bazire et al. / Cancer/Radiothérapie 23 (2019) 23–27 [12] Kirova YM, Servois V, Campana F, Dendale R, Bollet MA, Laki F, et al. CT-scan based localization of the internal mammary chain and supra clavicular nodes for breast cancer radiation therapy planning. Radiother Oncol 2006;79:310–5. [13] Landberg T, Chavaudra J, Dobbs J, Hanks G, Johansson KA, Möller T, et al. Report 50. JICRU 1993;os26, http://dx.doi.org/10.1093/jicru/os26.1.Report50. [14] Kirova YM, Chilles A, Ly N, Tardivon A, Alran S. Radiotherapy after sentinel lymph node biopsy using Sienna + ® , super paramagnetic iron oxide particles: prospective study of tolerance and toxicity. Radiother Oncol 2017;122:485. [15] Ly N, Sauvan M, Chillès A, Ratour J, Musmesci N, Rouzier R, et al. Feasibility and tolerance of Sienna + (® ) for the procedure of sentinel lymph node biopsy: Single centre pilot study of 30 consecutive patients. Cancer Radiother 2017;21:305–6. [16] Masannat Y, Shenoy H, Speirs V, Hanby A, Horgan K. Properties and characteristics of the dyes injected to assist axillary sentinel node localization in breast surgery. Eur J Surg Oncol 2006;32:381–4. [17] Paulinelli RR, Freitas JrR, Rahal RM de S, Oliveira LF de P, Vilela MHT, Moreira M, et al. A prospective randomized trial comparing patent blue and methylene
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blue for the detection of the sentinel lymph node in breast cancer patients. Rev Assoc Medica Bras 1992 2017;63:118–23. Shiozawa M, Lefor AT, Hozumi Y, Kurihara K, Sata N, Yasuda Y, et al. Sentinel lymph node biopsy in patients with breast cancer using superparamagnetic iron oxide and a magnetometer. Breast Cancer 2013;20:223–9. Douek M, Klaase J, Monypenny I, Kothari A, Zechmeister K, Brown D, et al. Sentinel node biopsy using a magnetic tracer versus standard technique: the SentiMAG Multicentre Trial. Ann Surg Oncol 2014;21: 1237–45. Thill M, Kurylcio A, Welter R, van Haasteren V, Grosse B, Berclaz G, et al. The Central-European SentiMag study: sentinel lymph node biopsy with superparamagnetic iron oxide (SPIO) vs. radioisotope. Breast 2014;23: 175–9. Teshome M, Wei C, Hunt KK, Thompson A, Rodriguez K, Mittendorf EA. Use of a magnetic tracer for sentinel lymph node detection in earlystage breast cancer patients: a meta-analysis. Ann Surg Oncol 2016;23: 1508–14.
Disponible en ligne sur
ScienceDirect www.sciencedirect.com
Original article
Radiation therapy after sentinel lymph node biopsy for early stage breast cancer using a magnetic tracer: Results of a single institutional prospective study of tolerance Tolérance de la radiothérapie après utilisation d’un traceur ferromagnétique pour la détection du ganglion sentinelle chez des patients opérés d’emblée pour un cancer du sein : résultats d’une étude prospective monocentrique L. Bazire a,∗ , S. Alran b,c , S. El Bamrani b , L. Gaujal b,d , A. Vincent-Salomon e , A. Tardivon f , Y.M. Kirova a a
Department of radiation oncology, institut Curie, 25, rue d’Ulm, 75005 Paris, France Department of surgery, institut Curie, 25, rue d’Ulm, 75005 Paris, France Department of surgery, hôpital Saint-Joseph, 185, rue Raymond-Losserand, 75014 Paris, France d Department of surgery, hôpital Delafontaine, 2, rue du docteur Delafontaine, BP 279, 93205 Saint-Denis cedex, France e Department of pathology, institut Curie, 25, rue d’Ulm, 75005 Paris, France f Department of radiology, institut Curie, 25, rue d’Ulm, 75005 Paris, France b c
a r t i c l e
i n f o
Article history: Received 21 January 2018 Received in revised form 11 March 2018 Accepted 22 March 2018 Keywords: Breast cancer Sentinel lymph node biopsy Super paramagnetic iron oxide Magnetic tracer Breast radiation therapy
a b s t r a c t Purpose. – . The aim of the study was, through a single institutional analysis of a large population of breast cancer patients, to assess the feasibility of and the tolerance to radiotherapy after the use of magnetic detection method for sentinel lymph node biopsy. Material and methods. – The super paramagnetic iron oxide particles database was collected prospectively and identified 520 cases from October 2013 to December 2016 at our institution. All of them received super paramagnetic iron oxide particles injection 20 minutes before the surgical procedure and some of them received also isotope technique. Injection site for super paramagnetic iron oxide particles and isotope was periareolar. Among them, 288 patients received adjuvant radiotherapy. In our study, we evaluated the tolerance of postoperative radiotherapy. Results. – The median age of the patients was 64 years. The median follow-up period was 16 months (range: 1–42 months). Double detection of sentinel lymph node was done in the first 30 patients (10.4%). The sentinel lymph node identification rate was 99.7% (287 out of 288). There were 34 axillary lymph node dissections, of which 58.8% were realized straightaway. The total radiation dose was 50 Gy EQD2 (range: 28.5–66 Gy). Regarding the occurrence of radiodermatitis, 95.8% of patients had grade 0–2 radiodermatitis and 1% had grade 3. During follow-up, 19.4% of patients developed grade 1–2 post-therapeutic fibrosis (of which 92.9% grade 1). Conclusion. – The results of this large-scale study show that the radiotherapy after sentinel lymph node biopsy using super paramagnetic iron oxide particles is feasible, and that no increase of the toxicity was observed. ´ e´ franc¸aise de radiotherapie ´ © 2018 Societ oncologique (SFRO). Published by Elsevier Masson SAS. All rights reserved.
r é s u m é Mots clés : Cancer du sein Ganglion sentinelle
Objectif de l’étude. – Évaluer la faisabilité et la tolérance de la radiothérapie après utilisation d’un traceur ferromagnétique pour la détection du ganglion sentinelle chez des patientes opérées d’emblée pour un cancer du sein.
∗ Corresponding author. E-mail address: [email protected] (L. Bazire). https://doi.org/10.1016/j.canrad.2018.03.008 ´ e´ franc¸aise de radiotherapie ´ 1278-3218/© 2018 Societ oncologique (SFRO). Published by Elsevier Masson SAS. All rights reserved.
24 Radio-isotope Traceur ferromagnétique Radiothérapie
L. Bazire et al. / Cancer/Radiothérapie 23 (2019) 23–27
Matériel et méthodes. – Une base de données d’utilisation d’un traceur ferromagnétique a été collectée prospectivement et a identifié 520 cas d’octobre 2013 à décembre 2016 dans notre établissement. Tous les patients ont rec¸u une injection de traceur ferromagnétique 20 minutes avant l’intervention chirurgicale et certains d’entre eux ont également rec¸u une injection d’isotope. Le site d’injection était périaréolaire. Parmi eux, 288 ont rec¸u une radiothérapie adjuvante. Dans notre étude, nous avons évalué la tolérance de la radiothérapie postopératoire. Résultats. – . L’âge médian des patients était de 64 ans. La période de suivi médian était de 16 mois (1–42). Une double détection du ganglion sentinelle a été réalisée chez les 30 premiers patients (10,4 %). Le taux d’identification du ganglion sentinelle était de 99,7 % (287/288). Il y avait 34 curages axillaires (dont 58,8 % ont été réalisés en situation peropératoire). La dose totale de radiothérapie était de 50 Gy en EQD2 (équivalence 2 Gy) (28,5–66). En ce qui concerne la survenue d’une radiodermite, 95,8 % des patients étaient atteints d’une radiodermite de grade 0–2 et 1 % d’une grade 3. Pendant le suivi, 19,4 % des patients ont été atteints d’une fibrose post-thérapeutique de grade 1-2 (dont 92,9 % de grade 1). Conclusion. – Cette large étude a montré que la radiothérapie après utilisation d’un traceur ferromagnétique pour détecter le ganglion sentinelle était faisable, sans augmentation de la toxicité. ´ e´ franc¸aise de radiotherapie ´ oncologique (SFRO). Publie´ par Elsevier Masson SAS. Tous © 2018 Societ ´ ´ droits reserv es.
1. Introduction Since 1990s, the use of sentinel lymph node biopsy is an appropriate alternative to axillary lymph node dissection for the management of early breast cancer with clinically negative axillary node [1]. The most widely used technique is the isotopic method. It uses a lymphophilic radioactive tracer, technetium-99 (99m Tc), injected into the breast [2]. The sentinel node is identified by a scintigraphy and the surgeon uses a hand-held gamma probe to locate it. This is a cumbersome technique, exposing to radioactivity and requiring access to a nuclear medicine unit. This technique may be combined with the colorimetric method that uses a patent blue dye, but this exposes the patient to the risk of an anaphylactic reaction [3]. Therefore, it is interesting to develop safer and/or easier techniques for detecting sentinel lymph node and to make a realistic assessment of the tolerance, including adjuvant radiotherapy. The aim of the study was, through a single institutional analysis of a large population of patients with breast cancer, to assess the feasibility of and the tolerance to radiotherapy after the use of magnetic detection method for sentinel lymph node biopsy. 2. Materiel and methods 2.1. Magnetic technique Twenty minutes before the surgical procedure, 2 mL of ® Sienna + , a super paramagnetic iron oxide particles tracer was ® injected in the peri-areolar area. The SentiMag hand-held magnetic sensor (magnetometer) was then used to detect the magnetic tracer spread in the lymphatic system. This enabled the surgeon to detect and excise the magnetic sentinel lymph node(s) that require ® histological analysis. The SentiMag probe emits first an alternating magnetic field that is absorbed by the tracer particles. The particles respond in emitting a magnetic field which is detected by the sensor and this guides the surgeon to the location of axillary lymph nodes. The surgeon identified the sentinel lymph nodes via both visual and audio cues, i.e. respectively, brown stain of the lymph node(s) ® and increased frequency on the SentiMag display. For the first 30 patients, double detection was implemented with the isotopic method. Then, only the magnetic procedure was performed. 2.2. Study design Axillary node lymph status was preoperatively studied by physical examination, ultrasound scan and, if necessary, node needle
aspiration cytology or true cut core biopsy. The sentinel lymph node biopsy indication was selected, based on a negative axillary lymph node status of preoperative patients. The super paramagnetic iron oxide particles database was collected prospectively and 520 cases were identified from October 2013 to December 2016 at our institution. A total of 364 histologically verified, consecutive early-stage breast cancer patients (cT0-T2N0) were operated without any neoadjuvant treatment. Among them, 288 patients received adjuvant radiotherapy (Fig. 1). Breast or chest wall radiotherapy was indicated in the presence of invasive breast carcinoma (lobular or ductal) after conservative surgery or mastectomy, respectively. After the conservative surgery, high-energy photons to the whole breast were delivered either by a normofractionated regimen (50 Grays (Gy) over 5 to 6 weeks, five fractions per week, 25 fractions) or by a hypofractionated regimen. There were three hypofractionated regimens, 40 Gy in 15 fractions over 3 weeks, 41.6 Gy in 13 fractions over 5 weeks or 28.5 Gy in five fractions over 5 weeks, using previously described techniques [4–6]. According to institutional indication (age less than 60 years or Elston–Ellis grade III, presence of vascular emboli, absence of hormone receptor expression, local lymph node involvement or tumour size at least 20 mm), a sequential boost (10 to 16 Gy in five to eight fractions) or simultaneous integrated boost (63 Gy in 28 fractions) was delivered to the tumour bed. After mastectomy, electrons to the chest wall were delivered at a dose of 50 Gy over 5 to 6 weeks (five fractions per week, 25 fractions), as previously published [7]. In case of positive sentinel lymph node biopsy (with or without axillary lymph node dissection), a normofractionated regimen was delivered (46 to 48 Gy in 23 to 24 fractions to the supraclavicular and axillary lymph nodes and a photon/electron mix to internal mammary lymph nodes). Patients were placed in the standard supine or isocentric lateral supine positions depending on anatomical and/or dosimetric constraints [8,9]. Delineation of lymph node areas was based on atlases published in the literature [10–13]. The recommendations of the International Commission on Radiation Units and Measurements (ICRU) reports 29, 50 and 62 were complied with [13]. An information sheet explaining radiotherapy, treatment procedures, the possible risks and the telephone number to be contacted in an emergency was given to each patient before starting treatment. Patients were also provided with oral and written information about skin care before and during radiotherapy. A local moisturizer (cream, lotion or oil) before starting radiotherapy and one lukewarm shower per day with neutral pH soap were recommended. Inversely, baths, swimming pools, excessive perspiration, prolonged exposure to sunlight, the use of razors, and the
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Fig. 1. Single institutional prospective study of tolerance of radiation therapy for early stage breast cancer after sentinel lymph node biopsy using a magnetic tracer: study flow-chart. SPIO: super paramagnetic iron oxide particles.
application of deodorants, Cologne or perfume were not recommended. We have described patient, tumour and surgery characteristics, and then the tolerance of the adjuvant radiotherapy. During and after completion of adjuvant treatment, patients underwent routine yearly follow-up in which toxicity (specifically radiodermatitis and fibrosis) was assessed according to Common Terminology Criteria for Adverse Events, version 4.0 (CTCAE v4.0). 3. Results Patients and treatments characteristics have been summarized in Tables 1 and 2. Out of 288 patients enrolled, there were 287 women (99.7%), the median age was 64 years (range 30–93) and the median body-mass index was 23.9 kg/m2 (range: 16.3–40.5 kg/m2 ). The median follow-up was 16 months (range: 1–42 months). All patients had preoperative mammography with or without ultrasound scan and 65 (22.6%) had preoperative magnetic resonance imaging. Two hundred and fifty-seven patients (89.2%) had breast conservative surgery (of whom five had a total mastectomy in a second time) and 31 patients had right away a total mastectomy. Of the patients who had conservative surgery, 46 (16%) had oncoplastic surgery. Seventy-two patients (25%) received adjuvant chemotherapy, based on the combination of 5-fluorouacil, epirubicin and cyclophosphamide, and taxanes (docetaxel or paclitaxel) or adriamycin and cyclophosphamide. Double detection of sentinel lymph node was done for the first 30 patients (10.4%). The sentinel lymph node identification rate was 99.7% (287/288). There were 34 axillary lymph node dissection (of which 58.8% were performed during the breast surgery). After surgery, 35 patients (12.2%) had histologically proven axillary lymph node involvement. Invasive carcinoma histologic subtype represented 89.2% of the population study. Sixty percent of the first 30 patients had pigmentation related to super paramagnetic iron oxide particles injection. Then, a deeper injection into the breast
Table 1 Single institutional prospective study of tolerance of radiation therapy for early stage breast cancer after sentinel lymph node biopsy using a magnetic tracer: patient characteristics (n = 288). Median age [range] Gender Female Male Median body mass index [range] Postoperative lymph node status pN0 pN0i+ pN1mi pN ≥ 1 Tumour size [range] Tumour stage (TNM staging) pTis pT1 pT2 pT3 NA Carcinoma histologic subtype Invasive ductal carcinoma Invasive lobular carcinoma Ductal carcinoma in situ Mixed Other Hormone receptor expression Estrogen receptor Progesterone receptor HER2 expression Ki67 < 20% ≥ 20% NA Grade (invasive tumour) I II III NA
64 years [30–93] 287 1 23.9 kg/m2 [16.3–40.5] 228 (79.2%) 8 (2.8%) 17 (5.9%) 35 (12.2%) 16.1 mm [2.5–150] 6 (2.1%) 226 (78.5%) 48 (16.6%) 6 (%) 2 (0.7%) 195 (67.7%) 54 (18.8%) 7 (2.4%) 8 (2.8%) 24 (8.3%) 263 (91.3%) 221 (76.7%) 17 (5.9%) 185 (64.2%) 86 (29.9%) 17 (5.9%) 68 (23.6%) 156 (54.2%) 53 (18.4%) 11 (3.8%)
TNM: Tumour, node, metastasis; HER2: Human epidermal growth factor receptor-2.
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Table 2 Single institutional prospective study of tolerance of radiation therapy for early stage breast cancer after sentinel lymph node biopsy using a magnetic tracer: treatment characteristics (n = 288). Surgery Breast conservative Mastectomy Breast conservative then mastectomy Sentinel node detection technique Magnetic Magnetic and isotopic Adjuvant systemic treatment Chemotherapy Hormonal therapy
252 (87.5%) 31 (10.8%) 5 (1.7%) 288 (100%) 30 (10.4%) 72 (25.0%) 238 (82.6%)
method (with or without blue dye) as the standard one [19]. Out of the 160 patients studied, the identification rate was 95.0% with the standard technique and 94.4% with the magnetic technique. Like® wise, the Central-European SentiMag prospective clinical study provides that magnetic tracer was performing to localize sentinel lymph node in 150 patients [20]. The detection rates per patient for 99m Tc and magnetic method were 97.3% (146 out of 150) and 98.0% (147 out of 150), respectively. Finally, a meta-analysis confirmed that the magnetic technique was non-inferior for sentinel lymph node detection when compared to standard tracers [21]. However, it is difficult to make any comparison because no other study has assessed the tolerance of radiotherapy in this context. Furthermore some questions remain unanswered: the moment of the disappearance of residual pigmentation related to the sentinel lymph node biopsy, as well as the feasibility of mammograms and MRI images in the follow-up period. Finally, some patients should not receive magnetic tracers, such as patients with genetic features requiring MRI in the follow-up period or patients planned for sparing skin mastectomy who should also avoid the residual pigmentation due to the magnetic technique. 5. Conclusion This large-scale study has shown that the radiotherapy after sentinel lymph node biopsy using super paramagnetic iron oxide particles is feasible, and that no increase of the toxicity was observed. But a longer follow-up period is needed to document the long-term toxicity, as well as the moment of disappearance of the residual pigmentation.
Fig. 2. 3-months super paramagnetic iron oxide particles residual pigmentation in a patient with early stage breast cancer after sentinel lymph node biopsy using a periareolar injection of the tracer.
Disclosure of interest The authors declare that they have no competing interest.
and a decrease in concentration of the tracer allowed to significantly reduce the risk of pigmentation. The total radiation dose was 50 Gy EQD2 (range: 28.5–66 Gy). Regarding the occurrence of radiodermatitis, 95.8% of patients had grade 0-2 radiodermatitis and 1% had grade 3. No grade 4 or above were observed. During the follow-up period, 19.4% of patients developed grade 1-2 posttherapeutic fibrosis (of which 92.9% grade 1). No grade 3 or above were observed. In only 27.8% of cases (n = 80) the moment of the residual pigmentation disappearance was documented and it was between 6 and 9 months after the surgery (Fig. 2). For the other patients, this information was missing in the patients’ records. 4. Discussion This is the largest series ever published in the literature dealing with the issue of the tolerance of radiotherapy after the use of magnetic tracer for sentinel lymph node detection in breast cancer in a single institutional study. Through this study, we have confirmed the previously published preliminary results from our institution reporting that the radiotherapy after sentinel lymph node biopsy using magnetic tracer is feasible and that there was no increased toxicity [14,15]. The super paramagnetic iron oxide particles technique had an excellent tolerance profile, without any increase in toxicity, especially radio induced by comparison with the usual techniques (isotopic and colorimetric methods) [16,17]. In addition, no anaphylactic reaction was observed with iron oxide particles in this study. Several studies evaluated the feasibility and noninferiority of the magnetic method. Shiozawa et al. published the first study combining the standard and isotopic methods [18]. The detection rates of the blue dye and magnetic methods were 80% (24 out of 30) and 77% (23 out of 30), respectively. The SentiMAG Multicentre Trial also compared detection rates using the radioisotope
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