Author: Rodrigo Arrangoiz MS, MD, FACS, FSSO

• Multiple groups have attempted to define a favorable subgroup of women:
  • In whom the omission of adjuvant irradiation following a partial mastectomy is reasonable
• One study (CALGB 9343):
  • Randomized women:
    • Ages 70 years and older:
      • Clinical stage I (T1, N0, M0) disease 
    • To tamoxifen for 5 years versus tamoxifen plus whole-breast irradiation
    • Patients with estrogen receptor-negative tumors:
      • Were excluded
    • Most tumors were 2 cm or less, and surgical margins were required to be negative (defined as the absence of tumor at the inked margin)
    • Adjuvant whole-breast irradiation:
      • Significantly reduced the risk of local or regional failure:
        • From 10% to 2% at 10 years
      • There were no significant differences in:
        • Distant disease-free survival or overall survival between the groups
• The PRIME II trial:
  • Enrolled 1326 patients:
    • Ages 65 years and older:
      • With T1 to T2, node-negative tumors and clear margins
  • Following breast-conserving surgery:
    • Patients received endocrine therapy and were randomized to:
      • Adjuvant radiation therapy or no further treatment
  • At 5 years:
    • Those undergoing radiation demonstrated a reduction in local recurrence:
      • 4.1% vs 1.3% with no difference in survival
• Typical breast tangents, without targeted nodal irradiation, would be appropriate for a patient with pN0 disease
• Adjuvant irradiation:
  • Reduces the risk of ipsilateral breast tumor recurrence regardless of whether the margins are positive:
    • A positive margin, however, significantly increases the risk of local failure despite irradiation
• References:
  • Hughes KS, Schnaper LA, Bellon JR, et al. Lumpectomy plus tamoxifen with or without irradiation in women age 70 years or older with early breast cancer: long-term follow up of CALGB 9343. J Clin Oncol. 2013;31:2382-2387.
  • Hughes KS, Schnaper LA, Berry D, et al. Lumpectomy plus tamoxifen with or without irradiation in women 70 years of age or older with early breast cancer. N Engl J Med. 2004;351:971-977.
  • Kunkler IH, William LJ, Jack WJ, Cameron DA, Dixon JM; PRIME II investigators. Breast-conserving surgery with or without irradiation in women aged 65 years or older with early breast cancer (PRIME II): a randomised controlled trial. Lancet Oncol. 2015;16:266-273.
  • Moran MS, Schnitt SJ, Giuliano AE, et al. Society of Surgical Oncology-American Society for Radiation Oncology consensus guideline on margins for breast-conserving surgery with whole-breast irradiation in stage I and II invasive breast cancer. Int J Radiat Oncol Biol Phys. 2014;88:553-564.

• Patients with large breasts can be a challenge for the delivery of adjuvant radiation therapy:
  • They have typically had higher acute and late toxicity as well as inferior cosmesis
• One potential explanation for this:
  • Is that they may have larger hot spots of increased dose compared to patients with smaller breasts
• Several techniques have been devised to improve these hot spots and reduce toxicity:
  • Intensity-modulated radiation therapy:
    • Has been shown in randomized trials to reduce acute and chronic toxicity:
      • With institutional data demonstrating reductions in toxicity in women with large breasts:
        • By reducing hot spots and improving homogeneity
• Proton therapy:
  • Is not widely utilized to deliver WBI with no data supporting improvement in toxicity in women with large breasts with WBI
• Electrons:
  • Are typically utilized in treating the chest wall or as part of a tumor bed boost and are not utilized to deliver WBI
• Neutron therapy:
  • Is limited in its availability and is not routinely used to deliver WBI

• References:
  • Donovan E, Bleakley N, Denholm E, et al; Breast Technology Group. Randomised trial of standard 2D radiotherapy (RT) versus intensity modulated radiotherapy (IMRT) in patients prescribed breast radiotherapy. Radiother Oncol. 2007;82:254-264.
  • Hille-Betz U, Baske B, Bremer M, et al. Late radiation side effects, cosmetic outcomes, and pain in breast cancer patients after breast-conserving surgery and three-dimensional conformal radiotherapy: risk modifying factors. Strahlenther Onkol. 2016;192:8-16.
  • Pignol JP, Olivotto I, Rakovitch E, et al. A multicenter randomized trial of breast intensity modulated radiation therapy to reduce acute radiation dermatitis. J Clin Oncol. 2008;26:2085-2092.
  • Shah C, Wobb J, Grills I, Wallace M, Mitchell C, Vicini FA. Use of intensity modulated radiation therapy to reduce acute and chronic toxicities of breast cancer patients treated with traditional and accelerated whole breast irradiation. Pract Radiat Oncol. 2012;2:e45-51.

• Multiple techniques have been used to aid in cardiac sparing including:
  • Assisted breathing control
  • Accelerated partial breast irradiation
  • Intensity-modulated radiation therapy
  • Prone breast irradiation
• A recent study from Mulliez et al:
  • Found that prone technique in conjunction with respiratory gating was associated with a:
    • Reduction in mean heart dose as well as dose to the left anterior descending coronary artery
• At this time:
  • There are limited data regarding long-term cardiac outcomes (eg, myocardial infarctions) with any cardiac sparing technique:
    • Due to the length of follow-up required
• Outcomes with prone breast irradiation have demonstrated:
  • Low rates of local recurrence
  • Excellent cosmetic outcomes
  • No suggestion of higher rates of skin toxicity
  • Lower doses to the lungs and heart
  • No suggestion of higher rates of pneumonitis

• References:
• Mulliez T, Speleers B, Mahjoubi K, et al. Prone left-sided whole-breast irradiation: significant heart dose reduction using end-inspiratory versus end-expiratory gating. Cancer Radiother. 2014;18:672-677.
• Mulliez T, Veldeman L, Speleers B, et al. Heart dose reduction by prone deep inspiration breath hold in left-sided breast irradiation. Radiother Oncol. 2015;114:79-84.
• Osa EO, DeWyngaert K, Roses D, et al. Prone breast intensity modulated radiation therapy: 5-year results. Int J Radiat Oncol Biol Phys. 2014;89:899-906.
• Shah C, Badiyan S, Berry S, et al. Cardiac dose sparing and avoidance techniques in breast cancer radiotherapy. Radiother Oncol. 2014;112:9-16.

• Hypofractionated WBI continues to increase in utilization:
  • Based on data from the Ontario Oncology trial as well as 5- and 10-year data from the UK Standardization of Breast Radiotherapy (START) A and B trials
• Standardized treatment schedules for hypofractionation typically are:
  • 15 to 16 fractions over 3 to 4 weeks depending on inclusion of a boost
  • The risk of local recurrence in the Ontario trial at 10 years was:
    • 6.7% among the 612 women assigned to standard irradiation compared with 6.2% among the 622 women assigned to the hypofractionated regimen:
      • Absolute difference, 0.5 percentage points; 95% confidence interval [CI], −2.5 to 3.5
    • 71.3% of women in the control group compared with 69.8% of the women in the hypofractionated radiation group had a good or excellent cosmetic outcome:
      • Absolute difference, 1.5 percentage points; 95% CI, −6.9 to 9.8)
  • In the START-B trial:
    • The proportion of patients with local-regional relapse at 10 years did not differ significantly:
      • Between the 40 Gy (hypofractionation) group (4.3%, 95% CI, 3.2–5.9) and the 50 Gy (standard) group (5.5%, 95% CI, 4.2–7.2; hazard ratio, 0.77, 95% CI, 0.51–1.6; P=0.21)
    • There was less breast shrinkage, telangiectasia, and edema in the 40 Gy/15 fraction arm
• Traditionally:
  • A separation (the distance from the medial to the lateral border of the tangential beam) of:
    • 25 cm was utilized as a cut off:
      • But now a maximum dose of 107% of prescription is used in light of advancements in planning techniques
• Current evidence-based American Society for Radiation Oncology (ASTRO) guidelines on fractionation recommend hypofractionated WBI be considered in:
  • Patients age 50 years and older:
    • With T1 to T2, N0 disease:
      • Who do not receive chemotherapy
• It should be noted that the percentage of patients with nodal positivity in these trials was quite low:
  • So the role of hypofractionated regimens in node-positive patients remains unanswered

• References:
  • Haviland JS, Owen JR, Dewar JA, et al; START Trialists’ Group. The UK Standardization of Breast Radiotherapy (START) trials of radiotherapy hypofractionation for treatment of early stage breast cancer: 10-year follow-up results of two randomised controlled trials. Lancet Oncol. 2013;14:1086-1094.
  • Smith BD, Bentzen SM, Correa CR, et al. Fractionation for whole breast irradiation: an American Society for Radiation Oncology (ASTRO) evidence-based guideline. Int J Radiat Oncol Biol Phys. 2011;81:59-68.
  • Whelan TJ, Pignol JP, Levine MN, et al. Long-term results of hypofractionated radiation therapy for breast cancer. N Engl J Med. 2010;362:513-520.

• Irradiation is an integral part of the tri-modality treatment of inflammatory breast cancer
• Rarely:
  • Radiation may be administered preoperatively:
    • Particularly in the context of a suboptimal response to neoadjuvant systemic therapy or progressive disease
• Following a mastectomy:
  • Postmastectomy irradiation is routinely given
  • Data from British Columbia:
    • Have demonstrated mastectomy with modern chemotherapy and radiation techniques:
      • Is associated with improved locoregional control
• Radiotherapy comprises:
  • Whole breast with comprehensive nodal irradiation:
    • In the setting of preoperative treatment
  • Chest wall with comprehensive nodal irradiation:
    • Following a mastectomy
• Most series report inclusion of the internal mammary lymph node chain in radiation portals:
  • Even if clinically negative
• For left-sided treatment:
  • Modern techniques, including:
    • Intensity-modulated radiation therapy:
      • May be employed to avoid dose to the heart and lungs while appropriately covering the regional lymph nodes

• References:
  • Panades M, Olivotto IA, Speers CH, et al. Evolving treatment strategies for inflammatory breast cancer: a population-based survival analysis. J Clin Oncol. 2005;23:1941-1950.
  • Scotti V, Desideri I, Meattini I, et al. Management of inflammatory breast cancer: focus on radiotherapy with an evidence-based approach. Cancer Treat Rev. 2012;39:119-124.
  • Ueno NT, Buzdar AU, Singletary SE, et al. Combined-modality treatment of inflammatory breast carcinoma: twenty years of experience at M.D. Anderson Cancer Center. Cancer Chemother Pharmacol. 1997;40:321-329.
  • Yim J, Suttie C, Bromley R, Morgia M, Lamoury G. Intensity modulated radiotherapy and 3D conformal radiotherapy for whole breast irradiation: a comparative dosimetric study and introduction of a novel qualitative index for plan evaluation, the normal tissue index. J Med Radiat Sci. 2015;62:184-191.

• Patients with left-sided breast cancers in particular:
  • Are candidates for cardiac sparing breast radiation techniques
• Multiple techniques exist to spare cardiac dose and include:
  • Active breathing coordinator techniques (ABC)
  • Prone breast irradiation
  • Intensity-modulated radiation therapy
  • Accelerated partial breast irradiation
• None however is considered superior to another and the choice of technique employed depends on multiple patient factors:
  • ABC has been used consistently as a method to reduce heart dose:
    • By increasing the distance from the chest wall to the heart
  • Prone breast irradiation:
    • Allows for the breast to fall away from the chest:
      • Potentially improving cardiac dose
  • Intensity-modulated radiation therapy:
    • Can create segments within the beam to limit heart dose
  • Accelerated partial breast irradiation:
    • Limits the volume treated to the area surrounding the lumpectomy cavity and thus spares the heart

• References:
• Eldredge-Hindy H, Lockamy V, Crawford A, et al. Active breathing coordinator reduces radiation dose to the heart and preserves local control in patients with left breast cancer: report of a prospective trial. Pract Radiat Oncol. 2015;5:4-10.
• Mulliez T, Veldeman L, Speleers B, et al. Heart dose reduction by prone deep inspiration breath hold in left-sided breast irradiation. Radiother Oncol. 2015;114:79-84. Shah C, Badiyan S, Berry S, et al. Cardiac dose sparing and avoidance techniques in breast cancer radiotherapy. Radiother Oncol. 2014;112:9-16.
• Yim J, Suttie C, Bromley R, Morgia M, Lamoury G. Intensity modulated radiotherapy and 3D conformal radiotherapy for whole breast irradiation: a comparative dosimetric study and introduction of a novel qualitative index for plan evaluation, the normal tissue index. J Med Radiat Sci. 2015;62:184-191.

• Studies continue to evaluate for a subset of patients with DCIS:
  • Who may not require adjuvant radiation therapy following breast-conserving surgery
• In a prospective non-randomized trial, ECOG E5194:
  • Evaluated two cohorts of patients:
    • Group 1 had ≤ 2.5-cm low- and intermediate-grade DCIS, and
    • Group 2 had ≤ 1 cm high-grade DCIS
  • Both cohorts had margins of at least 3 mm and did not:
    • Receive adjuvant radiation therapy
  • Tamoxifen was given to:
    • 30% of patients
  • Local recurrence at 5 years was:
    • 6.1% in group 1 and 15.3% in group 2
  • The rate at 12 years was:
    • 14.4% in group 1 and 24.6% in group 2
  • There was no plateau in the incidence of local recurrence over time
• The Radiation Therapy Oncology Group (RTOG) 9804 study:
  • Randomized patients with < 2.5 cm low- and intermediate-grade DCIS and margins ≥ 3 mm:
    • To adjuvant radiation or no radiation therapy following partial mastectomy
  • Seven-year outcomes demonstrated:
    • An increase in local recurrence with the omission of radiation therapy:
      • 6.7% vs 0.9%
  • Tamoxifen was given to 62% of patients
• Similar outcomes were also noted in the Dana Farber prospective trial of excision alone
• REFERENCES
  • McCormick B, Winter K, Hudis C, et al. RTOG 9804: a prospective randomized trial for good-risk ductal carcinoma in situ comparing radiotherapy with observation. J Clin Oncol. 2015;33:709-715.
  • Solin LJ, Gray R, Hughes LL, et al. Surgical excision without radiation for ductal carcinoma in situ of the breast: 12-year results from the ECOG-ACRIN E5194 study. J Clin Oncol. 2015;33:3938-3944.
  • Wong JS, Kaelin CM, Troyan SL, et al. Prospective study of wide excision alone for ductal carcinoma in situ of the breast. J Clin Oncol. 2006;24:1031-1036.

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• Several guidelines have been published to guide decision making for treating select patients with partial breast irradiation off protocol:
  • The American Society for Radiation Oncology consensus statement (Table 1) considers patients to be “suitable” if the following characteristics are met:
    • Age 50 years and older
    • BRCA 1 / 2 wild-type
    • Tumor size 2 cm or less:
    • Multi-focality is allowed:
      • Provided the total size is 2 cm or less
    • ER-positive
    • Invasive ductal (or other favorable) histology
    • Surgical margins 2 mm or greater
    • Absence of LVI
    • Pure ductal carcinoma in situ (DCIS) meeting trial criteria
    • Absence of an extensive intra-ductal component
    • The absence of lymph node involvement
  • American Society for Radiation Oncology consensus statement (Table 1) considers patients to be “unsuitable” if the following characteristics are met:
    • Age younger than 40 years
    • Presence of a BRCA 1 / 2 deleterious mutation
    • Tumor size greater than 3 cm:
    • Including multiple foci
    • Multi-centricity
    • Positive surgical margins
    • Extensive LVI
    • Lymph node involvement (or not assessed).
  • American Society for Radiation Oncology consensus statement (Table 1) considers patients to be “cautionary” if the characteristics fall between suitable and unsuitable
  • The recent American Brachytherapy Society (Table 2):
    • Defined acceptable criteria for partial breast irradiation as:
      • Age 50 years and older
      • Size ≤ 3 cm
      • All invasive subtypes
      • Pure DCIS
      • ER-positive
      • ER-negative
      • Negative surgical margins (“on ink”)
      • Negative lymph nodes
      • Absence of LVI
  • The Groupe Européen de Curiethérapie of European Society for Radiotherapy and Oncology (GEC-ESTRO) consensus statement (Table 3) also classifies patients as “low risk” and good candidates for partial breast irradiation with the following criteria:
    • Age 50 years and older
    • ER-negative (or positive) disease
    • Tumors 3 cm or less
  • The American Society of Breast Surgeons current guidelines (Table 4) include:
    • Age 45 years and older for invasive tumors
    • Age 50 years and older for DCIS
    • Tumor size < 3 cm
    • Negative margins
    • Negative lymph nodes

REFERENCES

• The American Society of Breast Surgeons. Consensus statement for accelerated partial breast irradiation. https://www.breastsurgeons.org/new_layout/about/statements/PDF_Statements/APBI.pdf. Updated August 15, 2011. Accessed January 21, 2016.
• Polgár C, Van Limbergen E, Potter R, et al; GEC-ESTRO breast cancer working group. Patient selection for accelerated partial-breast irradiation (APBI) after breast-conserving surgery: recommendations of the Groupe Européen de Curiethérapie-European Society for Therapeutic Radiology and Oncology (GEC-ESTRO) Breast Cancer Working Group based on clinical evidence (2009). Radiother Oncol. 2010;94:264-273.
• Shah C, Vicini F, Wazer DE, Arthur D, Patel RR. The American Brachytherapy Society consensus statement for accelerated partial breast irradiation. Brachytherapy. 2013;12:267-277.
• Smith BD, Arthur DW, Buchholz TA, et al. Accelerated partial breast irradiation consensus statement from the American Society for Radiation Oncology (ASTRO). Int J Radiat Oncol Biol Phys. 2009;74:987-1001.

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• Painful bone metastasis:
  • Is a well-recognized indication for palliative irradiation
• Whole-brain irradiation:
  • May also be offered as the primary treatment modality for brain metastases or in combination with surgical resection or stereotactic radio-surgery
• Studies have demonstrated an improvement in intracranial control:
  • With the addition of radiation following surgery
• For patients with choroidal involvement:
  • Treatment of the globe with or without concomitant whole-brain irradiation:
    • May be offered for vision preservation
• Locoregional radiation therapy:
  • In the setting of widely metastatic disease:
    • Is not otherwise indicated
• REFERENCES
  • Chow E, Harris K, Fan G, Tsao M, Sze WM. Palliative radiotherapy for bone metastases: a systematic review. J Clin Oncol. 2007;25:1423-1436.
  • Kocher M, Soffietti R, Abacioglu U, et al. Adjuvant whole-brain radiotherapy versus observation after radiosurgery or surgical resection of one to three cerebral metastases: results of the EORTC 22952-26001 study. J Clin Oncol. 2011;29:134-141.
  • Le Scodan R, Stevens D, Brain E, et al. Breast cancer with synchronous metastases: survival impact of exclusive locoregional radiotherapy. J Clin Oncol. 2009;27:1375-1381.
  • Ly BH, Nguyen NP, Vinh-Hung V, Rapiti E, Vlastos G. Loco-regional treatment in metastatic breast cancer patients: is there a survival benefit? Breast Cancer Res Treat. 2010;119:537-545.
  • Patchell RA, Tibbs PA, Regine WF, et al. Postoperative radiotherapy in the treatment of single metastases to the brain: a randomized trial. JAMA. 1998;280:1485-1489.

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• The European Organisation for Research and Treatment of Cancer (EORTC) boost trial:
  • Enrolled patients with:
    • Stage I and II breast cancer
    • Treated with lumpectomy and axillary dissection
• Patients with surgical margins free from invasive disease were randomized to receive:
  • Whole-breast irradiation:
    • With or without a subsequent boost targeting the tumor bed
• The 20-year overall survival and breast cancer specific mortality:
  • Were similar between the two groups
• The overall rate of ipsilateral breast tumor recurrence (IBTR) was lower in the boost group:
  • 12% vs 16.4% at 20 years
  • The absolute risk reduction was greatest in younger patients:
    • Nearly a 12% difference for patients younger than age 40 years compared to a 3% difference in patients older than age 60 years
• The local control conferred by a boost:
  • Translated into fewer salvage surgeries
• Adding a boost:
  • Did not increase cardiac mortality, contralateral breast tumors, or second primary tumors
  • But did increase fibrosis and impacted cosmetic results
• Similar results were noted:
  • In the randomized Lyon boost trial
• REFERENCES
  • Bartelink H, Maingon P, Poortmans P, et al; European Organisation for Research and Treatment of Cancer Radiation Oncology and Breast Cancer Groups. Whole-breast irradiation with or without a boost for patients treated with breast-conserving surgery for early breast cancer: 20-year follow-up of a randomised phase 3 trial. Lancet Oncol. 2015;16:47-56.
  • Romestaing P, Lehingue Y, Carrie C, et al. Role of a 10-Gy boost in the conservative treatment of early breast cancer: results of a randomized clinical trial in Lyon, France. J Clin Oncol. 1997;15:963-968.

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