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Synchronous bilateral chest wall irradiation with regional nodal irradiation: A literature review of techniques and a case study

Published:August 09, 2022DOI:https://doi.org/10.1016/j.ejmp.2022.07.005

      Highlights

      • Systematic review on synchronous bilateral breast cancer (SBBC) radiotherapy.
      • Dosimetric comparison studies included in the review follow the PRISMA guidelines.
      • Modern radiotherapy techniques deliver safe and efficient plans for SBBC patients.
      • Case report comparing IMRT and VMAT for SBBC with Truebeam-Edge.

      Abstract

      The optimal radiotherapy technique for patients requiring both breasts or chest walls simultaneous irradiation with or without regional nodal irradiation is currently under investigation. In the last decade several publications present case reports and case series of patients treated with adjuvant radiotherapy in both breasts or chest walls for synchronous bilateral breast cancer (SBBC) with modern radiotherapy techniques. This article presents a systematic review of relevant literature as well as a case report of a SBBC patient who received bilateral chest wall radiotherapy with regional nodal irradiation at our institution with Truebeam – Edge Linear Accelerator. Solid evidence is provided that the practice of avoiding adjuvant radiotherapy in SBBC out of fear of toxicity with older radiotherapy techniques is outdated. Modern techniques can safely and effectively deliver treatment to patients requiring both sides irradiation and even in mastectomy patients in need of regional nodal irradiation.

      Keywords

      Abbreviations:

      SBBC (synchronous bilateral breast cancer), RT (radiotherapy), SIB (simultaneous inetgrated boost), OAR (organs at risk), PTV (planning target volume)

      Introduction

      Synchronous bilateral breast cancer (SBBC) continues to present a therapeutic challenge as no uniform guidelines exist for this rare disease. Even though it is often diagnosed at an early stage, bilateral mastectomy is preferred in most cases and (neo)adjuvant chemotherapy and adjuvant radiotherapy (RT) are added according to the risk of recurrence and metastasis [
      • Sakai T.
      • Ozkurt E.
      • DeSantis S.
      • Wong S.M.
      • Rosenbaum L.
      • Zheng H.
      • et al.
      National trends of synchronous bilateral breast cancer incidence in the United States.
      ]. Adjuvant RT is decided independently for each chest wall or breast depending on their respective recurrence risk [
      • Jobsen J.J.
      • Palen J.V.D.
      • Ong F.
      • Meerwaldt J.H.
      Synchronous, bilateral breast cancer: Prognostic value and incidence.
      ,
      • Lee M.M.
      • Heimann R.
      • Powers C.
      • Weichselbaum R.R.
      • Chen L.M.
      Efficacy of Breast Conservation Therapy in Early Stage Bilateral Breast Cancer.
      ,
      • O’Brien J.A.
      • Ho A.
      • Wright G.P.
      • Stempel M.
      • Patil S.
      • Krause K.
      • et al.
      Breast-Conserving Surgery in Bilateral Breast Cancer.
      ]. When both breasts or chest walls are to be irradiated simultaneously, technical concerns arise for the optimal treatment plan [
      • O’Brien J.A.
      • Ho A.
      • Wright G.P.
      • Stempel M.
      • Patil S.
      • Krause K.
      • et al.
      Breast-Conserving Surgery in Bilateral Breast Cancer.
      ].
      Until recently, SBBC irradiation was avoided as the traditional tangential field irradiation either by two-dimensional (2D-RT) or by three- dimensional conformal radiation therapy (3D-CRT) significantly increased the dose of organs at risk and was technically difficult because of large irradiation fields and possible field overlaps [
      • Yamauchi C.
      • Mitsumori M.
      • Nagata Y.
      • Kokubo M.
      • Inamoto T.
      • Mise K.
      • et al.
      Bilateral breast-conserving therapy for bilateral breast cancer: results and consideration of radiation technique.
      ]. Βilateral mastectomy was preferred over breast conserving surgery (BCS) to eliminate the need for adjuvant RT and at least restrict it to the side with regional nodal disease [
      • Sakai T.
      • Ozkurt E.
      • DeSantis S.
      • Wong S.M.
      • Rosenbaum L.
      • Zheng H.
      • et al.
      National trends of synchronous bilateral breast cancer incidence in the United States.
      ]. In the last decade, modern techniques present new possibilities for the RT of SBBC with improved planning target volume (PTV) coverage and organs at risk (OAR) sparing. The option of BCS combined with bilateral irradiation should, therefore, be reconsidered. The optimal radiation therapy technique for this rare disease is actively being investigated; no consensus has yet been reached.
      Several studies have tried to compare different RT techniques for SBBC: (3D-CRT), intensity modulated RT (IMRT), volumetric modulated arc RT (VMAT), hybrid techniques, direct tomotherapy (DT), helical tomotherapy (HT) and intensity modulated proton therapy (IMPT). Hypofractionated treatments and simultaneous integrated boost (SIB) techniques have also been studied to find solutions better adapted to the clinical problem of ameliorating efficacy and eliminating toxicity of simultaneous breast/chest wall irradiation on both sides. In this review article the results of studies selected by PRISMA guidelines methodology [
      • Page M.J.
      • McKenzie J.E.
      • Bossuyt P.M.
      • Boutron I.
      • Hoffmann T.C.
      • Mulrow C.D.
      • et al.
      The PRISMA 2020 statement: An updated guideline for reporting systematic reviews.
      ], are presented in a comparative way to illustrate differences in dosimetric results depending on technique and fractionation. A qualitative analysis of these results has been made in this review to point out strengths and drawbacks of each technique to help physicians’ choice of treatment technique and fractionation for individual SBBC patients. Planning comparison between the most common modern RT techniques, IMRT and VMAT, was then undertaken for a SBBC patient from our institution requiring synchronous bilateral chest wall irradiation and unilateral regional nodal irradiation (RNI). Bilateral mastectomy patients in need of RNI have not been adequately represented in the SBBC RT studies and this case report further supports the conclusion of this review on the safety and efficacy of adjuvant RT in all SBBC patients.

      Methods

      For the systematic review process PRISMA guidelines were followed [
      • Page M.J.
      • McKenzie J.E.
      • Bossuyt P.M.
      • Boutron I.
      • Hoffmann T.C.
      • Mulrow C.D.
      • et al.
      The PRISMA 2020 statement: An updated guideline for reporting systematic reviews.
      ]. Bibliography on SBBC was researched to find studies with female patients treated on both breasts/chest walls with adjuvant RT after tumor resection and presenting real patient dosimetric data of external beam radiation therapy with the following techniques: conventional and hypofractionated treatment with 3D-CRT, IMRT, VMAT, hybrid techniques, DT, HT and IMPT. Studies where breasts were treated with no boost, sequential boost, or simultaneous integrated boost (SIB) were all included. Both breast and chest wall irradiation were included as long as it was simultaneously delivered on both sides. Studies allowing RNI were also included in the review process.
      English speaking literature was researched through the databases PubMed, Cochrane Datatbase, Scopus and Google Scholar from 01 January 1998 until 01 November 2021 with the combination of the terms “synchronous bilateral breast cancer” and “RT” resulting in 38, 2, 143 and 109 articles, respectively. All abstracts were read for relevancy, and this resulted in the elimination of 22 out the 38 articles of the PubMed Database, 2 out the 2 articles in Cochrane Database, 130 out of 143 articles of Scopus and 105 out of 109 articles of Google Scholar. Articles were eliminated for any of the following reasons: non-published studies, duplicate studies, metachronous bilateral breast cancer, unilatelal breast cancer, metastatic disease, different primary, brachytherapy, male patients, inoperable patients or non-dosimetric studies and studies of less common techniques such as opposed lateral beams with 2D-RT [
      • Farooqi A.S.
      • Sun T.-L.
      • Thang S.
      • Shaitelman S.F.
      Treatment of Bilateral Breast Cancer and Regional Nodes Using an Opposed Lateral Beam Arrangement.
      ], electron arc therapy [
      • Sharma P.K.
      • Jamema S.V.
      • Kaushik K.
      • Budrukkar A.
      • Jalali R.
      • Deshpande D.D.
      • et al.
      Electron arc therapy for bilateral chest wall irradiation: treatment planning and dosimetric study.
      ], and smaller than usual prescribed doses. The process of mining relevant articles for the review is depicted on Fig. 1.
      Figure thumbnail gr1
      Fig. 1Databases search by PRISMA guidelines.
      As for the case report, a patient with SBBC treated at our institution with bilateral chest wall and unilateral axillary and supraclavicular RT with the Truebeam-Edge Linear Accelerator is presented to elaborate how the treating radiation oncologist decided on the most appropriate technique parameters for the specific patient based on the results from the systemic review. Details of the medical records before and during treatment and follow-up period as well as the RT treatment dosimetric parameters were recorded prospectively and are presented in this article after the informed consent of the patient. The plan characteristics for our patient are then compared with those of the respective techniques presented in the articles included in the review.

      Results

      As a result of the PRISMA- based database search described above, in total 32 articles were included in the study. Each article was searched for number of patients included the percentage of patients with BCS in both sides, the percentage of patients receiving boost or RNI in any side, the prescription used, the fractionation and treatment technique chosen in each study and the PTV coverage, OAR sparing and treatment efficiency parameters. To present our findings in a more comparable way, articles were separated by fractionation and SIB technique. Of the 31 articles, 19 papers focused on comparing different RT techniques with conventional fractionation and no boost or sequential boost, six studies used SIB prescription for SBBC, and six articles investigated different RT techniques with hypofractionation. Table 1, Table 2, Table 3 present the main findings of the respective three types of articles.
      Table 1Dosimetric results of studies with conventional fractionation and no boost or sequential boost.
      StudyPtsBCS only (%)RNI (%)BOOSTTECNIQUEΒΟΤPTV V95%Dmax (Gy)MHD (Gy)MLD (Gy)LV20 (%)LADmax (Gy)LADmean (Gy)TNTVMUCIHI
      Alhefny et al.915NRNRno3D-CRTNRD95% L 47.2/R 47.3D5% L51.6/R 53.57.2NR13.731.413.3NRNR0.740.884
      IMRTD95% L48.4/R 48.4D5% L51.8/R 53.711.4NR17.436.7180.940.934
      VMATD95% L41.1/R 47.3D5% L53.5/R 53.78NR24.838240.940.884
      Cheng et al.2010100nonoHT11 minNR109.33.536.579.1NR19.3NRNR0.851.061
      VMAT3.9 minNR109.95.69.6614.4NR25.8NRNR0.851.081
      IMRTstep and shoot6.1 minNR110.13.88.5314.7NR27.9NRNR0.7511
      FIF4.6 minNR111.64.89.4216.4NR31NRNR0.751.11
      Sun et al.1811100nonoΙΜRTNRV100% 96.9D2% 54.258.815.647.321.5mean 613440.850.12
      VMATNR96.454.34.97.210.238.914.46.611130.850.112
      IMPTNR97.653.414.27.927.65.44NR0.850.082
      HTNR96.853.34.87.19.634.39.97.1NR0.850.072
      Cho et al.221566.7100 (L side)noVMAT115.3sec96.7D2% 5413.214.227.533.721.8NR795.11.561.071
      hybrid VMAT-3D-CRT73.5sec97.1D2% 54.4811.819.23314.7NR827.51.561.181
      modified hybrid −3D-CRT77.5sec95.3D2% 54811.61932.914.7NR811.71.561.111
      StudyPtsBCS only (%)RNI (%)BOOSTTECNIQUEΒΟΤPTV V95%Dmax (Gy)MHD (Gy)MLD (Gy)LV20 (%)LADmax (Gy)LADmean (Gy)TNTVMUCIHI
      Boman et al.171135100noVMAT iso-1NR90.6D2% 54.33.811.318.9NRNRV5 13626cc7090.155
      VMAT iso-2NR91.2D2% 54.33.610.918.5NRNRV5 13184cc8230.155
      Kim et al.1010100nono3D-CRT55secL 93.7/R 93.5V105% L16.1/R 14.98.2L 11.8/R 11.8NRNRNRNR458.3L 0.9/R 0.96L 0.33/R 0.372
      IMRT76.5secL99.1/R 98.8V105% L22.3/R22.29.5L 12/R 11.7NRNRNRNR1194.2L 1/R 16L 0.16/R 0.172
      VMAT39secL90.1/R 94.2V105% L18.6/R18.914.5L 15.8/R 18.3NRNRNRNR1205.7L 0.9/R 0.96L 0.32/R 0.262
      Subramanian et al.212100nonohybrid VMATNRD95 47.6–48.5D2% 51.4–51.45–5.48.3–1011–13.1NRNRNR612–5570.8–0.850.1–0.073
      VMATNRD95 47.5–47.5D2% 52.2–52.410.5–16.212.1–13.816.6–23.3NRNRNR761–7160.8–0.850.12–0.113
      Wadasadawala et al.1510NRnono3D-CRTNRL 93.7/R 95.3V107% L 3.1/R 5.15.36.89NRNRV107 47.5ccNR1.47L 13/R 122
      FIF-IMRTNRL 92.2/R 94.2V107% L 0.2/R 0.23.75.99.6NRNR1.6NR1.67L 14/R 142
      HT-IMRTNRL 94.9/R 96.4V107% L 1.1/R 0.64.767.3NRNR37.5NR1.37L 16/R 142
      TD-3D-CRTNRL 94.5/R 95V107% L 1.2/R 1.03.75.38.6NRNR80.4NR5.27L 11/R 92
      TD-IMRTNRL 96/R 97V107% L 1.7/R 1.63.44.87.6NRNR48.6NR2.17L 10/R 102
      Ekici et al.261464.38664.3HT-IMRTNRNRNRV25 6NR18.5NRNRNRNR1.340.134
      StudyPtsBCS only (%)RNI (%)BOOSTTECNIQUEΒΟΤPTV V95%Dmax (Gy)MHD (Gy)MLD (Gy)LV20 (%)LADmax (Gy)LADmean (Gy)TNTVMUCIHI
      Seppala et al.1225010050FIF-IMRTNRNRD5cc 675.711.6NRNRNRNR455–913NRNR
      VMATD5cc 52.76.610.11184–1585
      Chia et al.1110100100no3D-CRTNRNRNR10.219.238.5NRNRNRNRr (0.7–1)6NR
      IMRT14.41827.1r (0.9–1.0)6
      Dag et al.142100nonoFIFNRNRNR5.4–4.610.8–10.520.2–18.4NRNRNR478–5091.6–1.360.1–0.12
      IMRT5.7–811–13.515.7–20.71486–21861.1–1.160.09–0.092
      HT7.9–8.510.3–1015.7–16.98462–145550.9–160.03–0.052
      VMAT6.8–6.312.2–14.517.3–23.1781–8211.1–160.09–0.12
      Mani et al.49650NR50FIF-3D-CRTNRNRNR4.715.716.7NRNRNRNR1.3360.093
      Nagaraj et al.231527nonoFF-6MV-VMAT2.79min95.7D2% 107.411.810.413.3NRNRV3 48.1/V10 24.2963.31.1261.631
      FFF-VMAT2.72min95.5D2% 107.412.210.213.30V3 45.9/V10 231120.31.1261.121
      Rakici et al.13210050noVMATNRD95 48.6–45.2D2% 53.1–53.211.6–19.3NR11.2–32.821–34.810.5–28.7NR787–5171.1–0.960.11–1.193
      IMRTD95 48.7–48.1D2% 52.6–5310.9–21.7NR17–32.227.6–37.113.2–32.32032–30841.2–1.160.1–1.133
      StudyPtsBCS only (%)RNI (%)BOOSTTECNIQUEΒΟΤPTV V95%Dmax (Gy)MHD (Gy)MLD (Gy)LV20 (%)LADmax (Gy)LADmean (Gy)TNTVMUCIHI
      Mermut et al.1610NRnonoFiF-3D-CRT 1 isoNRNRNR5.110.518.9NRNRNR460.40.5550.123
      FiF-3D-CRT 2 iso5.510.819.1454.70.5350.123
      Gaudino et al.24141000100VMAT-DIBHNR96.267.16.513.318.114.5NRNRNRNRNR
      VMAT-FB9467.4814.320.718
      Vyfhuis et al.2530100noVMATNRr(97.5–99)NRr(9.1–10.9)r(17.1–21.8)r(29.5–48.1)NRNRNRNRr(1.3–1.9)6r(0.05–0.13)2
      IMPTr(94.8–99.1)r(1.0–2.6)r(6.3–9.3)r(11.9–21.2)NRNRNRNRr(1.3–1.8)6r(0.04–0.06)2
      Gomaa et al.199NRNRnoVMATNRD98 45.9D2 52.5V25 3.7NRR 12.7/L 10.7NRNRNRNRNRNR
      3D-CRTNRD98 44.2D2 53.9V25 7.8NRR 25.5/L 23.7NRNRNRNRNRNR
      Pts = patients, BCS = breast conserving surgery, RNI = regional nodal irradiation, BOT = beam on time, MHD = mean heart dose, MLD = mean lung dose, LV20 = lung V20Gy, TNTV = Total Normal Tissue Volume, MU = monitor units, CI = conformity index, HI = homogeneity index, NR = Not reported, DIBH = deep inspiration breath hold, FB = free breathing, L = left breast, R = right breast, r = range, 1=D5%D95%, 2=D2%-D98%DPrescribed, 3=D2%-D98%D50%, 4 = Not reported, 5=TVRI2TVVRI, 6=VRITV, 7=1+V100NV100PTV , where V100N and V100PTV the volume of normal tissue outside PTV and PTV volume, respectively.
      Table 2Dosimetric results of studies with conventional fractionation and simultaneous integrated boost.
      StudyPtsPrescription Breast/BoostFxMedian F/U(mo)BCS only (%)RNI (%)BOOST (%)TECNIQUESIB (%)ΒΟΤ/TT (min)PTV V95%Dmax (Gy)MHD (Gy)MLD (Gy)LV20 (%)TNTVMUCIHI
      Fiorentino et al.331650.4/54.4252410018.787.5IMRT87.5L/R 96.7/96.3NR8.311.815.7NRNRNRNR
      Wadasadawala et al.282150/612525629186HT100L/R 94.6/94.2L/R 60/60.65.79.213.3NRNRNRNR
      Valli et al.292550.4/64.4283666.720100VMAT100NRNRNR12.9*/11.2**18.5*/13.7**NRNRNRNR
      Nicolini et al.301050/6025NR1000100IMRT1002.2/3V90% 94V107% 146NRL 12.8/R 14.5mean 5/V10 18.3796NRNR
      VMAT2.3/11V90% 97.8V107% 8.37.4NRL 9.7/R 10.3mean 7.1/V 10 20.51398NRNR
      Lee et al.31350.4/56–61.62848.710066.7100HT100NRNRr(5.1–26.8)r (L5.6–16.8/R 6.4 16.1)r(L 9–20/R 8–20)NRNRNRNR
      Phurailatpan et al.321050/6125NA8080100VMAT100TT 3.295.156.24.910.512Whole Body mean 131306160.22
      HT100TT 6.894.457.44.88.811.5Whole Body mean 13.85767160.32
      Pts = patients, Fx = number of fractions, BCS = breast conserving surgery, RNI = regional nodal irradiation, SIB = simultaneous integrated boost, BOT = beam on time, TT = treatment time, MHD = mean heart dose, MLD = mean lung dose, LV20 = lung V20Gy, TNTV = Total Normal Tissue Volume, MU = monitor units, CI = conformity index, HI = homogeneity index, *patients with lung fibrosis, **patients without lung fibrosis, NA = not applicable, NR = non reported, L = left breast, R = right breast, r = range, TNTV = Total Normal Tissue Volume, 1=D5%D95%, 2=D2%-D98%DPrescribed, 3=D2%-D98%D50%, 4 = Not reported, 5=TVRI2TVVRI, 6=VRITV, 7=1+V100NV100PTV where V100N and V100PTV the volume of normal tissue outside PTV and PTV volume, respectively.
      Table 3Dosimetric results of studies with hypofractionation with or without boost.
      studyPtsMedian F/u (mo)Gy/fxBCS only (%)RNI (%)BOOST (%)TECNIQUEHYPOSIBPTV V95%Dmax (Gy)MHD (Gy)MLD (Gy)LV20 (%)MED (Gy)TNTVAcute toxicity ≥ gd3Late toxicity ≥ gd3MUCIHI
      Gadea et al.34202450 ± 10–14/2528.6 % lesions39.3 % lesions28.6 % lesionsVMATnoyesNRNRB 4.4/N 5B 11.5/N 10.8B 14.1/N 14.2B 8.9/N 9.3NRdermatits 7.1 %0NRNRNR
      14940.05 ± 18/1552.5 % lesions25 % lesions52.5 % lesionsVMATyesyesNRNRB 5.3/N 4.8B 10.5/N 9.8B 13.1/N 12.1B 5.0/N 7.4NR00NRNRNR
      Narasimhulu et al.3674840/15 ± 10/528.50 %10028.5FIF-IMRTyesno84.7NR3.710.823.53.6NR00NR0.9260.333
      Lancelotta et al.4011842.4/16100nonoHTyesnoD95% R 40.8/L 41.1NR3.5R 7.7/L 7.3V16Gy L 14.4/R 13NRV100% 0 %00NRNRL 0.1/R 0.093
      DTD95% R40.8/L 39.86R 10.1/L 8.7V16Gy L 20.8/R 14.9 %NRV100% 0.34 %NRNRNRNRL 0.16/R 0.13
      Huang et al.3712NA42.56/16100nonoIMRT-1isoyesnoV100% L 94.6/R 94.9V105% L 3.8/R 5.35.1L 7.5/R 6.8L 14.3/R 16.8NRNRNANA2743L0.98/R0.986L0.066/R 0.072
      IMRT-2isoV100% L 95.2/R 95.7V105% L 0.96/R 1.034.8L 6.8/R7.7L 12.4/R 14.9NRNRNANA2158L0.99/R0.996L0.061/R 0.0572
      VMATV100% L 93.3/R 94.4V105% L11.7/R 9.25.8L 7.9/R 8.8L 14.3/R 16.0NRNRNANA954L 0.98/R0.986L0.077/R 0.732
      Franco et al.391NA45 + 10/201000100IMRT(T)yesyesNRNR3.5NRV25Gy < 10 %NRNRNANANRNRNR
      Bosnic et al.3552NA50/2510053.303D-CRTnonoNRNR310.520NRNRNANANRNRNR
      4042.6/16yes26.412
      Srivastava et al.385NA40.05/15NRNRnoFiFyesnoD95% 37.342.60.96.6V17Gy L6.2/R 24.5NRNRNANA9101.360.33
      VMATD95% 38.842.53.210.5V17Gy L 8.2/R 15NRNRNANA15461.160.13
      Pts = patients, BCS = breast conserving surgery, RNI = regional nodal irradiation, HYPO = hypofractionation, SIB = simultaneous integrated boost, MHD = mean heart dose, MLD = mean lung dose, MED = mean esophagus dose, LV20 = lung V20Gy, TNTV = Total Normal Tissue Volume, NA = not applicable, NR = non reported, L = left breast, R = right breast, r = range, 1=D5%D95%, 2=D2%-D98%DPrescribed, 3=D2%-D98%D50%, 4 = Not reported, 5=TVRI2TVVRI, 6=VRITV, 7=1+V100NV100PTV where V100N and V100PTV the volume of normal tissue outside PTV and PTV volume, respectively.

      Studies with conventional fractionation and sequential or no boost

      In Table 1, details from the 19 studies using conventional fractionation and sequential or no boost, which include a total of 171 patients, are presented. Studies differ in their study populations as most include only or mainly lumpectomy only patients, while three studies do not mention type of previous surgery. Out of the total patient population included in all studies only 34 patients had a mastectomy of at least at one breast. Moreover, in 15 studies there was no boost dose delivered to the lumpectomy site and some studies explicitly state that plans without the boost irradiations are published as boost treatment at different areas of the breast, i.e medial, lateral, or central breast, would add a further confounding factor, especially in comparing OAR doses. Similarly, RNI inclusion is scarce, as are details of its extent when RNI is present. Nine out of 19 studies clearly state that there was no RNI and another three studies do not report on RNI. RNI has been prescribed to only 51 out of 171 patients and details concerning unilateral or bilateral RNI and its extent in the supraclavicular, axillar area and the internal mammary chain are limited.
      In the studies by Alhefny et al [
      • Alhefny M.M.
      • Attallah H.S.
      • Abdallah M.
      • Yassin A.
      • El-Shahat K.M.
      • Obaya A.A.
      Optimizing Adjuvant Radiation Planning Outcomes in Patients with Synchronous Bilateral Breast Cancer.
      ] and Kim et al [
      • Kim S.J.
      • Lee M.J.
      • Youn S.M.
      Radiation therapy of synchronous bilateral breast carcinoma (SBBC) using multiple techniques.
      ], 3D-CRT, IMRT and VMAT are compared. In both studies ΙMRT has the best coverage and conformity index (CI) and homogeneity index (HI) of all plans, but at the expense of higher doses to heart and lungs compared to 3D-CRT. VMAT has even higher doses to normal tissues in both studies, but the lowest beam on time (BOT), as measured at the study by Kim et al [
      • Kim S.J.
      • Lee M.J.
      • Youn S.M.
      Radiation therapy of synchronous bilateral breast carcinoma (SBBC) using multiple techniques.
      ]. Other studies follow the same general tendency, but with deviations in specific dosimetric parameters. In the study by Chia et al [
      • Chia D.
      • Yusoff S.B.
      • Chen D.
      • Tey J.
      • Tang J.
      • Koh V.
      • et al.
      Strategies for bilateral breast and comprehensive nodal irradiation in breast cancer—a comparison of IMRT and 3D conformal radiation therapy.
      ], mean heart dose (MHD) is also improved with 3D-CRT compared to IMRT, but the dose distribution for lungs as expressed by mean lung dose (MLD) and the lungs’ volume receiving 20 Gy (LV20) is better with IMRT. This could be explained by differences in RNI delivery between the studies. In this study, all 10 patients received RNI, whereas the study by Alhefny et al [
      • Alhefny M.M.
      • Attallah H.S.
      • Abdallah M.
      • Yassin A.
      • El-Shahat K.M.
      • Obaya A.A.
      Optimizing Adjuvant Radiation Planning Outcomes in Patients with Synchronous Bilateral Breast Cancer.
      ], does not report on RNI delivery and the study by Kim et al [
      • Kim S.J.
      • Lee M.J.
      • Youn S.M.
      Radiation therapy of synchronous bilateral breast carcinoma (SBBC) using multiple techniques.
      ], clearly states that all ten patients did not receive RNI. In three case reports of two patients each, one comparing 3D-CRT with VMAT, the other VMAT with IMRT and the latter comparing all three techniques the tendency that clinically significant doses to OAR are the lowest with 3D-CRT, the highest with VMAT and in between with IMRT seems to hold but there are deviations for individual patients as these studies also include one mastectomy patient and half of them received RNI [
      • Seppälä J.
      • Heikkilä J.
      • Myllyoja K.
      • Koskela K.
      Volumetric modulated arc therapy for synchronous bilateral whole breast irradiation – A case study.
      ,
      • Rakici S.
      • Cinar Y.
      Dual-isocentric volumetric modulated arc therapy in synchronous bilateral breast cancer irradiation: A dosimetric study.
      ,
      • Dağ Z.
      • Ertürk Ş.
      • Ayrancioğlu O.
      • et al.
      Comparison of VMAT, field in field, inverse IMRT, and helical tomotherapy planning in bilateral synchronous breast cancer: A case study.
      ]. In the study of 10 patients by Wadasadawala et al [
      • Wadasadawala T.
      • Visariya B.
      • Sarin R.
      • Upreti R.R.
      • Paul S.
      • Phurailatpam R.
      Use of tomotherapy in treatment of synchronous bilateral breast cancer: dosimetric comparison study.
      ], where no RNI and no boost where delivered, MHD and MLD are improved with field in field (FiF)-IMRT and only LV20 is smaller with 3D-CRT.
      Correct adjustment of planning parameters seems to be crucial to achieve the best equilibrium between PTV coverage, treatment efficacy and OAR dose distribution in both low and high doses. In the paper of Mermut et al [
      • Mermut Ö.
      • Ata A.O.
      • Trabulus D.C.
      • et al.
      Quantitative and dosimetric analysis for treating synchronous bilateral breast cancer using two radiotherapy planning techniques.
      ], a comparison between one and two isocenters using a field in field 3D-CRT technique in a series of 10 SBBC patients as for OAR dose distribution, shows better results with the single isocenter planning method, with a decrease in MHD, MLD and in LV20. Two studies have compared VMAT techniques with one and two isocenters and have reached the same conclusion. Boman et al [
      • Boman E.
      • Rossi M.
      • Kapanen M.
      The robustness of dual isocenter VMAT radiation therapy for bilateral lymph node positive breast cancer.
      ], was the first to show the superiority of 2-isocenter over 1-isocenter VMAT technique in a population of 11 patients, all of whom received RNI and a third had at least one mastectomy. The same was verified by Sun et al [

      Sun, T.; Lin, X.; Tong, Y.; et al. Heart and Cardiac Substructure Dose Sparing in Synchronous Bilateral Breast Radiotherapy: A Dosimetric Study of Proton and Photon Radiation Therapy. Front. Oncol. 9. 2020. Doi: 10.3389/fonc.2019.01456.

      ], in a population of 11 patients without mastectomy, RNI or boost delivery. Initially Kim et al [
      • Kim S.J.
      • Lee M.J.
      • Youn S.M.
      Radiation therapy of synchronous bilateral breast carcinoma (SBBC) using multiple techniques.
      ], argued that one isocenter was preferable as algorithms were not robust enough to accurately calculate dose distribution with two isocenters, but this seems to have been overcome with modern algorithms. The latter also compared 1- to 2- isocenter FiF-IMRT technique and its results found the 1- isocenter technique was superior because it achieved higher dose homogeneity and better OAR dose sparing, with no statistically significant differences in terms of PTV coverage and hot spots, further strengthening the results by Merlmut et al [
      • Mermut Ö.
      • Ata A.O.
      • Trabulus D.C.
      • et al.
      Quantitative and dosimetric analysis for treating synchronous bilateral breast cancer using two radiotherapy planning techniques.
      ]. The great impact of one or two isocenters in dose distribution can be clearly understood by the study of Sun et al [

      Sun, T.; Lin, X.; Tong, Y.; et al. Heart and Cardiac Substructure Dose Sparing in Synchronous Bilateral Breast Radiotherapy: A Dosimetric Study of Proton and Photon Radiation Therapy. Front. Oncol. 9. 2020. Doi: 10.3389/fonc.2019.01456.

      ], where the left anterior descending artery (LAD) mean doses are 21.5 Gy, 21.9 Gy, 21.3 Gy and 14.4 Gy for IMRT 1-isocenter, IMRT 2-isoceters, VMAT 1-isocenter and VMAT 2-isocenters respectively.
      There are also studies in support of VMAT over IMRT or 3D-CRT. In the study of 11 patients by Sun et al [

      Sun, T.; Lin, X.; Tong, Y.; et al. Heart and Cardiac Substructure Dose Sparing in Synchronous Bilateral Breast Radiotherapy: A Dosimetric Study of Proton and Photon Radiation Therapy. Front. Oncol. 9. 2020. Doi: 10.3389/fonc.2019.01456.

      ], with no mastectomy patients and without RNI or boost, the best VMAT technique, with 2-isocenters, was compared to the best IMRT technique, with 1-isocenter, and showed that VMAT provides better OAR sparing at high doses and improved CI over IMRT, with no statistically significant differences in terms of PTV coverage and HI. The low dose bath is the main disadvantage of VMAT. In the study of 9 patients by Gomaa et al [
      • Gomaa H.A.G.A.
      • Almaghrabi M.Y.
      • Al-Gaoud M.A.G.
      Comparative Dosimetric Study of 3D Conformal Radiotherapy versus Volumetric Modulated Arc Radiotherapy in Synchronous Bilateral Breast Cancer.
      ], both MHD and LV20 were increased and PTV coverage was decreased with 3D-CRT compared to VMAT and the only drawback of VMAT was again the increased low dose bath. Another study of 10 patients by Cheng et at [
      • Cheng H.-W.
      • Chang C.-C.
      • Shiau A.-C.
      • Wang M.-H.
      • Tsai J.-T.
      Dosimetric comparison of helical tomotherapy, volumetric-modulated arc therapy, intensity-modulated radiotherapy, and field-in-field technique for synchronous bilateral breast cancer.
      ], also shows the potential role of VMAT in SBBC. In this study LV20 and mean dose to LAD are lower with VMAT and higher with FiF, even though MHD and MLD follow the pattern set by most studies. The study used step and shoot IMRT technique with three beams for each breast and a VMAT technique with four partial arc arrangement, while the studies favoring IMRT used a dynamic sliding window IMRT and a VMAT with a 2–6 half arc or an 8 partial arc arrangement [
      • Alhefny M.M.
      • Attallah H.S.
      • Abdallah M.
      • Yassin A.
      • El-Shahat K.M.
      • Obaya A.A.
      Optimizing Adjuvant Radiation Planning Outcomes in Patients with Synchronous Bilateral Breast Cancer.
      ,
      • Kim S.J.
      • Lee M.J.
      • Youn S.M.
      Radiation therapy of synchronous bilateral breast carcinoma (SBBC) using multiple techniques.
      ,
      • Dağ Z.
      • Ertürk Ş.
      • Ayrancioğlu O.
      • et al.
      Comparison of VMAT, field in field, inverse IMRT, and helical tomotherapy planning in bilateral synchronous breast cancer: A case study.
      ].
      Several studies investigate techniques to ameliorate plans with VMAT because of its lower BOT, which decreases intrafraction motion and improves patient comfort. Subramanian et al [
      • Subramanian S.B.
      • Balaji K.
      • Thirunavukarasu M.
      • et al.
      Bilateral Breast Irradiation Using Hybrid Volumetric Modulated Arc Therapy (h-VMAT) Technique.
      ], supported that hybrid techniques incorporating 3D-CRT plans could have a comparative advantages over pure VMAT plans studying their concept on two patients both of whom had BCS on both sides and no RNI nor boost delivery. In their study Cho et al [
      • Cho Y.
      • Cho Y.J.
      • Chang W.S.
      • Kim J.W.
      • Choi W.H.
      • Lee I.J.
      Evaluation of optimal treatment planning for radiotherapy of synchronous bilateral breast cancer including regional lymph node irradiation.
      ], validated the initial concept of a hybrid plan in a larger patient cohort with 66.7 % mastectomy patients and the entire cohort receiving RNI. It also went a step forward by proposing a modified hybrid plan taking into consideration the dosimetry of the 3D-CRT in the combined 3D-CRT and VMAT plan. The latter technique improves not only the high-dose OAR distribution as did the previous hybrid technique, but also the PTV coverage. VMAT hybrid techniques are very promising for SBBC patients as demonstrated in the studies of Subramanian et al and Cho et al [
      • Subramanian S.B.
      • Balaji K.
      • Thirunavukarasu M.
      • et al.
      Bilateral Breast Irradiation Using Hybrid Volumetric Modulated Arc Therapy (h-VMAT) Technique.
      ,
      • Cho Y.
      • Cho Y.J.
      • Chang W.S.
      • Kim J.W.
      • Choi W.H.
      • Lee I.J.
      Evaluation of optimal treatment planning for radiotherapy of synchronous bilateral breast cancer including regional lymph node irradiation.
      ]. As these studies compared hybrid VMAT techniques to pure VMAT plans, a direct comparison of these hybrid VMAT techniques to IMRT are lacking.
      Other treatment planning strategies have managed to improve VMAT plans for SBBC patients. Increased low dose bath, a constant disadvantage of VMAT across studies of SBBC patients, has been improved in the study by Nagaraj et al [
      • Nagaraj J.
      • Veluraja K.
      Is Synchronous Bilateral Breast Irradiation Using Flattening Filter-Free Beam-Based Volumetric-Modulated Arc Therapy Beneficial?.
      ]. A VMAT technique with 2 isocenters and 2 partial arcs at each isocenter has been used and a flattening filter (FF)- beam was compared with a flattening filter free (FFF)-beam in a cohort of 15 patients, 11 of whom had at least one mastectomy. Only minimal dose distribution differences could be found between them in PTV coverage, OAR sparing and plan deliverability. Yet, FFF-beam technique provided a lower low-dose bath, with a statistically significant difference in both V3 and V10 and the authors provide as a possible explanation the lower energy of the FFF beam. Gaudino et al [
      • Gaudino D.
      • Cima S.
      • Frapolli M.
      • Daniele D.
      • Muoio B.
      • Pesce G.A.
      • et al.
      Volumetric modulated arc therapy applied to synchronous bilateral breast cancer radiotherapy: Dosimetric study on deep inspiration breath hold versus free breathing set up.
      ], investigated the potential influence of deep inspiration breath hold (DIBH) in VMAT plans of 14 SBBC patients with BCS at both sides and boost delivery. The dose received by the 95 % of PTV breast (D95) was improved from 94 % with free breathing to 96,2% with DIBH. OAR sparing was also improved with DIBH in all dosimetric parameters studied by Gaudino et al [
      • Gaudino D.
      • Cima S.
      • Frapolli M.
      • Daniele D.
      • Muoio B.
      • Pesce G.A.
      • et al.
      Volumetric modulated arc therapy applied to synchronous bilateral breast cancer radiotherapy: Dosimetric study on deep inspiration breath hold versus free breathing set up.
      ], MHD, MLD, LV20, LAD maximum dose and LAD mean dose.
      IMPT and HT have also been found to be valid treatment options for SBBC patients. IMPT is the best treatment option based on dosimetric results of the studies of Sun et al [

      Sun, T.; Lin, X.; Tong, Y.; et al. Heart and Cardiac Substructure Dose Sparing in Synchronous Bilateral Breast Radiotherapy: A Dosimetric Study of Proton and Photon Radiation Therapy. Front. Oncol. 9. 2020. Doi: 10.3389/fonc.2019.01456.

      ] and Vyfhuis et al [
      • Vyfhuis M.A.L.
      • Zhu M.
      • Agyepong B.
      • et al.
      Techniques for Treating Bilateral Breast Cancer Patients Using Pencil Beam Scanning Technology.
      ], showing that IMPT plans had a statistically significant decrease in the low-dose and high-dose distribution to LAD, heart, and lungs. However, Sun et al [

      Sun, T.; Lin, X.; Tong, Y.; et al. Heart and Cardiac Substructure Dose Sparing in Synchronous Bilateral Breast Radiotherapy: A Dosimetric Study of Proton and Photon Radiation Therapy. Front. Oncol. 9. 2020. Doi: 10.3389/fonc.2019.01456.

      ], also noted that IMPT plans had a statistically significant increase in skin dose. Long-term toxicity implications of IMPT on SBBC patients need further follow-up monitoring. Similarly, skin dose increase with HT is statistically significant according to Sun et al [

      Sun, T.; Lin, X.; Tong, Y.; et al. Heart and Cardiac Substructure Dose Sparing in Synchronous Bilateral Breast Radiotherapy: A Dosimetric Study of Proton and Photon Radiation Therapy. Front. Oncol. 9. 2020. Doi: 10.3389/fonc.2019.01456.

      ]. HT breast cancer treatments also need longer follow-up periods to monitor possible skin toxicity and cosmetic outcomes.
      Tomotherapy treatments, either DT or HT, for SBBC have been studied by several research groups. PTV coverage and OAR sparing are considered comparable with other modern techniques. Both DT and HT plans had increased hot spot volume compared to FIF-IMRT treatments for SBBC, while HT increases the low dose spillage as seen by an increase in V5 of healthy tissue [
      • Dağ Z.
      • Ertürk Ş.
      • Ayrancioğlu O.
      • et al.
      Comparison of VMAT, field in field, inverse IMRT, and helical tomotherapy planning in bilateral synchronous breast cancer: A case study.
      ,
      • Wadasadawala T.
      • Visariya B.
      • Sarin R.
      • Upreti R.R.
      • Paul S.
      • Phurailatpam R.
      Use of tomotherapy in treatment of synchronous bilateral breast cancer: dosimetric comparison study.
      ,

      Sun, T.; Lin, X.; Tong, Y.; et al. Heart and Cardiac Substructure Dose Sparing in Synchronous Bilateral Breast Radiotherapy: A Dosimetric Study of Proton and Photon Radiation Therapy. Front. Oncol. 9. 2020. Doi: 10.3389/fonc.2019.01456.

      ,
      • Cheng H.-W.
      • Chang C.-C.
      • Shiau A.-C.
      • Wang M.-H.
      • Tsai J.-T.
      Dosimetric comparison of helical tomotherapy, volumetric-modulated arc therapy, intensity-modulated radiotherapy, and field-in-field technique for synchronous bilateral breast cancer.
      ,

      Ekici, K.; Gokce, T.; Karadogan. I Is helical tomotherapy-based intensity-modulated radiotherapy feasible and effective in bilateral synchronous breast cancer? A two-center experience – PubMed. J BUON. Jan-Feb(1). 46–52. 2016.

      ]. Further research is necessary to elucidate potential advantages of tomotherapy in SBBC. HT plan delivery has been studied in several papers [
      • Dağ Z.
      • Ertürk Ş.
      • Ayrancioğlu O.
      • et al.
      Comparison of VMAT, field in field, inverse IMRT, and helical tomotherapy planning in bilateral synchronous breast cancer: A case study.
      ,
      • Wadasadawala T.
      • Visariya B.
      • Sarin R.
      • Upreti R.R.
      • Paul S.
      • Phurailatpam R.
      Use of tomotherapy in treatment of synchronous bilateral breast cancer: dosimetric comparison study.
      ,
      • Cheng H.-W.
      • Chang C.-C.
      • Shiau A.-C.
      • Wang M.-H.
      • Tsai J.-T.
      Dosimetric comparison of helical tomotherapy, volumetric-modulated arc therapy, intensity-modulated radiotherapy, and field-in-field technique for synchronous bilateral breast cancer.
      ,

      Ekici, K.; Gokce, T.; Karadogan. I Is helical tomotherapy-based intensity-modulated radiotherapy feasible and effective in bilateral synchronous breast cancer? A two-center experience – PubMed. J BUON. Jan-Feb(1). 46–52. 2016.

      ,
      • Sun T.
      • Lin X.
      • Zhang G.
      • Qiu Q.
      • Li C.
      • Yin Y.
      Treatment planning comparison of volumetric modulated arc therapy with the trilogy and the Halcyon for bilateral breast cancer.
      ], while direct tomotherapy both with 3D-CRT and IMRT has only been studied by Wadasadawala et al [
      • Wadasadawala T.
      • Visariya B.
      • Sarin R.
      • Upreti R.R.
      • Paul S.
      • Phurailatpam R.
      Use of tomotherapy in treatment of synchronous bilateral breast cancer: dosimetric comparison study.
      ]. Based on the results of these studies, both techniques are efficient and safe, recording no clinically significant toxicities in SBBC patients treated with tomotherapy and presenting similar target coverage and healthy tissue sparing to other most common techniques. IMPT is even more rarely used due to the paucity of proton accelerators; yet, it is also a valid technique for SBBC patients as shown in the studies by Sun et al and Vyfhuis et al [

      Sun, T.; Lin, X.; Tong, Y.; et al. Heart and Cardiac Substructure Dose Sparing in Synchronous Bilateral Breast Radiotherapy: A Dosimetric Study of Proton and Photon Radiation Therapy. Front. Oncol. 9. 2020. Doi: 10.3389/fonc.2019.01456.

      ,
      • Vyfhuis M.A.L.
      • Zhu M.
      • Agyepong B.
      • et al.
      Techniques for Treating Bilateral Breast Cancer Patients Using Pencil Beam Scanning Technology.
      ].

      Studies with conventional fractionation and simultaneous integrated boost

      Table 2 presents the major findings in studies of SIB technique with normofractionated treatments. In five studies all patients received a SIB technique [
      • Wadasadawala T.
      • Jain S.
      • Paul S.
      • Phurailatpam R.
      • Joshi K.
      • Popat P.
      • et al.
      First clinical report of helical tomotherapy with simultaneous integrated boost for synchronous bilateral breast cancer.
      ,
      • Valli M.
      • Cima S.
      • Gaudino D.
      • Cartolari R.
      • Deantonio L.
      • Frapolli M.
      • et al.
      Skin and lung toxicity in synchronous bilateral breast cancer treated with volumetric-modulated arc radiotherapy: a mono-institutional experience.
      ,
      • Nicolini G.
      • Clivio A.
      • Fogliata A.
      • Vanetti E.
      • Cozzi L.
      Simultaneous integrated boost radiotherapy for bilateral breast: a treatment planning and dosimetric comparison for volumetric modulated arc and fixed field intensity modulated therapy.
      ,
      • Lee Y.-C.
      • Yao C.-C.
      • Tseng H.-C.
      • et al.
      Tomotherapy for synchronous bilateral breast irradiation.
      ,
      • Phurailatpam R.
      • Wadasadawala T.
      • Chauhan K.
      • Panda S.
      • Sarin R.
      Dosimetric comparison of volumetric-modulated arc therapy and helical tomotherapy for adjuvant treatment of bilateral breast cancer.
      ], while in one study most patients received a SIB technique [
      • Fiorentino A.
      • Mazzola R.
      • Naccarato S.
      • Giaj-Levra N.
      • Fersino S.
      • Sicignano G.
      • et al.
      Synchronous bilateral breast cancer irradiation: clinical and dosimetrical issues using volumetric modulated arc therapy and simultaneous integrated boost.
      ]. All studies include a similar number of patients ranging from 10 to 25 patients, except one study with three patients [
      • Lee Y.-C.
      • Yao C.-C.
      • Tseng H.-C.
      • et al.
      Tomotherapy for synchronous bilateral breast irradiation.
      ]. A conventionally fractionated treatment of either 25 or 28 fractions was prescribed. RNI was scarcely delivered in three studies (range 0–20 %) [
      • Valli M.
      • Cima S.
      • Gaudino D.
      • Cartolari R.
      • Deantonio L.
      • Frapolli M.
      • et al.
      Skin and lung toxicity in synchronous bilateral breast cancer treated with volumetric-modulated arc radiotherapy: a mono-institutional experience.
      ,
      • Nicolini G.
      • Clivio A.
      • Fogliata A.
      • Vanetti E.
      • Cozzi L.
      Simultaneous integrated boost radiotherapy for bilateral breast: a treatment planning and dosimetric comparison for volumetric modulated arc and fixed field intensity modulated therapy.
      ,
      • Fiorentino A.
      • Mazzola R.
      • Naccarato S.
      • Giaj-Levra N.
      • Fersino S.
      • Sicignano G.
      • et al.
      Synchronous bilateral breast cancer irradiation: clinical and dosimetrical issues using volumetric modulated arc therapy and simultaneous integrated boost.
      ] but was delivered in 91 % and 80 % of patients in two studies [
      • Wadasadawala T.
      • Jain S.
      • Paul S.
      • Phurailatpam R.
      • Joshi K.
      • Popat P.
      • et al.
      First clinical report of helical tomotherapy with simultaneous integrated boost for synchronous bilateral breast cancer.
      ,
      • Phurailatpam R.
      • Wadasadawala T.
      • Chauhan K.
      • Panda S.
      • Sarin R.
      Dosimetric comparison of volumetric-modulated arc therapy and helical tomotherapy for adjuvant treatment of bilateral breast cancer.
      ], respectively. Three studies delivered HT [
      • Wadasadawala T.
      • Jain S.
      • Paul S.
      • Phurailatpam R.
      • Joshi K.
      • Popat P.
      • et al.
      First clinical report of helical tomotherapy with simultaneous integrated boost for synchronous bilateral breast cancer.
      ,
      • Lee Y.-C.
      • Yao C.-C.
      • Tseng H.-C.
      • et al.
      Tomotherapy for synchronous bilateral breast irradiation.
      ,
      • Phurailatpam R.
      • Wadasadawala T.
      • Chauhan K.
      • Panda S.
      • Sarin R.
      Dosimetric comparison of volumetric-modulated arc therapy and helical tomotherapy for adjuvant treatment of bilateral breast cancer.
      ], while the rest delivered VMAT [
      • Wadasadawala T.
      • Jain S.
      • Paul S.
      • Phurailatpam R.
      • Joshi K.
      • Popat P.
      • et al.
      First clinical report of helical tomotherapy with simultaneous integrated boost for synchronous bilateral breast cancer.
      ,
      • Valli M.
      • Cima S.
      • Gaudino D.
      • Cartolari R.
      • Deantonio L.
      • Frapolli M.
      • et al.
      Skin and lung toxicity in synchronous bilateral breast cancer treated with volumetric-modulated arc radiotherapy: a mono-institutional experience.
      ,
      • Nicolini G.
      • Clivio A.
      • Fogliata A.
      • Vanetti E.
      • Cozzi L.
      Simultaneous integrated boost radiotherapy for bilateral breast: a treatment planning and dosimetric comparison for volumetric modulated arc and fixed field intensity modulated therapy.
      ], with one comparing VMAT and IMRT treatments [
      • Nicolini G.
      • Clivio A.
      • Fogliata A.
      • Vanetti E.
      • Cozzi L.
      Simultaneous integrated boost radiotherapy for bilateral breast: a treatment planning and dosimetric comparison for volumetric modulated arc and fixed field intensity modulated therapy.
      ] and another comparing VMAT with HT [
      • Phurailatpam R.
      • Wadasadawala T.
      • Chauhan K.
      • Panda S.
      • Sarin R.
      Dosimetric comparison of volumetric-modulated arc therapy and helical tomotherapy for adjuvant treatment of bilateral breast cancer.
      ]. To the best of our knowledge, no study has compared SIB with sequential boost.
      Nicolini et al [
      • Nicolini G.
      • Clivio A.
      • Fogliata A.
      • Vanetti E.
      • Cozzi L.
      Simultaneous integrated boost radiotherapy for bilateral breast: a treatment planning and dosimetric comparison for volumetric modulated arc and fixed field intensity modulated therapy.
      ], compared IMRT and VMAT in a study population of 10 patients with bilateral BCS without RNI. As opposed to VMAT, IMRT plans had worse coverage, a higher V107 and higher LV20, but lower MHD, lower MUs and a lower low dose bath. Phurailatpan et al [
      • Phurailatpam R.
      • Wadasadawala T.
      • Chauhan K.
      • Panda S.
      • Sarin R.
      Dosimetric comparison of volumetric-modulated arc therapy and helical tomotherapy for adjuvant treatment of bilateral breast cancer.
      ] compared VMAT with HT in10 patients with 20 % mastectomy patients and 80 % RNI delivery. VMAT delivered a more homogenous plan with less MU and less whole body mean dose, with marginally improved PTV coverage and Dmax, at the expense of marginally worse OAR sparing compared to HT. Among studies with most patients, MHD ranged from 4.8 to 5.7 Gy with HT, 6 Gy with IMRT and 4.9 to 8.3 with VMAT. MLD ranged from 8.8 to 9.2 Gy with HT and from 10.5 to 11.8 Gy with VMAT, across the same studies [
      • Valli M.
      • Cima S.
      • Gaudino D.
      • Cartolari R.
      • Deantonio L.
      • Frapolli M.
      • et al.
      Skin and lung toxicity in synchronous bilateral breast cancer treated with volumetric-modulated arc radiotherapy: a mono-institutional experience.
      ,
      • Nicolini G.
      • Clivio A.
      • Fogliata A.
      • Vanetti E.
      • Cozzi L.
      Simultaneous integrated boost radiotherapy for bilateral breast: a treatment planning and dosimetric comparison for volumetric modulated arc and fixed field intensity modulated therapy.
      ]. Mean esophagus dose was recorded in only one study, being 6.4 Gy. In all studies there was an adequate PTV volume receiving at least 95 % of the prescribed dose (V95) coverage, except in the one study using a field in field forward planning IMRT technique [
      • Nicolini G.
      • Clivio A.
      • Fogliata A.
      • Vanetti E.
      • Cozzi L.
      Simultaneous integrated boost radiotherapy for bilateral breast: a treatment planning and dosimetric comparison for volumetric modulated arc and fixed field intensity modulated therapy.
      ].
      The two studies following patients for acute and late toxicity and radiation-induced lung changes for a median follow-up period of 25 and 36 months respectively, found no case with clinically significant toxicities [
      • Wadasadawala T.
      • Jain S.
      • Paul S.
      • Phurailatpam R.
      • Joshi K.
      • Popat P.
      • et al.
      First clinical report of helical tomotherapy with simultaneous integrated boost for synchronous bilateral breast cancer.
      ,
      • Valli M.
      • Cima S.
      • Gaudino D.
      • Cartolari R.
      • Deantonio L.
      • Frapolli M.
      • et al.
      Skin and lung toxicity in synchronous bilateral breast cancer treated with volumetric-modulated arc radiotherapy: a mono-institutional experience.
      ]. However, in the study by Valli et al [
      • Valli M.
      • Cima S.
      • Gaudino D.
      • Cartolari R.
      • Deantonio L.
      • Frapolli M.
      • et al.
      Skin and lung toxicity in synchronous bilateral breast cancer treated with volumetric-modulated arc radiotherapy: a mono-institutional experience.
      ], of the 15 SBBC patients who were treated with VMAT, of whom 20 % with RNI, 24 % presented at 6-months follow-up with imaging radiation-induced lung changes with a median fibrotic lung volume of 6.5 cc, but no symptomatic pneumonitis. MHD and LV20 were 12.9 Gy and 18.5 % respectively, in patients with fibrotic changes, while MHD and LV20 were 11.2 Gy and 13.7 %, respectively, in patients without lung fibrosis. Another study of 16 patients, using an IMRT technique, with a similar percentage of patients with RNI and a MHD and LV20 11.8 Gy and 15.7 % respectively, showed no grade 3 acute or late toxicity within a 24-month median follow-up period [
      • Fiorentino A.
      • Mazzola R.
      • Naccarato S.
      • Giaj-Levra N.
      • Fersino S.
      • Sicignano G.
      • et al.
      Synchronous bilateral breast cancer irradiation: clinical and dosimetrical issues using volumetric modulated arc therapy and simultaneous integrated boost.
      ]. Similar were the results in the study by Wadasadawala et al [
      • Wadasadawala T.
      • Jain S.
      • Paul S.
      • Phurailatpam R.
      • Joshi K.
      • Popat P.
      • et al.
      First clinical report of helical tomotherapy with simultaneous integrated boost for synchronous bilateral breast cancer.
      ], which used HT in treating SBBC with RNI involvement on most patients. In this study MHD and LV20 were 5.7 Gy and 9.2 %, respectively. No clinically significant lung toxicity was observed after a 24-month follow-up period, even though radiation-induced lung changes were monitored in two-thirds of the patient population.

      Hypofractionation studies

      In Table 3 the dosimetric and clinical details of seven studies, including two case reports, with a hypofractionated treatment are presented. One study and one case report use a SIB, while two include a sequential boost. Three studies have excluded boost delivery from dosimetric data presented to avoid biases introduced by boost delivery. Gadea et al [
      • Gadea J.
      • Ortiz I.
      • Roncero R.
      • Alastuey I.
      • Mestre F.
      • Aymar N.
      • et al.
      Synchronous bilateral breast cancer treated with a 3-week hypofractionated radiotherapy schedule: clinical and dosimetric outcomes.
      ], compared OAR doses (MHD, MLD and LV20) between hypofractionated RT and conventional fractionation in VMAT. Patients receiving the normofractionated regimen had a higher percentage of mastectomies and a lower percentage of RNI and boost delivery. Although the demographic characteristics differ considerably between groups, both fractionation regimens achieved the given constraints. With a median follow up of 24 and 9 months in the normofractioanted and hypofractionated patient population respectively, no late toxicity and only 1 patient with grade 3 or higher acute toxicity (dermatitis) was recorded. Bosnic et al [
      • Bosnic S.
      • McKenzie E.
      • Razvi Y.
      • Wronski M.
      • Zhang L.
      • Vesprini D.
      • et al.
      Heart and Lung Dose Metrics in Radiation Therapy Patients Treated for Synchronous Bilateral Breast Cancer (SBBC): A Decade in Review (2011–2018).
      ], is another study comparing normofractionation and hypofracrionation with 3D-CRT at a patient population with no mastectomy and half of the population receiving RNI. No correlation was found in this study between fractionation and MHD or MLD. The only factors associated were RNI and wide tangents, stressing the importance of the presence and extent of RNI in the dosimetric results of RT plans for SBBC patients. In the study of Narasimhulu et al [
      • Narasimhulu B.C.
      • Valiyaveettil D.
      • Joseph D.
      • et al.
      Synchronous bilateral breast cancer patients treated with hypofractionated bilateral breast irradiation: A dosimetric and clinical study.
      ], where, contrary to most dosimetric SBBC studies, RNI to the suprclavicular fossa was prescribed to all patients, PTV coverage was inadequate (V95% 84.7 %). This is possibly due to a combination of RNI and FIF-IMRT technique used in this study.
      The study of Huang et al [
      • Huang J.-H.
      • Wu X.-X.
      • Lin X.
      • Shi J.-T.
      • Ma Y.-J.
      • Duan S.
      • et al.
      Evaluation of fixed-jaw IMRT and tangential partial-VMAT radiotherapy plans for synchronous bilateral breast cancer irradiation based on a dosimetric study.
      ], on 12 patients with SBBC compared between one-isocenter IMRT, two- isocenter IMRT and two-isocenter VMAT with hypofractionation. Overall, two-isocenter IMRT technique outperformed the other two planning methods in both terms of PTV coverage and high-dose exposure to healthy tissue. SBBC treatments with the IMRT were superior at low dose levels, while VMAT kept high doses to OAR at lower levels. The 2-isocenter IMRT technique was overall similar to 1-isocenter IMRT, but proved more beneficent in obese patients [
      • Huang J.-H.
      • Wu X.-X.
      • Lin X.
      • Shi J.-T.
      • Ma Y.-J.
      • Duan S.
      • et al.
      Evaluation of fixed-jaw IMRT and tangential partial-VMAT radiotherapy plans for synchronous bilateral breast cancer irradiation based on a dosimetric study.
      ]. Similar results were published the study by Srivastava et al [
      • Srivastava R.P.
      • Vandeputte K.
      • De Wagter C.
      Benefits and Limitations of Volumetric Modulated Arc Therapy in Treating Bilateral Breast Cancer with Regional Lymph Nodes.
      ] comparing a FiF technique with VMAT, with the former providing increased sparing in the low-dose region, delivering less MU, while the latter has a better PTV coverage conformity, homogeneity and better sparing at high doses.
      The FiF technique was also used in the paper on seven patients by Narasimhulu et al [
      • Narasimhulu B.C.
      • Valiyaveettil D.
      • Joseph D.
      • et al.
      Synchronous bilateral breast cancer patients treated with hypofractionated bilateral breast irradiation: A dosimetric and clinical study.
      ], where, after 48 months of follow-up, clinically significant acute or late toxicities were not observed. In this paper FiF technique did not provide adequate PTV coverage, while constraints for healthy tissue were respected. Franco et al [
      • Franco P.
      • Migliaccio F.
      • Torielli P.
      • Sciacero P.
      • Girelli G.
      • Cante D.
      • et al.
      Bilateral breast radiation delivered with static angle tomotherapy (TomoDirect): clinical feasibility and dosimetric results of a single patient.
      ], provide a case study of a SBBC patient treated with IMRT, providing further evidence that IMRT can be used for the treatment of such patients with a hypofractionated schedule. To the best of our knowledge, the only published study on tomotherapy on SBBC with hypofractionation is by Lancelotta et al [
      • Lancellotta V.
      • Iacco M.
      • Perrucci E.
      • Zucchetti C.
      • Dipilato A.C.
      • Falcinelli L.
      • et al.
      Comparison of helical tomotherapy and direct tomotherapy in bilateral whole breast irradiation in a case of bilateral synchronous grade 1 and stage 1 breast cancer.
      ], which has the benefit of a very low dose bath for healthy tissue. While both HT and DT provided acceptable treatment plans for a single patient, HT achieved a better coverage, a better high-dose OAR distribution to both lungs and heart and a lower dose to healthy tissue compared to DT.

      Case report

      Medical history

      Our patient, aged 61, presented with abnormal findings at her annual mammogram and was diagnosed in September 2020 with SBBC. Her imaging studies with CT thorax, abdomen, pelvis and brain were negative for metastasis. Her staging was completed with a bone scan, which was also negative. Patient was treated with bilateral mastectomy and lymph node dissection of both axillae, with 16 and 12 lymph nodes dissected in the right and left axilla respectively. Patient was stage pT2No ER + PR + HER2- Ki67 20 % for right breast cancer and pT3N1 for left breast cancer. Adjuvant chemotherapy comprised of 4 cycles of adriamycin and cyclophosphamide and 4 cycles of taxotere. After chemotherapy completion, patient was referred to the Radiation Oncology Department of Mediterraneo Hospital for adjuvant RT.
      Patient was clinically examined, and the only pathological finding was a mild lymphedema in both hands and was referred to an angiologist. There was no prior history of lung or heart disease or other comorbidities. Her family history was also negative with no known relatives of 1st or 2nd degree having been diagnosed with malignancies. Patient was a non-smoker. Both mastectomies’ scar had healed well with no post-surgical complications.

      Treatment contouring

      Patient has a CT simulation with Toshiba Aquillon LB CT scanner. Clinical target volume (CTV) included right and left chestwall, right supraclavicular region, right axilla (level III) and right internal mammary nodes. OAR (heart, LAD, lung right and left, spinal cord and the contralateral breast) were contoured. PTV was created from CTV by adding a 5 mm margin and cropping 3 mm from the body surface. The dose of 50 Gy in 25 fractions was prescribed to PTV.

      Treatment planning

      Two plans, one IMRT and one VMAT plan, were generated in Eclipse treatment planning system (Eclipse TPS v15.6, Varian Medical Systems Inc., Palo Alto, CA, USA), using photon optimizer and the Anisotropic Analytical Algorithm (AAA) version 15.6.06 with dose calculation grid size of 2.5 mm. The photon energy used was 6 MV, with a 600 MU/min maximum dose rate. Plans were designed for a Varian TrueBeam Edge Linear Accelerator equipped with the High Definition HD120 MLCs.
      The planning objectives for the PTV were at least 95 % of PTV volume should receive minimum 95 % of prescribed dose, along with a near-maximum dose (D2) ≤ 107 % of prescribed dose. Minimum plan objectives were spinal cord maximum dose ≤ 45 Gy, LV20 ≤ 30 % and MHD ≤ 6 Gy. Optimization was performed to minimize dose to all OAR without compromising PTV coverage.

      IMRT

      A single isocenter, located under the sternum, was used, as Huang et al. [
      • Huang J.-H.
      • Wu X.-X.
      • Lin X.
      • Shi J.-T.
      • Ma Y.-J.
      • Duan S.
      • et al.
      Evaluation of fixed-jaw IMRT and tangential partial-VMAT radiotherapy plans for synchronous bilateral breast cancer irradiation based on a dosimetric study.
      ] have shown a 2-isocenter technique to have an advantage only in obese patients, which was not the case with our patient. Twelve beams with fixed gantry were applied as described in Kim et al. and Chia et al. [
      • Kim S.J.
      • Lee M.J.
      • Youn S.M.
      Radiation therapy of synchronous bilateral breast carcinoma (SBBC) using multiple techniques.
      ,
      • Chia D.
      • Yusoff S.B.
      • Chen D.
      • Tey J.
      • Tang J.
      • Koh V.
      • et al.
      Strategies for bilateral breast and comprehensive nodal irradiation in breast cancer—a comparison of IMRT and 3D conformal radiation therapy.
      ], as shown in Fig. 2. Six beams arranged, starting from 20°to 120°, spaced every 20°and 6 more beams were applied, starting from 240°to 340°, similarly spaced. All beams were coplanar, the collimator angle was 1°, 14°, 39.6°, 14°, 12°, 92.5°, 90°, 356°, 352.9°, 352°, 350° and 354°, for each of the respective 12 beams. For IMRT sliding window method was in the optimization with high fluence smoothing factor. Additionally, the fixed jaw technique was adopted to decrease heart and lungs irradiation doses. This technique can decrease dose to OAR by reducing inter and intra leakage radiation and scatter dose. Finally, skin flash tool was applied, generating fluence outside of the body, due to intra-fraction respiratory motion.
      Figure thumbnail gr2
      Fig. 2Case study: beam arrangements for IMRT plan (A) and VMAT plan (B). (A). Beam arrangements for fixed-jaw IMRT plan. (B). Beam arrangements for VMAT plan.

      VMAT

      In the VMAT plan, dual isocenter technique was applied as described in Boman et al [
      • Boman E.
      • Rossi M.
      • Kapanen M.
      The robustness of dual isocenter VMAT radiation therapy for bilateral lymph node positive breast cancer.
      ], resulting in one plan with two isocenters, one for each side. The total arc rotation was 2×230° per isocenter (gantry start – split – stop angles: 190° – 300° – 60° for right and 300° – 60° – 170° for left isocenter) resulting 4×230° total arc rotation. The field split intends to adjust collimator and jaws maximizing sparing of OAR, along with acceptable target coverage. The median x-jaw was limited to reduce the exposure of lungs and heart while the lateral x-jaw was opened to encompass all breast in the beam eye view. Collimator angles were 75°, 290°, 350°, 355°, 350°, 350°, 20° and 18°, respectively. Beam arrangements are shown in Fig. 2.
      As no skin flash is available for VMAT, a 1 cm virtual bolus of −450 HU (relative electron density 0.5413) was created to provide density for the photon optimizer beyond the patient’s body contour. Optimization used both PTV and an additional PTV that was extended 5 mm outside the skin. Final dose calculation was performed without bolus.

      Plan evaluation

      To evaluate target coverage and plan quality, the CI was calculated:
      CI=TVRI2TVVRI


      where CI is the conformity index (CI), TVRI is the target volume covered by the reference isodose (95 %), TV is the target volume, and VRI is the volume of the reference isodose. The CI varies from 0 to 1, where 1 is the optimal value.
      PTVs heterogeneity was determined with HI, according to ICRU 83:
      HI=D2%-D98%D50%


      where D2%, D98%, D50% are minimum dose to 2 %, 98 % and 50 % volume respectively. A HI close to zero indicates that the absorbed-dose distribution is almost homogeneous.
      Two treatment plans, one with IMRT and the other with VMAT technique, were calculated and the resulting dosimetric characteristics of each plan are presented on Table 4, Table 5. IMRT plan has slightly increased beam on time (BOT), 3min50sec vs 3 min 05sec with VMAT and monitor units (MU), 1582.1 vs 1224.2 with VMAT. VMAT plan has a slightly increased low dose bath, e.g., increased V5 lungs, V5 heart and increased V5 TNTV. However, in the clinically significant doses, the VMAT plan surpasses the IMRT plan in most OAR parameters (LV20, MLD, MHD, mean LAD. Moreover, the VMAT plan outweighs the IMRT plan in terms of PTV coverage, with an increased V95% and D98% and a lower D2% and V107%. Plan evaluation parameters, homogeneity index (HI) and conformity PTV slightly favor the VMAT plan as well. Although in the plan comparison, VMAT was favorable over IMRT, IMRT plan was delivered to the patient by institutional protocol for breast RT. Patient completed the treatment in 25 fractions with IMRT from 28 April 2020 till 02 June 2020 without any treatment break.
      Table 4Case study: Dosimetric plan parameters.
      StructureFixed jaws IMRTVMAT
      PTV (cc)672.6
      Reference isodose 95 % (cc)1137.5935.0
      Target volume covered by reference isodose (cc)646.4639.8
      PTV D98%(Gy)47.648
      PTV D2%(Gy)52.752.2
      PTV D50%(Gy)50.850.6
      PTV V95% (%)98.298.9
      PTV107%(%)0.10
      Conformity PTV0.550.65
      Homogeneity index0.10.08
      MUs1582.11224.2
      Table 5Dosimetric values of OAR.
      OARDosimetric values of OAR
      Fixed jaws IMRTVMAT
      V5% (%)V20% (%)Dmean (Gy)Dmax (Gy)V5% (%)V20% (%)Dmean (Gy)Dmax (Gy)
      Lungs52.322.912.1NR53.315.79.9NR
      Body29.5NRNRNR35.2NRNRNR
      TNTV27.2NRNRNR33.1NRNRNR
      Heart31.5NR5.2NR21.6NR3.7NR
      LADNRNR15.724.8NRNR10.220.6
      PRV SCNRNRNR23NRNRNR24.9
      EsophagusNRNR9.9NRNRNR11.1NR
      *TNTV = Total Normal Tissue Volume, NR = Not reported, LAD = Left anterior descending artery.
      Throughout her treatment a physical exam and laboratory blood tests were performed weekly. Patient did not present with any acute side effects other than dermatitis grade 2 and treatment was well tolerated. Lymphedema was stable and mild, without any change compared to before RT initiation. Arm exercises were prescribed as per department protocol for all patients presenting with mild lymphedema post- operatively.
      Follow-up was performed at 2- and 9-months post treatment, with a complete physical examination, blood exams and imaging restaging exams and patient is free of recurrence or metastasis, but her right arm lymphedema mildly deteriorated at 9 months follow-up from grade 1 to grade 2. As patient presented with lymphedema before RT initiation and did not have a significant deterioration at follow-up, it is mainly considered as a post-operative side effect. Yet, RT’ s contribution to its deterioration cannot be excluded. Patient was referred to the angiologist, who prescribed hand gloves for both hands to prevent lymphedema deterioration.

      Discussion

      Synchronous bilateral breast cancer is a rare disease, representing only 1 % of newly diagnosed breast cancer patients with a prognosis equivalent or possibly even poorer to that of unilateral breast cancer [
      • Jobsen J.J.
      • Palen J.V.D.
      • Ong F.
      • Meerwaldt J.H.
      Synchronous, bilateral breast cancer: Prognostic value and incidence.
      ]. Only a few dosimetric studies with a limited number of patients have compared different RT techniques on SBBC patients, sometimes presenting conflicting evidence for available techniques. This makes treatment planning choices very difficult for each single SBBC patient in the clinical setting. This systematic review tried to gather, organize, and interpret existing data from relevant dosimetric studies to guide the clinicians and researchers on RT for SBBC.
      Traditional tangential fields result in field overlaps increasing hot and cold spots, resulting in inhomogeneous dose delivery to the target, with possible poor cosmetic outcomes [
      • Huang J.-H.
      • Wu X.-X.
      • Lin X.
      • Shi J.-T.
      • Ma Y.-J.
      • Duan S.
      • et al.
      Evaluation of fixed-jaw IMRT and tangential partial-VMAT radiotherapy plans for synchronous bilateral breast cancer irradiation based on a dosimetric study.
      ]. The studies comparing techniques for SBBC patients show that 3D-CRT has worst PTV coverage than IMRT, but with a tendency for better OAR sparing, which, however, cannot be generalized to all studies [
      • Alhefny M.M.
      • Attallah H.S.
      • Abdallah M.
      • Yassin A.
      • El-Shahat K.M.
      • Obaya A.A.
      Optimizing Adjuvant Radiation Planning Outcomes in Patients with Synchronous Bilateral Breast Cancer.
      ,
      • Kim S.J.
      • Lee M.J.
      • Youn S.M.
      Radiation therapy of synchronous bilateral breast carcinoma (SBBC) using multiple techniques.
      ,
      • Chia D.
      • Yusoff S.B.
      • Chen D.
      • Tey J.
      • Tang J.
      • Koh V.
      • et al.
      Strategies for bilateral breast and comprehensive nodal irradiation in breast cancer—a comparison of IMRT and 3D conformal radiation therapy.
      ]. 3D-CRT can adequately deliver adjuvant RT in SBBC patients especially when no RNI, boost or mastectomy is involved [
      • Alhefny M.M.
      • Attallah H.S.
      • Abdallah M.
      • Yassin A.
      • El-Shahat K.M.
      • Obaya A.A.
      Optimizing Adjuvant Radiation Planning Outcomes in Patients with Synchronous Bilateral Breast Cancer.
      ,
      • Kim S.J.
      • Lee M.J.
      • Youn S.M.
      Radiation therapy of synchronous bilateral breast carcinoma (SBBC) using multiple techniques.
      ,
      • Wadasadawala T.
      • Visariya B.
      • Sarin R.
      • Upreti R.R.
      • Paul S.
      • Phurailatpam R.
      Use of tomotherapy in treatment of synchronous bilateral breast cancer: dosimetric comparison study.
      ,
      • Gomaa H.A.G.A.
      • Almaghrabi M.Y.
      • Al-Gaoud M.A.G.
      Comparative Dosimetric Study of 3D Conformal Radiotherapy versus Volumetric Modulated Arc Radiotherapy in Synchronous Bilateral Breast Cancer.
      ,
      • Mani K.R.
      • Basu S.
      • Bhuiyan M.A.
      • Ahmed S.
      • Sumon M.A.
      • Haque K.A.
      • et al.
      Three dimensional conformal radiotherapy for synchronous bilateral breast irradiation using a mono iso-center technique.
      ]. Only few studies have used 3D-CRT when RNI was delivered [
      • Chia D.
      • Yusoff S.B.
      • Chen D.
      • Tey J.
      • Tang J.
      • Koh V.
      • et al.
      Strategies for bilateral breast and comprehensive nodal irradiation in breast cancer—a comparison of IMRT and 3D conformal radiation therapy.
      ,
      • Bosnic S.
      • McKenzie E.
      • Razvi Y.
      • Wronski M.
      • Zhang L.
      • Vesprini D.
      • et al.
      Heart and Lung Dose Metrics in Radiation Therapy Patients Treated for Synchronous Bilateral Breast Cancer (SBBC): A Decade in Review (2011–2018).
      ] or with a hypofractionated prescription [
      • Bosnic S.
      • McKenzie E.
      • Razvi Y.
      • Wronski M.
      • Zhang L.
      • Vesprini D.
      • et al.
      Heart and Lung Dose Metrics in Radiation Therapy Patients Treated for Synchronous Bilateral Breast Cancer (SBBC): A Decade in Review (2011–2018).
      ]. Modern techniques have solved the problem of field overlaps, making 3D-CRT a less appropriate technique for SBBC patients with RNI. For these patients most use modern techniques, such as VMAT and tomotherapy, while even the use of IMRT seems to be reduced.
      Comparison between IMRT with VMAT techniques for SBBC patients has been undertaken by several SBBC dosimetric studies; still, the debate remains inconclusive as each study uses different beam and arc arrangements and angles, making comparisons difficult. This is the case with LAD mean dose, which is lower with IMRT technique (18 Gy vs 24 Gy with VMAT) in the study of Alhefny et al [
      • Alhefny M.M.
      • Attallah H.S.
      • Abdallah M.
      • Yassin A.
      • El-Shahat K.M.
      • Obaya A.A.
      Optimizing Adjuvant Radiation Planning Outcomes in Patients with Synchronous Bilateral Breast Cancer.
      ], and higher with the same technique (21.5 Gy vs 14.4 Gy with VMAT) in the study of Sun et al [

      Sun, T.; Lin, X.; Tong, Y.; et al. Heart and Cardiac Substructure Dose Sparing in Synchronous Bilateral Breast Radiotherapy: A Dosimetric Study of Proton and Photon Radiation Therapy. Front. Oncol. 9. 2020. Doi: 10.3389/fonc.2019.01456.

      ]. Contrary to our case report, IMRT provides better OAR sparing in terms of MHD and MLD in the studies of Kim et al and in the high-dose areas in Alhefny et al [
      • Alhefny M.M.
      • Attallah H.S.
      • Abdallah M.
      • Yassin A.
      • El-Shahat K.M.
      • Obaya A.A.
      Optimizing Adjuvant Radiation Planning Outcomes in Patients with Synchronous Bilateral Breast Cancer.
      ,
      • Kim S.J.
      • Lee M.J.
      • Youn S.M.
      Radiation therapy of synchronous bilateral breast carcinoma (SBBC) using multiple techniques.
      ]. However, other studies provide evidence that with careful choice of planning parameters VMAT technique can result in adequate and even improved OAR dose distribution compared to IMRT, as in Sun et al [

      Sun, T.; Lin, X.; Tong, Y.; et al. Heart and Cardiac Substructure Dose Sparing in Synchronous Bilateral Breast Radiotherapy: A Dosimetric Study of Proton and Photon Radiation Therapy. Front. Oncol. 9. 2020. Doi: 10.3389/fonc.2019.01456.

      ], supporting the results presented in our case study. A constant drawback of VMAT throughout all studies is its increased low dose bath compared to IMRT and 3D-CRT [
      • Sun T.
      • Lin X.
      • Zhang G.
      • Qiu Q.
      • Li C.
      • Yin Y.
      Treatment planning comparison of volumetric modulated arc therapy with the trilogy and the Halcyon for bilateral breast cancer.
      ,
      • Nicolini G.
      • Clivio A.
      • Fogliata A.
      • Vanetti E.
      • Cozzi L.
      Simultaneous integrated boost radiotherapy for bilateral breast: a treatment planning and dosimetric comparison for volumetric modulated arc and fixed field intensity modulated therapy.
      ]. On the other hand, VMAT is shown to reduce BOT, which has a direct impact on patient comfort and intrafraction motion [
      • Kim S.J.
      • Lee M.J.
      • Youn S.M.
      Radiation therapy of synchronous bilateral breast carcinoma (SBBC) using multiple techniques.
      ,
      • Cheng H.-W.
      • Chang C.-C.
      • Shiau A.-C.
      • Wang M.-H.
      • Tsai J.-T.
      Dosimetric comparison of helical tomotherapy, volumetric-modulated arc therapy, intensity-modulated radiotherapy, and field-in-field technique for synchronous bilateral breast cancer.
      ]. Techniques such as 2 isocenters technique [

      Sun, T.; Lin, X.; Tong, Y.; et al. Heart and Cardiac Substructure Dose Sparing in Synchronous Bilateral Breast Radiotherapy: A Dosimetric Study of Proton and Photon Radiation Therapy. Front. Oncol. 9. 2020. Doi: 10.3389/fonc.2019.01456.

      ], hybrid techniques with 3D-CT [
      • Cho Y.
      • Cho Y.J.
      • Chang W.S.
      • Kim J.W.
      • Choi W.H.
      • Lee I.J.
      Evaluation of optimal treatment planning for radiotherapy of synchronous bilateral breast cancer including regional lymph node irradiation.
      ], DIBH [
      • Gaudino D.
      • Cima S.
      • Frapolli M.
      • Daniele D.
      • Muoio B.
      • Pesce G.A.
      • et al.
      Volumetric modulated arc therapy applied to synchronous bilateral breast cancer radiotherapy: Dosimetric study on deep inspiration breath hold versus free breathing set up.
      ] and FFF technique [
      • Nagaraj J.
      • Veluraja K.
      Is Synchronous Bilateral Breast Irradiation Using Flattening Filter-Free Beam-Based Volumetric-Modulated Arc Therapy Beneficial?.
      ] are shown to overcome the disadvantages of VMAT and have succeeded in improving the PTV coverage and decreasing the high dose to OAR.
      Most of the studies comparing IMRT with VMAT techniques for SBBC patients do not include mastectomies and RNI. Most of the studies that have included mastectomy patients [
      • Seppälä J.
      • Heikkilä J.
      • Myllyoja K.
      • Koskela K.
      Volumetric modulated arc therapy for synchronous bilateral whole breast irradiation – A case study.
      ,
      • Boman E.
      • Rossi M.
      • Kapanen M.
      The robustness of dual isocenter VMAT radiation therapy for bilateral lymph node positive breast cancer.
      ,
      • Cho Y.
      • Cho Y.J.
      • Chang W.S.
      • Kim J.W.
      • Choi W.H.
      • Lee I.J.
      Evaluation of optimal treatment planning for radiotherapy of synchronous bilateral breast cancer including regional lymph node irradiation.
      ,
      • Nagaraj J.
      • Veluraja K.
      Is Synchronous Bilateral Breast Irradiation Using Flattening Filter-Free Beam-Based Volumetric-Modulated Arc Therapy Beneficial?.
      ,

      Ekici, K.; Gokce, T.; Karadogan. I Is helical tomotherapy-based intensity-modulated radiotherapy feasible and effective in bilateral synchronous breast cancer? A two-center experience – PubMed. J BUON. Jan-Feb(1). 46–52. 2016.

      ,
      • Gadea J.
      • Ortiz I.
      • Roncero R.
      • Alastuey I.
      • Mestre F.
      • Aymar N.
      • et al.
      Synchronous bilateral breast cancer treated with a 3-week hypofractionated radiotherapy schedule: clinical and dosimetric outcomes.
      ,
      • Narasimhulu B.C.
      • Valiyaveettil D.
      • Joseph D.
      • et al.
      Synchronous bilateral breast cancer patients treated with hypofractionated bilateral breast irradiation: A dosimetric and clinical study.
      ] or RNI [
      • Wadasadawala T.
      • Jain S.
      • Paul S.
      • Phurailatpam R.
      • Joshi K.
      • Popat P.
      • et al.
      First clinical report of helical tomotherapy with simultaneous integrated boost for synchronous bilateral breast cancer.
      ,
      • Valli M.
      • Cima S.
      • Gaudino D.
      • Cartolari R.
      • Deantonio L.
      • Frapolli M.
      • et al.
      Skin and lung toxicity in synchronous bilateral breast cancer treated with volumetric-modulated arc radiotherapy: a mono-institutional experience.
      ,
      • Gadea J.
      • Ortiz I.
      • Roncero R.
      • Alastuey I.
      • Mestre F.
      • Aymar N.
      • et al.
      Synchronous bilateral breast cancer treated with a 3-week hypofractionated radiotherapy schedule: clinical and dosimetric outcomes.
      ,
      • Narasimhulu B.C.
      • Valiyaveettil D.
      • Joseph D.
      • et al.
      Synchronous bilateral breast cancer patients treated with hypofractionated bilateral breast irradiation: A dosimetric and clinical study.
      ,
      • Phurailatpam R.
      • Wadasadawala T.
      • Chauhan K.
      • Panda S.
      • Sarin R.
      Dosimetric comparison of volumetric-modulated arc therapy and helical tomotherapy for adjuvant treatment of bilateral breast cancer.
      ] have used VMAT and HT and to a lesser degree IMRT or 3D-CRT. When target areas are larger, as in the case of RNI, and when targets are closer to OAR, as in the case of mastectomy, SBBC RT becomes an even more complex problem. Results from studies including neither RNI nor mastectomies should not be transferred to mastectomy patients or patients requiring RNI. Phurailatpan et al [
      • Phurailatpam R.
      • Wadasadawala T.
      • Chauhan K.
      • Panda S.
      • Sarin R.
      Dosimetric comparison of volumetric-modulated arc therapy and helical tomotherapy for adjuvant treatment of bilateral breast cancer.
      ] compared VMAT to HT for 10 SBBC patients with RNI. Both techniques were comparable with adequate coverage and good OAR sparing, but VMAT was marginally better due a more homogeneous plan with less MUs and a better PTV coverage.
      In the case report presented in this article, VMAT technique is marginally advantageous both in terms of PTV coverage, as indicated by V95, V107 and D2, and in terms of OAR dose distribution with lower LMD, HMD, LAD mean and lung V20. IMRT provides a superior plan only for low dose volumes. VMAT plan also has a slightly decreased homogeneity index (0.08 vs 0.1 with IMRT) and a higher PTV conformity (0.65 vs 0.55 with VMAT). The larger MUs and increased BOT favor VMAT over IMRT. A possible explanation of the increased MUs and BOT with the IMRT plan is the 12 beam arrangement chosen, which has been previously shown to increase MUs and BOT [
      • Rakici S.
      • Cinar Y.
      Dual-isocentric volumetric modulated arc therapy in synchronous bilateral breast cancer irradiation: A dosimetric study.
      ,
      • Nicolini G.
      • Clivio A.
      • Fogliata A.
      • Vanetti E.
      • Cozzi L.
      Simultaneous integrated boost radiotherapy for bilateral breast: a treatment planning and dosimetric comparison for volumetric modulated arc and fixed field intensity modulated therapy.
      ]. In our study the VMAT plan followed the two-isocenter technique, supported by the litterature [
      • Boman E.
      • Rossi M.
      • Kapanen M.
      The robustness of dual isocenter VMAT radiation therapy for bilateral lymph node positive breast cancer.
      ,

      Sun, T.; Lin, X.; Tong, Y.; et al. Heart and Cardiac Substructure Dose Sparing in Synchronous Bilateral Breast Radiotherapy: A Dosimetric Study of Proton and Photon Radiation Therapy. Front. Oncol. 9. 2020. Doi: 10.3389/fonc.2019.01456.

      ]. Differences between IMRT and VMAT plans dose-volume histograms, however, were found minimal and the conclusion based on the literature review and case study is that with carefully selected planning techniques both IMRT and VMAT can result in a high-quality plan for SBBC patients.
      Hypofractionated RT for early breast cancer is the current golden standard based on the Canadian, UK and Dutch trials and a meta-analysis [
      • Thomsen M.S.
      • Berg M.
      • Zimmermann S.
      • Lutz C.M.
      • Makocki S.
      • Jensen I.
      • et al.
      Dose constraints for whole breast radiation therapy based on the quality assessment of treatment plans in the randomised Danish breast cancer group (DBCG) HYPO trial.
      ,
      • Haviland J.S.
      • Owen J.R.
      • Dewar J.A.
      • et al.
      The UK Standardisation of Breast Radiotherapy (START) trials of radiotherapy hypofractionation for treatment of early breast cancer: 10-year follow-up results of two randomised controlled trials.
      ,
      • Hickey B.E.
      • James M.L.
      • Lehman M.
      • et al.
      Fraction size in radiation therapy for breast conservation in early breast cancer.
      ]. Several published articles have also proven the feasibility and safety of hypofractionated adjuvant RT in SBBC [
      • Gadea J.
      • Ortiz I.
      • Roncero R.
      • Alastuey I.
      • Mestre F.
      • Aymar N.
      • et al.
      Synchronous bilateral breast cancer treated with a 3-week hypofractionated radiotherapy schedule: clinical and dosimetric outcomes.
      ,
      • Narasimhulu B.C.
      • Valiyaveettil D.
      • Joseph D.
      • et al.
      Synchronous bilateral breast cancer patients treated with hypofractionated bilateral breast irradiation: A dosimetric and clinical study.
      ,
      • Huang J.-H.
      • Wu X.-X.
      • Lin X.
      • Shi J.-T.
      • Ma Y.-J.
      • Duan S.
      • et al.
      Evaluation of fixed-jaw IMRT and tangential partial-VMAT radiotherapy plans for synchronous bilateral breast cancer irradiation based on a dosimetric study.
      ,
      • Srivastava R.P.
      • Vandeputte K.
      • De Wagter C.
      Benefits and Limitations of Volumetric Modulated Arc Therapy in Treating Bilateral Breast Cancer with Regional Lymph Nodes.
      ,
      • Franco P.
      • Migliaccio F.
      • Torielli P.
      • Sciacero P.
      • Girelli G.
      • Cante D.
      • et al.
      Bilateral breast radiation delivered with static angle tomotherapy (TomoDirect): clinical feasibility and dosimetric results of a single patient.
      ,
      • Lancellotta V.
      • Iacco M.
      • Perrucci E.
      • Zucchetti C.
      • Dipilato A.C.
      • Falcinelli L.
      • et al.
      Comparison of helical tomotherapy and direct tomotherapy in bilateral whole breast irradiation in a case of bilateral synchronous grade 1 and stage 1 breast cancer.
      ]. PTV coverage was adequate in most studies, with the lowest V100% being 93.3 % with VMAT technique in the study by Huang et al [
      • Huang J.-H.
      • Wu X.-X.
      • Lin X.
      • Shi J.-T.
      • Ma Y.-J.
      • Duan S.
      • et al.
      Evaluation of fixed-jaw IMRT and tangential partial-VMAT radiotherapy plans for synchronous bilateral breast cancer irradiation based on a dosimetric study.
      ] and the lowest D95% being 37.3 Gy for a prescribed dose of 40.05 Gy in the study of Srivastava et al [
      • Srivastava R.P.
      • Vandeputte K.
      • De Wagter C.
      Benefits and Limitations of Volumetric Modulated Arc Therapy in Treating Bilateral Breast Cancer with Regional Lymph Nodes.
      ].
      Another technique to shorten overall treatment course in adjuvant breast cancer RT is SIB, which is continuously gaining grounds also due to dosimetric advantages. Currently, a large phase III trial with 2 years follow-up reassures caregivers of its safety and its good cosmetic outcomes [
      • Hörner-Rieber J.
      • Forster T.
      • Hommertgen A.
      • Haefner M.F.
      • Arians N.
      • König L.
      • et al.
      Intensity Modulated Radiation Therapy (IMRT) With Simultaneously Integrated Boost Shortens Treatment Time and Is Noninferior to Conventional Radiation Therapy Followed by Sequential Boost in Adjuvant Breast Cancer Treatment: Results of a Large Randomized Phase III Trial (IMRT-MC2 Trial).
      ,
      • Forster T.
      • Hommertgen A.
      • Häfner M.F.
      • Arians N.
      • König L.
      • Harrabi S.B.
      • et al.
      Quality of life after simultaneously integrated boost with intensity-modulated versus conventional radiotherapy with sequential boost for adjuvant treatment of breast cancer: 2-year results of the multicenter randomized IMRT-MC2 trial.
      ]. SIB technique has long been explored in small studies for SBBC patients with PTV coverage and OAR distribution data being similar to those from conventional and hypofractionated studies that used a sequential boost [
      • Phurailatpam R.
      • Wadasadawala T.
      • Chauhan K.
      • Panda S.
      • Sarin R.
      Dosimetric comparison of volumetric-modulated arc therapy and helical tomotherapy for adjuvant treatment of bilateral breast cancer.
      ,
      • Fiorentino A.
      • Mazzola R.
      • Naccarato S.
      • Giaj-Levra N.
      • Fersino S.
      • Sicignano G.
      • et al.
      Synchronous bilateral breast cancer irradiation: clinical and dosimetrical issues using volumetric modulated arc therapy and simultaneous integrated boost.
      ,
      • Valli M.
      • Cima S.
      • Gaudino D.
      • Cartolari R.
      • Deantonio L.
      • Frapolli M.
      • et al.
      Skin and lung toxicity in synchronous bilateral breast cancer treated with volumetric-modulated arc radiotherapy: a mono-institutional experience.
      ,
      • Nicolini G.
      • Clivio A.
      • Fogliata A.
      • Vanetti E.
      • Cozzi L.
      Simultaneous integrated boost radiotherapy for bilateral breast: a treatment planning and dosimetric comparison for volumetric modulated arc and fixed field intensity modulated therapy.
      ].
      Dosimetric results of all relevant studies have been collected and analyzed in this systematic review to guide physicians make the appropriate treatment choices for the rare SBBC patient. All techniques have proven to be safe and efficient. Evidence from several studies shows that the correct choice of planning parameters, such as one or two isocenters, the number and angle of arcs or beams or the use of a fixed-jaw technique can be of higher importance than choosing between VMAT or IMRT technique. Therefore, depending on available equipment and experience with techniques, careful planning is necessary to achieve adequate PTV coverage and OAR dose sparing for such extensive PTV volume as in SBBC, regardless the technique chosen. Moreover, for each single patient, physicians should take into consideration their precise characteristics, such as type of surgery, need for RNI or boost and breast size, as not all studies included an adequate number of patients from each category.
      The importance of adjuvant RT for SBBC patients is supported by the clinical studies included in this review. Both conventional and hypofractionated studies, with either sequential or simultaneous boost studies, report minimal skin toxicity and no clinically evident case of radiation pneumonitis. Modern RT techniques can safely deliver adequate dose to large volumes while sparing the lungs and the heart. Patients with SBBC have the same or worse prognosis with unilateral breast cancer and adjuvant RT can greatly benefit all breast cancer patients not only in terms of local control but also by improving overall survival [

      Early Breast Cancer Trialists’ Collaborative Group (EBCTCG); Darby, S.; McGale, P.; et al. Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10 801 women in 17 randomised trials. Lancet 378(9804):1707–16; 2011. Doi: 10.1016/S0140-6736(11)61629-2.

      ,

      EBCTCG (Early Breast Cancer Trialists’ Collaborative Group); McGale, P.; Taylor, C.; et al. Effect of radiotherapy after mastectomy and axillary surgery on 10-year recurrence and 20-year breast cancer mortality: meta-analysis of individual patient data for 8135 women in 22 randomised trials. Lancet 383(9935):2127–35; 2014. Doi: 10.1016/S0140-6736(14)60488-8.

      ].

      Declaration of Competing Interest

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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