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Intensity Modulated Proton Therapy for Bilateral Breast or Chest Wall and Comprehensive Nodal Irradiation for Synchronous Bilateral Breast Cancer: Initial Clinical Experience and Dosimetric Comparison

Open AccessPublished:January 24, 2022DOI:https://doi.org/10.1016/j.adro.2022.100901

      Abstract

      Purpose

      Synchronous bilateral breast cancer (SBBC) poses distinct challenges for radiation therapy planning. We report our proton therapy experience in treating patients with SBBC. We also provide a dosimetric comparison of intensity modulated proton therapy (IMPT) versus photon therapy.

      Methods and Materials

      Patients with SBBC who received IMPT at our institution were retrospectively analyzed. The clinical target volume (CTV) included the breast or chest wall and comprehensive regional lymph nodes, including axilla, supraclavicular fossa, and the internal mammary chain. Intensity modulated proton therapy and volumetric modulated arc therapy (VMAT) plans were generated with the goal that 90% of the CTV would recieve at least 90% of the prescription dose (D90>=90%). Comparisons between modalities were made using the Wilcoxon signed rank test. Physician-reported acute toxic effects and photography were collected at baseline, end of treatment, and each follow-up visit.

      Results

      Between 2015 and 2018, 11 patients with SBBC were treated with IMPT. The prescription was 50 Gy in 25 fractions. The median CTV D90 was 99.9% for IMPT and 97.6% for VMAT (P = .001). The mean heart dose was 0.7 Gy versus 7.2 Gy (P = .001), the total lung mean dose was 7.8 Gy versus 17.3 Gy (P = .001), and the total lung volume recieving 20 Gy was 13.0% versus 27.4% (P = .001). The most common acute toxic effects were dermatitis (mostly grade 1-2 with 1 case of grade 3) and grade 1 to 2 fatigue. The most common toxic effects at the last-follow up (median, 32 months) were grade 1 skin hyperpigmentation, superficial fibrosis, and extremity lymphedema. No nondermatologic or nonfatigue adverse events of grade >1 were recorded.

      Conclusions

      Bilateral breast and/or chest wall and comprehensive nodal IMPT is technically feasible and associated with low rates of severe acute toxic effects. Treatment with IMPT offered improved target coverage and normal-tissue sparing compared with photon therapy. Long-term follow-up is ongoing to assess efficacy and toxic effects.

      Introduction

      Synchronous bilateral breast cancer (SBBC), defined as contralateral breast cancer diagnosed within 12 months of primary breast cancer, occurs in 1% to 3% of all breast cancer cases.
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      Proton therapy may also allow for better clinical target volume (CTV) coverage, especially of the IMNs.
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      Multiple institutions have reported experiences with postlumpectomy and postmastectomy plus regional nodal PBT for unilateral breast cancer. These studies have suggested this technique is technically feasible and associated with acceptable patient outcomes.
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      A randomized phase 3 trial of photon versus proton therapy is ongoing.

      Pragmatic randomized trial of proton vs. photon therapy for patients with non-metastatic breast cancer: A Radiotherapy Comparative Effectiveness (RADCOMP) Consortium trial. Available at: https://clinicaltrials.gov/ct2/show/NCT02603341. Accessed February 14, 2022.

      We hypothesized that the normal-tissue sparing of PBT would be pronounced in bilateral radiation therapy owing to the greater volume of irradiated tissue and more challenging treatment geometry. The ability of intensity modulated proton therapy (IMPT) to provide a smooth gradient that is robust to setup uncertainty between fields with multiple isocenters may also avoid hot or cold junctions, potentially decreasing the risk of adverse events or undercoverage of the CTV. The goal of this study was to demonstrate the feasibility of IMPT for SBCC by reporting our institutional experience, including technique, dosimetry, and acute toxicity, as well as comparison with volumetric modulated arc therapy (VMAT) plans.

      Methods and Materials

      After institutional review board approval, we queried our prospectively collected outcomes database to identify all patients who received IMPT for bilateral breast cancer between 2015 and 2018. Since opening our proton center in 2015, we have routinely considered IMPT in patients requiring bilateral chest wall and/or breast and comprehensive nodal irradiation based on improvements in target coverage and normal-tissue sparing in studies of patients treated with unilateral proton therapy.
      • Lin LL
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      • Dimofte A
      • et al.
      Proton beam versus photon beam dose to the heart and left anterior descending artery for left-sided breast cancer.
      • Fagundes M
      • Hug EB
      • Pankuch M
      • et al.
      Proton therapy for local-regionally advanced breast cancer maximizes cardiac sparing.
      • Jimenez RB
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      • et al.
      Intensity modulated proton therapy for postmastectomy radiation of bilateral implant reconstructed breasts: A treatment planning study.
      • Hernandez M
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      A treatment planning comparison of volumetric modulated arc therapy and proton therapy for a sample of breast cancer patients treated with post-mastectomy radiotherapy.
      • Patel SA
      • Lu HM
      • Nyamwanda JA
      • et al.
      Postmastectomy radiation therapy technique and cardiopulmonary sparing: A dosimetric comparative analysis between photons and protons with free breathing versus deep inspiration breath hold.
      ,
      • Lomax AJ
      • Cella L
      • Weber D
      • Kurtz JM
      • Miralbell R.
      Potential role of intensity-modulated photons and protons in the treatment of the breast and regional nodes.
      ,
      • Dasu A
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      • Edvardsson A
      • Witt Nystrom P
      Normal tissue sparing potential of scanned proton beams with and without respiratory gating for the treatment of internal mammary nodes in breast cancer radiotherapy.
      Patients were included in this study if they had a proton plan that was approved for clinical use.
      Patient immobilization was performed with an angled breast board with both arms above the head or with arms down holding indexed hand grips, with the head and neck immobilized in a 3- or 5-point thermoplastic mask with custom neck rest.
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      Initial clinical experience of postmastectomy intensity modulated proton therapy in patients with breast expanders with metallic ports.
      The latter position is considered for comfort owing to prolonged treatment times. Planning computed tomography (CT) scans were routinely obtained with free breathing. Breath hold scans were occasionally obtained at initial simulation in anticipation of clinical photon planning owing to uncertain insurance coverage for proton therapy. The CTV included the breast or chest wall and regional lymph nodes, including levels 1, 2, and 3 of the axilla, supraclavicular lymph nodes (SCVs), and IMNs. The CTV resembled the Radiation Therapy Oncology Group Breast Cancer Atlas with some notable exceptions. The chest wall CTV did not routinely extend deeper than the anterior surface of the ribs and intercostal muscles. The CTV excluded the first 3 mm of tissue under the skin for the chest wall or 5 mm for intact breasts. The SCV volumes included the medial and lateral SCV, except the CTV was not routinely extended medial to the lateral border of the internal carotid artery to reduce the dose to midline organs, because nodal recurrences and presentations are rare in that location.
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      The IMN volume was a 4- to 5-mm medial and lateral expansion on the internal mammary vessels and extended from the most caudal extent of the SCV volume near the junction of the internal mammary and brachiocephalic veins to the cranial CT slice of the fourth rib.
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      delineation of internal mammary nodal target volumes in breast cancer radiation therapy.
      The CTV coverage goal was for the minimum dose received by 90% of the volume (D90) to be >90%, and the second-priority goal was for the D95% to be >95%, with the exception of the IMN CTV, where the coverage goal was for the D90% to be >80%. The dose prescription for the CTV was 50 Gy (relative biological effectiveness [RBE] of 1.1) in 25 fractions. Lumpectomy cavity boosts were routinely administered, whereas chest wall boosts were administered at physician discretion for adverse clinical features. Nodal boosts were considered in patients with undissected nodal disease. To ensure adequate coverage of dermal lymphatics while minimizing dermatologic toxic effects, we attempted to constrain the skin by using target coverage planning objectives of D90 >90%. For patients with inflammatory breast cancer, we attempted to treat the skin to prescription dose while limiting the skin 1 cc (D1cc) to <105%.
      Proton planning was performed using the Eclipse treatment planning system (Varian Medical Systems, Palo Alto, CA) using multifield optimization. Two beams per side angled 45° to 60° apart were chosen to account for the metallic expander port as previously described,
      • Mutter RW
      • Remmes NB
      • Kahila MM
      • et al.
      Initial clinical experience of postmastectomy intensity modulated proton therapy in patients with breast expanders with metallic ports.
      with occasional use of a fifth posterior field to cover a limited scanning target volume. Plans were evaluated for robustness to ensure CTV coverage in 8 separate worst-case scenarios of ±5-mm isocenter shifts in the x, y, and z directions and an uncertainty range of ±3%. Plans were verified in a Monte Carlo physical dose simulation based in an in-house graphics processing unit and an in-house Monte Carlo biologic dose simulation that assumes a linear relationship between RBE and linear energy transfer.
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      Plans generated by Monte Carlo biologic dose simulation (RBE 1.1) were evaluated side by side for target coverage and increased RBE within organs at risk (OARs), such as the brachial plexus and chest wall, and were modified as necessary to limit hot spots in these structures.
      • Mutter RW
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      Incorporation of Biologic Response Variance Modeling Into the Clinic: Limiting Risk of Brachial Plexopathy and Other Late Effects of Breast Cancer Proton Beam Therapy.
      Protons were delivered using pencil-beam scanning IMPT on a Hitachi PROBEAT-V system with a range shifter with 4.5-cm water-equivalent thickness. Daily image alignment included oblique pair kilovoltage x-rays with 6° of freedom matching to the chest wall and intrafraction body-surface monitoring using AlignRT (Vision RT Inc, London, United Kingdom). Verification CT scans were obtained at least once during the treatment course with additional verification scans per physician discretion. Replanning was done if target coverage or normal-tissue constraints on the verification scan did not meet original planning objectives.
      Several patients had VMAT plans generated during treatment planning as a backup option in case of proton outage or in the event that IMPT was not approved by insurance. For patients who did not have a VMAT plan, an experienced breast dosimetrist generated a VMAT plan in Eclipse for comparison. To achieve comparable target coverage with acceptable homogeneity and dose to normal tissues, all photon comparison plans used VMAT rather than 3-dimensional techniques. The CTVs were the same as the ones used for proton planning plus a CTV to a planning target volume (PTV) expansion of 5 mm, excluding the lungs and cropped from the skin. A tissue equivalent bolus was used to achieve adequate skin dose when indicated. A single isocenter was placed at the level of the midsternum, and 4 to 5 partial arcs were used per side. Volumetric modulated arc therapy plans were generated using the same target coverage parameters used in proton planning. No plan normalization was used in either proton or photon planning.
      Standard skin care included topical emollients, with the addition of topical steroidal creams or dilute vinegar soaks as indicated for more severe radiation dermatitis. Mepitel film, which has been shown to reduce the severity of radiation dermatitis,
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      was used at the discretion of the treating physician and patient as an out-of-pocket expense.
      Adverse events were prospectively collected using the Common Terminology Criteria for Adverse Events, version 4.0. Baseline toxic effects were assessed by the treating radiation oncologist before the start of radiation. End-of-treatment toxic effects were assessed at the last on-treatment visit. Acute treatment toxic effects were assessed at the first clinical follow-up. Photography was obtained with patient consent at baseline, end-of-treatment, and follow-up visits to document skin toxic effects and cosmetic outcomes.
      ProKnowDS (Elekta AB, Stockholm, Sweden) was used to aggregate CT images, structure sets, Digital Imaging and Communications in Medicine plans, and dose files and to generate comparative dose-volume histograms (DVHs) for target volumes and normal tissues. Plan comparisons were performed in terms of dosimetric parameters characterizing target coverage and OARs. Although dose was prescribed to the PTV for photon plans, comparison of target coverage was made for the CTV because this volume was the same for both modalities. Differences between modalities were tested using the Wilcoxon signed rank test, with a P value <.05 considered statistically significant.

      Results

      A total of 11 patients, 10 female and 1 male, were identified who met study criteria. Patient and tumor characteristics are shown in Table 1. The median age of the patients at diagnosis was 51.5 years (range, 38-69 years). Two patients had inflammatory breast cancer (T4d). Three patients had recurrence after prior breast-conserving therapy including radiation therapy. All patients received chemotherapy with or without HER2 directed therapy and hormone therapy as indicated: neoadjuvant (n = 4), adjuvant (n = 5), and neoadjuvant plus adjuvant (n = 2). Five patients had reconstruction with immediate tissue expanders (n = 3) or autologous reconstruction (n = 2). The CTVs included bilateral postmastectomy with regional nodal irradiation (n = 9) and bilateral whole breast with regional nodal irradiation (n = 2). The prescription was 50 Gy (RBE 1.1) in 25 fractions. Seven patients received boosts: 4 to the chest wall, 1 to the lumpectomy cavity, and 2 to one or more nodal regions. Boosts were typically delivered with a simultaneous integrated technique to 54.05-58.75 Gy in 25 fractions (n = 6). A sequential boost was administered in 1 patient (12.5 Gy in 5 fractions). Six patients were treated with arms up and 5 patients were treated with arms down. Four patients had arms-down immobilization chosen at initial simulation, and 1 patient required resimulation owing to intolerance of arms-up positioning. All patients had at least 1 CT verification scan. Replanning occurred for 4 patients: 3 owing to unacceptable target coverage and 1 after new immobilization was made for better patient tolerance. All 11 patients received all planned fractions with protons, and backup photon plans were not used.
      Table 1Patient, cancer, and treatment characteristics of 11 patients with 22 tumors treated with intensity modulated proton therapy
      CharacteristicNumber%
      Histology
       Invasive ductal carcinoma2195
       Invasive lobular carcinoma15
       Hormone receptor at diagnosis
       ER and/or PR+/HER2–1673
       ER and/or PR+/HER2+29
       ER–/PR–/HER2–418
      Clinical stage at diagnosis
       0418
       I15
       II
      Includes patients who had recurrence after breast-conserving therapy.
      1045
       III
      Includes patients who had recurrence after breast-conserving therapy.
      732
      Pathologic stage at surgery
       0314
       I
      Includes patients who had recurrence after breast-conserving therapy.
      314
       II
      Includes patients who had recurrence after breast-conserving therapy.
      836
       III
      Includes patients who had recurrence after breast-conserving therapy.
      836
      Axillary surgery
       Sentinel lymph node dissection735
       Axillary lymph node dissection1365
      low asterisk Includes patients who had recurrence after breast-conserving therapy.
      Volumetric modulated art therapy comparison plans were generated for 7 patients who did not have photon plans as part of the treatment workflow. The CTV coverage goals of D90 >90% and D95 >95% were achieved in both proton and photon plans for all patients. Intensity modulated proton therapy achieved better D90% coverage of the CTV (P = .001). Volumetric modulated art therapy achieved better D90% and D95% coverage of the boost CTV (P = .016 for both). Otherwise, there was no statistical difference in coverage of the CTV or IMNs between modalities (Table 2). The DVHs for the CTV and IMNs are depicted in Figure 1, A-B. Figure 2 shows plan comparisons for 2 representative patients.
      Table 2Comparison of target coverage and organs at risk between proton and VMAT photon plans
      Doses are given as Gy (VMAT) or Gy RBE (proton) received by volume (%) of targets.
      StructureParameterProton, mean (range)VMAT, mean (range)Wilcox signed rank P value
      Target volumes
       CTVD90%99.9% (94.9%-101.5%)97.6% (92.7%-100.0%).001
      D95%96.3% (92.2%-99.8%)97.7% (91.8%-99.5%).520
      Boost CTVD90%95.6% (78.5%-100.5%)99.2% (81.9%-101.8%).016
      D95%95.1% (77.1%-99.3%)98.5% (80.0%-101.2%).016
      IMN
       RightD90%95.9% (84.2%-99.3%)91.8% (81.7%-103.1%).465
       LeftD90%96.2% (92.1%-99.7%)92.9% (76.9%-100.8%).250
      Organ at risk
       HeartV5Gy3.8% (0.7%-7.9%)83.6% (46.8%-100%).001
      V15Gy0.8% (0.0%-2.8%)4.3% (0.1%-12.2%).002
      V25Gy0.1% (0.0%-1.2%)0.7% (0.0%-4.3%).009
      Mean (Gy)0.7 Gy (0.3 Gy to 1.4 Gy)7.2 Gy (5.3 Gy to 9.7 Gy).001
      Coronary arteries
       RightMax (Gy)11.3 Gy (1.9 Gy to 27.9 Gy)19.6 Gy (8.6 Gy to 35.0 Gy).003
      Mean (Gy)1.0 Gy (0.02 Gy to 3.9 Gy)10.4 Gy (5.4 Gy to 15.2 Gy).001
       Left anterior descendingMax (Gy)10.1 Gy (3.4 Gy to 30.3 Gy)31.8 Gy (10.1 Gy to 42.5 Gy).001
      Mean (Gy)1.3 Gy (0.3 Gy to 4.9 Gy)13.3 Gy (6.5 Gy to 28.4 Gy).001
      Lungs
       TotalV5Gy42.8% (16.9%-48.4%)99.6% (92.3%-100%).001
      V20Gy13.0% (5.2%-15.4%)27.4% (18.0%-45.8%).001
      Mean7.8 Gy (3.3 Gy to 8.6 Gy)17.3 Gy (13.7 Gy to 23.2 Gy).001
       RightV5Gy43.3% (13.0%-50.2%)99.4% (94.2%-100.0%).001
      V20Gy13.5% (3.0%-18.7%)27.9% (17.8%- 46.4%).001

       LeftV5Gy41.8% (6.6%-50.2%)99.8% (90.1%-100%).001

      V20Gy12.3% (0.1%-14.8%)27.9% (17.6%-45.0%).001
      Brachial plexus
       LeftMax (Gy)50.7 Gy (49.4 Gy to 58.4 Gy)54.9 Gy (53.3 Gy to 60.9 Gy).008
       RightMax (Gy)50.9 Gy (48.5 Gy to 55.7 Gy)54.2 Gy (51.7 Gy to 58.1 Gy).010
      EsophagusMax (Gy)4.9 Gy (0.0 Gy to 16.4 Gy)15.4 Gy (6.9 Gy to 34.9 Gy)<.001
      Abbreviations: CTV = clinical target volume; D90% = minimum dose received by 90% of the volume; IMN = internal mammary lymph node; RBE = relative biological effectiveness; V5Gy = volume recieving 5 Gy; V20Gy = volume recieving 20 Gy; VMAT = volumetric modulated arc therapy.
      low asterisk Doses are given as Gy (VMAT) or Gy RBE (proton) received by volume (%) of targets.
      Fig 1
      Fig. 1Dose-volume histograms for photon (blue) and proton (red) plans for 11 patients.
      Target volumes: (A) clinical target volume (CTV) and (B) left internal mammary lymph nodes. Coverage goals for the CTV were for the minimum dose received by 90% of the volume (D90) to be greater than 90%, with a second priority for D95% to be greater than 95%. Coverage goals for internal mammary lymph nodes were a D90% greater than 80%. Organs at risk: (C) heart; (D) right coronary artery; (E) left anterior descending artery; and (F) total lung.
      Fig 2
      Fig. 2Axial slices through the level of the heart comparing volumetric modulated arc therapy photon (A and D) and pencil-beam scanning intensity modulated proton therapy (B and E) plans for 2 patients in the study. Both patients were simulated in deep inspiratory breath hold for photon planning and free breathing for proton planning. One patient was immobilized with arms down (A-C) and 1 patient with arms above the head (D-F). The clinical target volume for both patients included the bilateral chest wall and regional lymph nodes plus chest wall boosts. The color wash displays 2000 to 6000 cGy isodose levels.
      Intensity modulated proton therapy was associated with a significant improvement in normal-tissue sparing for all evaluated OARs (Table 2) and was also associated with significant reduction in the mean heart dose (0.7 Gy vs 7.2 Gy; P = .001), total lung mean dose (7.8 Gy vs 17.3 Gy; P = .001), and total lung volume recieving 20 Gy (13.0% vs 27.4%; P = .001). The DVHs for the heart, coronary arteries, and lungs are depicted in Figure 1, C-F. Comparison of VMAT plans for patients simulated in deep inspiratory breath hold (DIBH) (n = 3) versus free-breathing (n = 8) showed no statistically significant differences in target coverage or dose to all evaluated OARs. There were no differences in IMPT or VMAT treatment planning or dosimetry for patients positioned with arms down.
      Baseline and end-of-treatment toxicity data are shown in Table 3. The most common end-of-treatment toxic effect was radiation dermatitis, which occurred in all patients: grade 1 in 5 patients, grade 2 in 5 patients, and grade 3 in 1 patient. Five patients in the study had Mepitel film applied to the treatment area, of whom 4 had grade 1 dermatitis and 1 had grade 3 dermatitis. Of those who did not use Mepitel, 1 patient had grade 1 dermatitis and 5 patients had grade 2 dermatitis. Fatigue was reported by 8 patients at the end of treatment, mostly grade 1 (7 patients) and grade 2 (1 patient). Toxic effects were assessed in 11 patients at the first follow-up visit, which occurred at a median of 98 days (range, 84-134 days) posttreatment. Toxic effects were assessed in 8 patients at last follow-up at a median of 32 months (range, 8-48 months) posttreatment. The most common toxic effects at the last follow-up were superficial fibrosis, skin hyperpigmentation, and extremity lymphedema, all grade 1. No nondermatologic or nonfatigue adverse events greater than grade 1 were recorded. There were no differences in toxic effects between patients treated with arms up or arms down. There were no numerical differences in acute (<90 days) or longer-term (median, 27.5 months) toxic effects in the 3 patients receiving reirradiation. Figure 3 shows photographs taken at baseline, end of treatment, and the 3-month follow-up. At a median follow-up of 22 months (range, 2-48 months), 3 patients had developed recurrence (1 local, 1 distant, and 1 local and distant), and 2 of those patients died of their disease.
      Table 3Physician-assessed toxic effects at baseline, end of treatment, first follow-up visit, and most recent clinical follow-up visit
      Toxic effectPatients, n
      Baseline(n = 11)End of treatment (n = 11)First follow-up (n = 11)Last follow-up (n = 8)
      Fatigue68
      Grade 1 (n = 7) and grade 2 (n = 1).
      71
      Esophagitis0100
      Limb edema1013
      Noncardiac chest pain2100
      Breast infection0000
      Radiation dermatitis011
      Grade 1 (n = 5), grade 2 (n = 5), and grade 3 (n = 1).
      00
      Fracture0000
      Seroma1000
      Superficial connective tissue fibrosis0023
      Deep connective tissue fibrosis0011
      Decreased joint range of motion11
      Present in 1 patient at baseline.
      5
      Present in 1 patient at baseline.
      2
      Present in 1 patient at baseline.
      Brachial plexopathy0001
      Owing to recurrent inflammatory breast cancer.
      Pneumonitis0000
      Skin hyperpigmentation0082
      Skin hypopigmentation0030
      Lymphedema0211
      low asterisk Grade 1 (n = 7) and grade 2 (n = 1).
      Grade 1 (n = 5), grade 2 (n = 5), and grade 3 (n = 1).
      Present in 1 patient at baseline.
      § Owing to recurrent inflammatory breast cancer.
      Fig 3
      Fig. 3(A-C) A patient who underwent reconstruction with immediate tissue expanders. She received 50 Gy (relative biological effectiveness [RBE] of 1.1) to the bilateral chest wall and axilla. (D-F) A patient who received 50 Gy (RBE 1.1) to the bilateral chest wall and axilla with simultaneous integrated boost of 56.25 Gy (RBE 1.1) to the right chest wall. Photos were taken at postsurgical baseline (A and D), at the end of treatment (B and E), and at the 3-month follow-up (C and F).

      Discussion

      Radiation therapy for bilateral breast cancer is challenging to deliver with photon and/or electron techniques without compromises to target coverage or increased doses to OARs. This study demonstrated promising initial outcomes of a cohort of patients with SBBC treated with IMPT, which resulted in excellent target coverage with superior normal-tissue sparing compared with VMAT.
      Attention to immobilization, beam arrangements, planning parameters, and daily image guidance is crucial for the safe delivery of IMPT. We occasionally position patients supine with arms down along their sides holding indexed handgrips or immobilized in a Vac-Lok (Fig 2C).
      • Mutter RW
      • Remmes NB
      • Kahila MM
      • et al.
      Initial clinical experience of postmastectomy intensity modulated proton therapy in patients with breast expanders with metallic ports.
      Pain and reduced mobility are common after surgery, which may be further exacerbated by long treatment times, on the order of 45 minutes, required for bilateral IMPT. Arms-up positioning may necessitate a break between fields, leading to longer daily treatment times and increased room use. In cases requiring a supraclavicular or high axillary boost, the arms-down position allows for use of additional posterior beam angles to avoid end-of-range elevated biologic dose in the brachial plexus, which may put patients at greater risk of brachial plexophathy.
      • Mutter RW
      • Jethwa KR
      • Wan Chan Tseung HS
      • et al.
      Incorporation of Biologic Response Variance Modeling Into the Clinic: Limiting Risk of Brachial Plexopathy and Other Late Effects of Breast Cancer Proton Beam Therapy.
      A similar arms-down technique was first described by Depauw et al
      • Depauw N
      • Batin E
      • Daartz J
      • et al.
      A novel approach to postmastectomy radiation therapy using scanned proton beams.
      but was used in only 1 patient in their series. Otherwise, published reports of PBT for breast cancer most commonly reference simulation in the supine position with arms raised above the head, as is done in photon radiation therapy.
      • Dasu A
      • Flejmer AM
      • Edvardsson A
      • Witt Nystrom P
      Normal tissue sparing potential of scanned proton beams with and without respiratory gating for the treatment of internal mammary nodes in breast cancer radiotherapy.
      ,
      • Luo L
      • Cuaron J
      • Braunstein L
      • et al.
      Early outcomes of breast cancer patients treated with post-mastectomy uniform scanning proton therapy.
      ,
      • Smith NL
      • Jethwa KR
      • Viehman JK
      • et al.
      Post-mastectomy intensity modulated proton therapy after immediate breast reconstruction: Initial report of reconstruction outcomes and predictors of complications.
      In our practice, unique patient factors and anatomic considerations for target coverage determine the most appropriate setup. Additionally, no respiratory gating or DIBH techniques were used with IMPT in this study. In our experience, select patients with unfavorable cardiac anatomy undergoing IMPT may have a dosimetric improvement with DIBH from displacement of the heart and coronary arteries away from the IMN CTV.
      • Corbin K
      • Park S
      • Remmes N
      • Beltran C
      • Mutter R
      Feasibility of Intensity Modulated Proton Therapy (IMPT) in Deep Inspiratory Breath Hold (DIBH) for Breast Cancer with Unfavorable Anatomy.
      However, owing to excellent target volume coverage and normal-tissue sparing achieved with IMPT, we infrequently use DIBH and only when there is an indication for additional benefit in normal-tissue sparing that outweighs the increase in complexity and time of treatment delivery.
      Acute toxic effects in the study patients compared favorably with previously published reports of proton therapy for breast cancer.
      • Jimenez RB
      • Hickey S
      • DePauw N
      • et al.
      Phase II study of proton beam radiation therapy for patients with breast cancer requiring regional nodal irradiation.
      • Luo L
      • Cuaron J
      • Braunstein L
      • et al.
      Early outcomes of breast cancer patients treated with post-mastectomy uniform scanning proton therapy.
      • MacDonald SM
      • Patel SA
      • Hickey S
      • et al.
      Proton therapy for breast cancer after mastectomy: Early outcomes of a prospective clinical trial.
      ,
      • Mutter RW
      • Remmes NB
      • Kahila MM
      • et al.
      Initial clinical experience of postmastectomy intensity modulated proton therapy in patients with breast expanders with metallic ports.
      ,
      • Verma V
      • Iftekaruddin Z
      • Badar N
      • et al.
      Proton beam radiotherapy as part of comprehensive regional nodal irradiation for locally advanced breast cancer.
      ,
      • DeCesaris CM
      • Rice SR
      • Bentzen SM
      • Jatczak J
      • Mishra MV
      • Nichols EM.
      Quantification of acute skin toxicities in patients with breast cancer undergoing adjuvant proton versus photon radiation therapy: A single institutional experience.
      For example, a recently published phase 2 trial reported an 86% incidence of acute grade 2 to 3 skin toxic effects using passively scattered and pencil-beam scanning proton therapy.
      • Jimenez RB
      • Hickey S
      • DePauw N
      • et al.
      Phase II study of proton beam radiation therapy for patients with breast cancer requiring regional nodal irradiation.
      We applied skin dose constraints to limit hot spots at the surface but made adjustments based on the risk profile of individual patients. Skin in the supraclavicular region was contoured as a separate OAR because dermal lymphatics are not at risk and a lower skin dose can routinely be achieved without compromising coverage of the underlying nodal basins. Additionally, only 1 patient in our study developed dysphagia, compared with more than 70% in a series of patients treated with photon radiation therapy for SBBC.
      • Wadasadawala T
      • Jain S
      • Paul S
      • et al.
      First clinical report of helical tomotherapy with simultaneous integrated boost for synchronous bilateral breast cancer.
      At a median follow-up of 22 months, no patient had developed rib fractures, symptomatic pneumonitis, or cardiac disease.
      Although the clinical benefit of proton therapy has not been proven in randomized trials, there is compelling data that superior normal-tissue sparing may be associated with reduced late toxic effects. Owing to proximity of the IMNs to the heart and coronary vessels, there is concern that increased risk of late cardiac mortality may outweigh the potential disease-control benefits.
      • Thorsen LB
      • Thomsen MS
      • Berg M
      • et al.
      CT-planned internal mammary node radiotherapy in the DBCG-IMN study: Benefit versus potentially harmful effects.
      Dose to the heart has been associated with increased risk of ischemic heart disease and cardiac mortality.
      • Bouillon K
      • Haddy N
      • Delaloge S
      • et al.
      Long-term cardiovascular mortality after radiotherapy for breast cancer.
      ,
      • Darby SC
      • Ewertz M
      • McGale P
      • et al.
      Risk of ischemic heart disease in women after radiotherapy for breast cancer.
      More recently, the mean dose to cardiac substructures, including the coronary vessels, has been associated with an increase of nearly 5% per Gy in coronary artery stenosis and need for revascularization.
      • Correa CR
      • Litt HI
      • Hwang WT
      • Ferrari VA
      • Solin LJ
      • Harris EE.
      Coronary artery findings after left-sided compared with right-sided radiation treatment for early-stage breast cancer.
      • Moignier A
      • Broggio D
      • Derreumaux S
      • et al.
      Coronary stenosis risk analysis following Hodgkin lymphoma radiotherapy: A study based on patient specific artery segments dose calculation.
      • Wennstig A
      • Garmo H
      • Isacsson U.
      The relationship between radiation doses to coronary arteries and location of coronary stenosis requiring intervention in breast cancer survivors.
      There is no known safe dose to the coronary vessels. We were able to achieve adequate target coverage while keeping the mean heart dose to 0.7 Gy and the maximum dose to the coronary vessels <12 Gy. Patients treated for breast cancer have increased incidence of and mortality from lung and esophageal cancer,
      • Clarke M
      • Collins R
      • Darby S
      • et al.
      Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: An overview of the randomised trials.
      which may be reduced with sparing of the lungs and esophagus with IMPT. Further prospective evaluation is needed to confirm whether IMPT will reduce the risk of pneumonitis and other late toxic effects.
      We selected VMAT as a gold standard comparison to IMPT in this study because multiple planning studies have shown that VMAT and hybrid techniques achieve superior normal-tissue avoidance compared with 3-dimensional techniques.
      • Lancellotta V
      • Iacco M
      • Perrucci E
      • 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.
      ,
      • Kim SJ
      • Lee MJ
      • Youn SM.
      Radiation therapy of synchronous bilateral breast carcinoma (SBBC) using multiple techniques.
      ,
      • 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.
      • Cho Y
      • Cho YJ
      • Chang WS
      • Kim JW
      • Choi WH
      • Lee IJ.
      Evaluation of optimal treatment planning for radiotherapy of synchronous bilateral breast cancer including regional lymph node irradiation.
      • Huang JH
      • Wu XX
      • Lin X
      • et al.
      Evaluation of fixed-jaw IMRT and tangential partial-VMAT radiotherapy plans for synchronous bilateral breast cancer irradiation based on a dosimetric study.
      ,
      • Seppälä J
      • Heikkilä J
      • Myllyoja K
      • Koskela K.
      Volumetric modulated arc therapy for synchronous bilateral whole breast irradiation - A case study.
      Respiratory management with DIBH or respiratory gating also reduces the dose to the heart and lungs.
      • Gaudino D
      • Cima S
      • Frapolli M
      • 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.
      Two clinical series of adjuvant photon radiation therapy for SBBC reported good oncologic outcomes and low rates of radiation-associated lung toxic effects. Twenty-one patients were treated with tomotherapy and assessed with pulmonary function tests and high-resolution CT scans.

      Pragmatic randomized trial of proton vs. photon therapy for patients with non-metastatic breast cancer: A Radiotherapy Comparative Effectiveness (RADCOMP) Consortium trial. Available at: https://clinicaltrials.gov/ct2/show/NCT02603341. Accessed February 14, 2022.

      At 3 years, 14 patients had subclinical grade 1 to 2 radiographic changes, and 1 patient had grade 3 radiographic changes. No patient had a significant change in pulmonary function tests. In a series of 25 patients treated with RapidArc and followed with high-resolution CT scans, there was a 30% rate of grade 1 radiation-induced lung fibrosis at 3 years.
      • Verma V
      • Iftekaruddin Z
      • Badar N
      • et al.
      Proton beam radiotherapy as part of comprehensive regional nodal irradiation for locally advanced breast cancer.
      These studies had a relatively short follow-up and did not report late toxic effects. Advanced planning techniques, including IMRT and respiratory management, should be considered when treating patients with SBBC when proton therapy is unavailable.
      This study has several limitations. Photon plans for 7 patients were generated solely for the purposes of this study. We attempted to minimize differences between plans intended for clinical use and for research by having an experienced photon breast dosimetrist generate VMAT plans with the objective of achieving comparable CTV coverage. Computed tomography simulation scans in DIBH for photon comparison planning were available for only 3 patients, and 2 patients had simulation scans with only arms-down immobilization, which is not ideal for VMAT planning. The heterogeneous use of DIBH and immobilization positioning for VMAT comparison plans limits the interpretation of the results of the dosimetric comparisons. The number of patients in this study was small. However, owing to the relative rarity of SBBC requiring bilateral adjuvant radiation therapy, this is, to our knowledge, the largest reported series of IMPT in this setting. Long-term toxic effects and outcome data in this study are limited, and follow-up is ongoing.

      Conclusion

      To our knowledge, this is the first report of adjuvant IMPT for SBBC. Delivery of bilateral IMPT was technically feasible and well-tolerated in 11 patients treated at our institution; it was associated with significantly improved sparing of the lungs, heart, coronary vessels, and esophagus compared with VMAT and should be considered an excellent treatment option for SBBC. Additional research to determine the potential long-term benefits of proton therapy compared with photon radiation therapy is ongoing.

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