Radiation Oncology/Breast/RT technique

Anatomy: Regional LNs
Surgical lymphatic drainage
 * PMID 14745331 (Full text) (2004), Netherlands &mdash; "Lymphatic drainage patterns from the breast." Estourgie SH et al. Ann Surg. 2004 Feb;239(2):232-7.
 * Lymphatic mapping using sentinal lymph node technique. Provides maps of lymphatic drainage from each of 5 quadrants of the breast.

CT-based anatomy
 * Netherlands; 2004 PMID 15172144 -- "Loco-regional conformal radiotherapy of the breast: delineation of the regional lymph node clinical target volumes in treatment position." (Dijkema IM, Radiother Oncol. 2004 Jun;71(3):287-95.)


 * Michigan; 2001 PMID 11687672 -- "Definition of the supraclavicular and infraclavicular nodes: implications for three-dimensional CT-based conformal radiation therapy." (Madu CN, Radiology. 2001 Nov;221(2):333-9.)


 * Boundaries and anatomy of axilla - from Gray's anatomy


 * Axillary clearance - surgical approach from Royal College of Surgeons of Edinburgh


 * Lateral Pharyngeal Region - cadaveric sections, useful for identifying scalene muscles

Multifield breast technique
The patient lies on a breast board that is inclined to ensure that the sternum is horizontal. The arm on the ipsilateral side is abducted to 90 degrees and is supported by arm supports on the breast board.

Tangential fields to the breast/chest wall The chest wall or breast is treated isocentrically and is covered by a pair of wedged tangential fields. The posterior beam edges are parallel to reduce divergence into the lung. The superior beam edges are also parallel to allow matching of the fields to any supraclavicular or axillary fields. The whole breast is included to ensure any residual or microscopic disease is irradicated.

Borders Superior: suprasternal notch Inferior: 1 - 2 cm inferior of the inframammary fold, enough to ensure full breast coverage Medial: anatomical midline Lateral: midaxillary line (may be moved posteriorly to ensure complete coverage of breast tissue) Anterior: about 1cm anterior of breast, to ensure coverage during normal breathing Posterior: to cover chest wall, with a maximum lung depth of 2cm

Prescriptions 50Gy to isocentre in 25# daily over 5 weeks, 6 or 10 MV photons 40Gy to isocentre in 15# daily over 3 weeks, 6 or 10 MV photons Both prescriptions are widely used in the UK.

Supraclavicular field If the supraclavicular and/or axillary nodes are involved then a supraclavicular field will be used. This field is matched to the tangential fields of the breast to prevent any overdose to the junction of the fields. Shielding (from either lead or MLCs) is used to shield the shoulder joint (preventing fibrosis of the joint) and the apex of the lung.

Borders Medial: 1cm ipsilateral to anatomical midline (to avoid the oesophagus) Lateral: insertion of pectoralis major; lateral border of the coracoid process to cover insertion of pectoralis minor Inferior: to match breast tangentials Superior: to cover

Prescription The dose is prescribed to the depth of the supraclavicular nodes. The prescriptions are generally the same as for the breast.

IM or Medial Field

PAB If coverage of deep nodes lymph node levels is desired or dose coverage for supraclavicular field provides inadequate coverage due to axillary node separation, then a posterior axillary boost may be prescribed to provide optimal dose distribution.

Borders Medial: 1.5-2.0 cm of lung Lateral: Lateral posterior axillary fold Inferior: to match breast tangentials Superior: splits clavicle Prescription Anterior SCV field and the posterior PAB field overlap varies from patient to patient. Dose is prescribed such that the combined dose distribution is optimal and provides coverage of nodal volumes. Additional edits may be made to borders of PAB to block high dose regions due to overlap with SCV field.

RT Prescription

 * North Puget, 2000 PMID 10837972 -- "The impact of dose-specification policies upon nominal radiation dose received by breast tissue in the conservation treatment of breast cancer." (Kantorowitz DA, Int J Radiat Oncol Biol Phys. 2000 Jun 1;47(3):841-8.)
 * Absorbed dose normalized as a function of different prescription methods. Idealized breast slice, RT dose 46 Gy + 20 Gy boost = 66 Gy
 * Results: for 66 Gy prescription, absorbed dose varied from 66 Gy (100% isodose line for both breast and boost) to 76.11 Gy (breast 90% isodose line and boost 80% isodose line); difference of 13%
 * Recommendation: use ICRU 50, with Breast PTV1 = whole breast + 1-2 cm margin, specified at tangent beam intersection on the central plane, or 2/3 distance from dorsal beam edge to skin along perpendicular breast bisector. Boost PTV2 = lumpectomy cavity + 1-3 cm margin, specified at 90% with electron energy sufficient to provide 85% isodose coverage

Target Delineation

 * RTOG Breast Cancer Atlas


 * RTOG; 2009 PMID 19215827 -- "Variability of target and normal structure delineation for breast cancer radiotherapy: an RTOG Multi-Institutional and Multiobserver Study." (Li XA, Int J Radiat Oncol Biol Phys. 2009 Mar 1;73(3):944-51.)
 * Prospective. 9 breast radiation oncologists, target and organ at risk delineation, 3 representative BCA patients
 * Outcome: Substantial variability, structure overlaps as low as 10%, standard deviations of up to 60%. Differences both due to target/organ boundaries, incorporation of setup uncertainty, and dosimetric limitations
 * Conclusion: Differences clinically and dosimetrically significant; consensus highly desirable


 * Netherlands Cancer Institute, The Netherlands; 2001 PMID 11483349 -- "Variability in target volume delineation on CT scans of the breast." (Hurkmans CW, Int J Radiat Oncol Biol Phys. 2001 Aug 1;50(5):1366-72.)
 * Retrospective. 7 patient scans, 4 radiation oncologists, 3 sets of contours per patient
 * Outcome: Average deviations posterior (4.2 cm), anterior (0.6 cm), cranial (2.8 cm), caudal (1.5 cm), medial (2.4 cm), lateral (0.8 cm). Intraobserver variation in volume 5.5%, interobserver variability 17.5%, overall agreement 0.43
 * Conclusion: Large intra- and inter-observer variation in delineation of breast target on CT scan

Accelerated Partial Breast Irradiation

 * Please see the APBI page for clinical outcomes

Seroma cavity delineation

 * British Columbia; 2009 PMID 18692322 -- "3D ultrasound can contribute to planning CT to define the target for partial breast radiotherapy." (Berrang TS, Int J Radiat Oncol Biol Phys. 2009 Feb 1;73(2):375-83. Epub 2008 Aug 7.)
 * Prospective. 20 women, early BCA, candidate for APBI. 3D ultrasound at CT-sim. 3 RT oncologists contoured volumes on CT and U/S image sets. Coregistration within 2mm in 95%
 * Outcome: Improved interobserver consistency in U/S over CT in 40% cases, mainly in low CT seroma clarity or heterogenous/dense breast parenchyma
 * Conclusion: 3D ultrasound can be useful adjuct to CT planning

IMRT
Randomized
 * Canada (2003-2005) -- 2D vs. IMRT
 * Randomized. 331 patients, early-stage BCA (no >=4 LN+) treated with breast-only RT. Arm 1) 2D tangent + wedge vs. Arm 2) IMRT. RT dose 50/25 + optional 16 Gy electron boost.
 * 2008 PMID 18285602 -- "A Multicenter Randomized Trial of Breast Intensity-Modulated Radiation Therapy to Reduce Acute Radiation Dermatitis." (Pignol JP, J Clin Oncol. 2008 Feb 19 [Epub ahead of print])
 * IMRT associated with decreased moist desquamation ), in inframammary fold (26% vs 43%). The breast volume (V95) is associated with acute skin toxicity.
 * Outcome: Dose distribution: IMRT better. Moist desquamation anywhere in breast: IMRT 31% vs 2D 48% (SS), 26% vs. 43% (SS), no difference in pain 23% vs. 25% (NS) or QoL
 * Conclusion: Breast IMRT reduced occurrence of moist desquamation


 * Royal Marsden -- 2D vs. IMRT
 * Randomized. 240/306 patients. Early stage. Treated with Arm 1) IMRT vs. Arm 2) 2D using standard wedges. Dose 50/25 + boost 11.1/5.
 * 2007 PMID 17224195 -- "Randomised trial of standard 2D radiotherapy (RT) versus intensity modulated radiotherapy (IMRT) in patients prescribed breast radiotherapy." (Donovan E, Radiother Oncol. 2007 Mar;82(3):254-64.) Minimum F/U 5 years
 * Change in breast: IMRT 40% vs. 2D 58% (SS); significantly fewer developed palpable induration. No difference in pain, hardness, or QoL
 * Conclusion: Minimisation of inhomogeneity reduces late adverse effects

Retrospective
 * Pittsburgh; 2009 PMID 19624420 -- "Initial outcomes analysis for large multicenter integrated cancer network implementation of intensity modulated radiation therapy for breast cancer." (Bhatnagar AK, Breast J. 2009 Sep-Oct;15(5):468-74. Epub 2009 Jul 13.)
 * Retrospective. 495 patients, IMRT after BCS, large integrated cancer center network (7 community centers and 2 academic centers). Centralized IMRT planning. IMRT 50/25 + 10 Gy boost
 * Outcome: Erythema Grade 1 55%, 2 28%, 3 1%; skin desquammation 20%, 4%, 1%. No difference between community and academic centers
 * Conclusion: IMRT can be safely and effectively administered in a large health system


 * Toronto, 2006 PMID 16457966 -- "Body radiation exposure in breast cancer radiotherapy: impact of breast IMRT and virtual wedge compensation techniques." (Woo TC, Int J Radiat Oncol Biol Phys. 2006 May 1;65(1):52-8.)
 * Evaluation of radiation body exposure, given higher risk of leukemia for BCA patients receiving adjuvant anthracycline. 120 women, measurements taken during RT
 * Standard 50 Gy: abdomen 0.45 Gy (0.06-1.55 Gy). Physical wedges result in 3x more exposure compared to IMRT


 * Fox Chase, 2006 PMID 16462506 -- "Intensity modulated radiation therapy (IMRT) decreases acute skin toxicity for women receiving radiation for breast cancer." (Freedman GM, Am J Clin Oncol. 2006 Feb;29(1):66-70.)
 * Matched case control. 73 women with IMRT vs. 60 women with conventional planning.
 * Acute toxicity: no difference using CTC grading. Degree of desquamation greater for conventional patients. Large breasts worse
 * Conclusion: IMRT decreases severity of acute desquamation; CTC grading not sensitive

Active Breath Hold

 * William Beaumont, 2003 PMID 12788176 -- "Initial clinical experience with moderate deep-inspiration breath hold using an active breathing control device in the treatment of patients with left-sided breast cancer using external beam radiation therapy." (Remouchamps VM, Int J Radiat Oncol Biol Phys. 2003 Jul 1;56(3): 704-15.)
 * Moderate deep-inspiration breath hold (75% of max inspiration) with active breathing control device. Goal to reduce heart dose in L BCA. 5 patients where >2% of heart received >30 Gy on free breath
 * RT: during breath hold; durations ranging 18-26 seconds; 2-3 per beam. Step-and-shoot IMRT. 45 Gy or 50.4 Gy. Interfraction setup max 3.2mm, intrafraction max 2mm
 * Outcome: V30 reduction of 3.6% and NTCP reduction of 1.5%; however increased lung V20
 * Comment: not clear if this will translate into a meaningful clinical difference with modern RT techniques, and especially with more patients potentially receiving APBI

Axilla

 * MD Anderson
 * Match Line; 2009 PMID 18676090 -- "Effects of variable placement of superior tangential/supraclavicular match line on dosimetric coverage of level III axilla/axillary apex in patients treated with breast and supraclavicular radiotherapy." (Garg AK, Int J Radiat Oncol Biol Phys. 2009 Feb 1;73(2):370-4.)
 * Treatment planning. 20 patients, w/p surgery and Level I-II axillary dissection. Match line placed caudal, bisecting, and cranial to ipsilateral clavicular head. Nodal volume coverage evaluated.
 * Outcome: Mean volume of Level III LN covered by 90% isodose line caudal 100% vs. bisecting 92% vs. cranial 68% (SS)
 * Conclusion: Placement of match line should be caudal to clavicular head
 * SLN; 2001 PMID 11597808 &mdash; "Relationship of sentinel and axillary level I-II lymph nodes to tangential fields used in breast irradiation." Schlembach PJ et al. Int J Radiat Oncol Biol Phys. 2001 Nov 1;51(3):671-8.
 * Retrospective. Analyzed simulation films of pts treated with sentinel lymph node biopsy (in 65 pts) and pts with clips marking the extent of axillary dissection (39 pts).
 * With the cranial field edge 2 cm below humeral head, the sentinel LN was included in the field in 95% of cases and the entire extent of axillary dissection (level I-II) was included in 43% of cases and covered 80% of the axillary dissection field in the rest of patients.
 * Conclusion: By extending the tangent field edge to 2 cm below the humeral head and 2 cm deep to the chest wall - lung interface, the RT fields will include the SLN and most of level I and II axilla.


 * Colorado; 2008 PMID 17967511 -- "Evaluation of breast sentinel lymph node coverage by standard radiation therapy fields." (Rabinovitch R, Int J Radiat Oncol Biol Phys. 2008 Apr 1;70(5):1468-71. Epub 2007 Oct 29.)
 * Retrospective. 106 data sets. Patients who underwent SLN biopsy and had surgical clips placed.
 * Outcome: SLN clips varied in vertebral level position between T2-T7 (most common T4). Within standard tangents 90% (below head of clavicle), within standard SCV field in 10% (above head of clavicle)
 * Conclusion: Standard axillary fields do not encompass lymph nodes at highest risk of containing tumor, but 90% are included in standard tangents


 * University of Washington; 2005 PMID 15667953 &mdash; "Axillary lymph node dose with tangential breast irradiation." (Reed DR et al. Int J Radiat Oncol Biol Phys. 2005 Feb 1;61(2):358-64.)
 * Retrospective. 50 consecutive patients with standard tangents. Dose distribution to axillary Level I and II evaluated
 * Outcome: 95% isodose line encompassed 55% (23-87%) of anatomic Level I-II volume; it encompassed 81% (58-98%) of surgical clips
 * Conclusion: Standard tangents failed to deliver a therapeutic dose to axillary Level I-II anatomic volume


 * Stanford; 1999 - PMID 9885612 &mdash; "Utility of three-dimensional planning for axillary node coverage with breast-conserving radiation therapy: early experience." Smitt MC et al. Radiology. 1999 Jan;210(1):221-6.

SCV field

 * Mayo; 2015 PMID 25936809 -- "Delineation of Supraclavicular Target Volumes in Breast Cancer Radiation Therapy." (Brown LC, Int J Radiat Oncol Biol Phys. 2015 Jul 1;92(3):642-9.)
 * Map the location of gross supraclavicular metastases in patients with breast cancer
 * Conclusion: "coverage of the posterior triangle and the lateral low supraclavicular region should be considered. For women with known supraclavicular disease, extension of neck coverage superior to the cricoid cartilage may be warranted."


 * MD Anderson
 * SCV failure location; 2008 PMID 18164831 -- "Risk of subclinical micrometastatic disease in the supraclavicular nodal bed according to the anatomic distribution in patients with advanced breast cancer." (Reed VK, Int J Radiat Oncol Biol Phys. 2008 Jun 1;71(2):435-40. Epub 2007 Dec 31.)
 * Retrospective. 33 patients with advanced/metastatic BCA, PET+ in SCV LN. 52 LN identified. Locations mapped onto 4 separate planning CT done previously for SCV field (2 SCV+ and 2 SCV- by biopsy).
 * Outcome: 10% in H&N Level III, 63% in H&N Level IV, 21% in H&N Level V (in 5 patients posterior to vertebral transverse process), 6% Axilla Level III. Close proximity to medial border in several patients
 * Conclusion: Distribution of LNs identified. Increased coverage medially and posteriorly may be warranted with locally advanced disease
 * SCV depth; 2007 PMID 17889264 -- "Treatment Optimization Using Computed Tomography-Delineated Targets Should be Used for Supraclavicular Irradiation for Breast Cancer." (Liengsawangwong R, Int J Radiat Oncol Biol Phys. 2007 Nov 1;69(3):711-5.)
 * Retrospective. 32 patients, plan adequacy evaluated for depth of SC and Level III LNs. Plans evaluated were 6 MV @ 1.5cm, 6 MV @ 3.0 cm, 18 MV @ 3.3 cm, and mixed beam to optimize target volume to 90%
 * Outcome: mean depth SC 3.2 cm (1.4-6.7 cm), mean depth LIII 3.1 cm (1.7-5.8 cm); significant variance with BMI. CT plans better than standard 3cm prescription
 * Conclusion: CT-based treatment planning should be used for SC fields vs. traditional 3cm prescription depth

PAB field

 * Duke, 2000 - PMID 10837961 &mdash; "Variability of the depth of supraclavicular and axillary lymph nodes in patients with breast cancer: is a posterior axillary boost field necessary?" Bentel GC et al. Int J Radiat Oncol Biol Phys. 2000 Jun 1;47(3):755-8.
 * PAB field was used historically based on the assumption that the axillary LNs lie deeper than the SCLV nodes (based on pre-CT era). This study shows that the dose to the axillary LN is within 90% of the SCLV dose. Suggests that the role of the PAB field needs to be refined.

IMN irradiation

 * MD Anderson; 2009 PMID 19564530 -- "Internal mammary node radiation: a proposed technique to spare cardiac toxicity." (Oh JL, J Clin Oncol. 2009 Nov 1;27(31):e172-3; author reply e174. Epub 2009 Jun 29.)
 * Technique description: matched 2 electron fields to IM nodes, with shallow tangents


 * Danish BCCG; 2008 PMID 18465333 -- "Post-mastectomy radiotherapy in Denmark: from 2D to 3D treatment planning guidelines of The Danish Breast Cancer Cooperative Group." (Thomsen MS, Acta Oncol. 2008;47(4):654-61.)
 * Dosimetric comparison of photon/electron (3F) technique vs partial wide tangent (PWT) technique
 * Conclusion: PWT technique superior, appropriate choice for future RT. Guideline developed


 * Michigan; 2002 PMID 11955732 -- "Postmastectomy radiotherapy of the chest wall: dosimetric comparison of common techniques." (Pierce LJ, Int J Radiat Oncol Biol Phys. 2002 Apr 1;52(5):1220-30.)
 * Dosimetric comparison. Seven techniques (standard tangents; electron CW and IMN; cobalt; reverse hockey stick; 30/70 photon electron mix angled; 20/80 photon/electron mix AP, partial wide tangent fields). Dose 50/25
 * Outcome: Standard tangents significantly less IMN dose than all others, then reverse hockey stick and cobalt, then all others, which were statistically similar. Partial wide tangents smallest heart V30
 * Conclusion: No one technique best CW and IMN coverage, with minimal heart and lung complication probabilities. Partial wide tangents most appropriate balance


 * Medical College of Virginia; 2000 PMID 10924983 -- "Internal mammary node coverage: an investigation of presently accepted techniques." (Arthur DW, Int J Radiat Oncol Biol Phys. 2000 Aug 1;48(1):139-46.)
 * Dosimetric comparison. Four techniques (standard tangents/SCV, wide tangents, partial wide tangents, medial electron/shallow tangents). Dose 50/25
 * Conclusion: Significant anatomic variation, need to use CT planning. Partial wide tangent best choice


 * Duke; 1994 PMID 8040041 -- "To treat or not to treat the internal mammary nodes: a possible compromise." (Marks LB, Int J Radiat Oncol Biol Phys. 1994 Jul 1;29(4):903-9.)
 * Dosimetric technique. 15 patients. Partial wide tangential fields irradiating 1st/2nd/3rd IM intercostal spaces


 * NIH; 1983 PMID 6404865 -- "Dose to lung in primary breast irradiation." (Roberson PL, Int J Radiat Oncol Biol Phys. 1983 Jan;9(1):97-102.)
 * Dosimetric technique. Five techniques (standard tangents, wide tangents, medial IMN AP/shallow tangent, medial IMN 20 degree/shallow tangent, medial IMN angled to match shallow tangent)
 * Conclusion: No technique best for all patients, depends on patient anatomy

Postmastectomy IMRT

 * Memorial Sloan Kettering
 * Expander/implant; 2010 (2004-2007) PMID 20096946 -- "Postmastectomy intensity modulated radiation therapy following immediate expander-implant reconstruction." (Koutcher L, Radiother Oncol. 2010 Jan 21. [Epub ahead of print])
 * Retrospective. 41 patients, s/p mastectomy with immediate expander/implant reconstruction. Left-sided 56%, PMRT with IMRT to 50-50.4 Gy. SCV in 100%, PAB in 29%, IMN in 17% (deep tangents)
 * Outcome: Chest wall coverage adequate 73%, 1 border inadequate 22%. Mean lung V20 13% (3-32%), mean heart Dmean 2.8 Gy (0.5-9.6). Specific numbers provided for left vs right and IMN+ vs IMN-
 * Conclusion: In women with expanders/implants, PMRT can have acceptable heart and lung doses, even when IMN are being treated
 * Isocentric 3F technique; 2005 PMID 15990027 -- "Intensity-modulated radiotherapy technique for three-field breast treatment." (Chui CS, Int J Radiat Oncol Biol Phys. 2005 Jul 15;62(4):1217-23.)
 * Treatment planning. 15 patients. Isocentric 3 field technique described

Proton Therapy

 * Please see the partial breast irradiation page for APBI proton studies

Clinical

 * Harvard; 2013 PMID 23523326 -- "Proton therapy for breast cancer after mastectomy: early outcomes of a prospective clinical trial." (Macdonald SM, Int J Radiat Oncol Biol Phys. 2013 Jul 1;86(3):484-90. doi: 10.1016/j.ijrobp.2013.01.038. Epub 2013 Mar 21.)
 * Prospective. 12 patients (5 permanent implants and 7 no reconstruction), postmastectomy proton radiation therapy, 50.4 Gy to chest wall and regional lymphatics (SCL, axilla, IMN). Passive scatter. Feathering over 1 cm in 2 steps. No photon/electrons used
 * Toxicity: maximum skin grade 2 radiation dermatitis; maximum fatigue grade 3. No pneumonitis
 * Conclusion: Proton RT for postmastectomy RT is feasible and well tolerated.

Dosimetry

 * Harvard
 * Postmastectomy IMPT; 2013 PMID 23647751 -- "Intensity modulated proton therapy for postmastectomy radiation of bilateral implant reconstructed breasts: A treatment planning study." (Jimenez RB, Radiother Oncol. 2013 May;107(2):213-7. doi: 10.1016/j.radonc.2013.03.028. Epub 2013 May 3.)
 * Planning study. 5 patients with bilateral breast implants. IMPT, conformal photon/electron, and partial wide tangents. Dose 50.4 Gy, target 95% coverage of chest wall IMN, SCV, axilla
 * Outcome: IMPT comparable target coverage, better homogeneity, improved heart and lung mean doses
 * Conclusion: IMPT provides improved dosimetry
 * Postmastectomy; 2013 PMID 23521809 -- "Proton radiotherapy for chest wall and regional lymphatic radiation; dose comparisons and treatment delivery." (Macdonald SM, Radiat Oncol. 2013 Mar 24;8:71. doi: 10.1186/1748-717X-8-71.)
 * Planning study. 11 patients planned with protons, partial wide tangents, photon/electrons
 * Outcome: Reasonable coverage with all, but proton superior covereage with more homogenous plan and substantial cardiac / pulmonary sparing. Akimbo positioning was necessary in 1 patient
 * Conclusion: Proton RT feasible


 * Paul Scherrer Institute
 * 2010 PMID 19615828 -- "Postoperative proton radiotherapy for localized and locoregional breast cancer: potential for clinically relevant improvements?" (Ares C, Int J Radiat Oncol Biol Phys. 2010 Mar 1;76(3):685-97. Epub 2009 Jul 15.)
 * Treatment planning. 20 left-sided BCA. Three volumes: 1) whole breast or chest wall (PTV1) vs 2) WB/CW + level III axilla + SCV (PTV2) vs 3) WB/CW + SCV + IM. Comparison between 3DCRT vs IMRT vs IMPT
 * Outcome: Good coverage of PTV, except 3DCRT in PTV3 scenario, where all plans exceeded left lung V20. IMPTV reduced OAR vs 3DCRT and IMRT
 * Conclusion: Potential role of protons for extended locoregional RT of left breast cancer
 * 2006 PMID 16857055 -- "Radiation therapy planning with photons and protons for early and advanced breast cancer: an overview." (Weber DC, Radiat Oncol. 2006 Jul 20;1:22.)
 * Overview of evidence
 * Comment PMID 17476135
 * 2003 PMID 12573766 -- "Potential role of intensity-modulated photons and protons in the treatment of the breast and regional nodes." (Lomax AJ, Int J Radiat Oncol Biol Phys. 2003 Mar 1;55(3):785-92.)
 * Treatment plan comparison: standard photon/electron, IMRT, and forward planned protons. Target involved breast, axilla, SCV, and IM nodes.
 * Conclusion: IMRT can greatly improve target homogeneity, but proton plan had potential to also minimize dose delivered to organs at risk
 * 2002 PMID 11937240 -- "Critical appraisal of treatment techniques based on conventional photon beams, intensity modulated photon beams and proton beams for therapy of intact breast." (Fogliata A, Radiother Oncol. 2002 Feb;62(2):137-45.)
 * Treatment planning. 5 patients, highly concave breast tissue. 2 field conventional vs 2 field IMRT vs 3 field conventional vs 3 field IMRT and single field protons
 * Outcome: PTV comparable for photon techniques, improved with single field protons. Lung volume and cardiac volume better with protons
 * Conclusion: Geometrically difficult breast cancer patients benefited from proton therapy


 * Uppsala; 2002 PMID 12443804 -- "Node-positive left-sided breast cancer patients after breast-conserving surgery: potential outcomes of radiotherapy modalities and techniques." (Johansson J, Radiother Oncol. 2002 Nov;65(2):89-98.)
 * Treatment planning. 11 patients with left-sided node-positive breast cancer. Conventional plan vs. IMRT vs. protons
 * Conclusion: Proton plans significantly better for lung and heart dose


 * Indiana University; 1997 PMID 9240659 -- "Phantom assessment of lung dose from proton arc therapy." (Sandison GA, Int J Radiat Oncol Biol Phys. 1997 Jul 1;38(4):891-7.)
 * Chest wall irradiation of Rando phantom. 200 MeV beam, modulated to 4cm, 20x4 field size, rotated at 1 rpm. Comparison to 12 MeV electron arc therapy
 * Outcome: Reduced lung dose at all levels, 50% integral lung dose
 * Conclusion: Potential role for proton arc therapy in chest wall RT

Effect of surgery to radiotherapy interval (SRI)

 * See also: Chemotherapy section for effect of chemotherapy and radiotherapy sequencing


 * IBCSG Trials
 * Adjuvant chemotherapy; 2016 (1986-1993) PMID 27598802 -- "Timing of Radiation Therapy and Chemotherapy After Breast-Conserving Surgery for Node-Positive Breast Cancer: Long-Term Results From International Breast Cancer Study Group Trials VI and VII." (Karlsson P, Int J Radiat Oncol Biol Phys. 2016 Oct 1;96(2):273-279. doi: 10.1016/j.ijrobp.2016.06.2448.)
 * Retrospective, from 2 randomized trials (Trial VI: premenopausal randomized to 3 months vs 6 months CT followed by RT; Trial VII: postmenopausal no CT vs 3 months CT, followed by RT). Comparison of 718 patients. Median follow up > 15 years
 * Outcomes: Premenopausal LF HR 0.9 (NS) and 1.5 (NS). Also no difference in RF, DF, DFS
 * Conclusion: It is reasonable to delay RT after completion of standard chemotherapy
 * Adjuvant endocrine therapy; 2011 PMID 20729007 -- "Timing of radiotherapy and outcome in patients receiving adjuvant endocrine therapy." (Karlsson P, Int J Radiat Oncol Biol Phys. 2011 Jun 1;80(2):398-402. doi: 10.1016/j.ijrobp.2010.02.042. Epub 2010 Aug 21.)
 * Retrospective analysis from IBCSG trials. 964 patients treated with BCS, RT, and adjuvant endocrine therapy. Median RT start 77 days, correlated with age/menopause status, ER status
 * Outcomes: Adjusted HR for 77 days 0.94 (NS) for local recurrence, DFS, and OS
 * Conclusion: RT delay of <= 20 days no significantly associated with LR, DFS, or OS


 * Harvard; 2010 (1991-2002) PMID 20197326 -- "Impact of interval from breast conserving surgery to radiotherapy on local recurrence in older women with breast cancer: retrospective cohort analysis." (Punglia RS, BMJ. 2010 Mar 2;340:c845. doi: 10.1136/bmj.c845.)
 * Retrospective. SEER-Medicare linked database. 18,050 women, age >65, Stage 0-II BCA, treated with BCS + RT, no chemo.
 * Outcome: Median time surgery->RT 34 days. LR in 4%. Interval >6 weeks associated with 0.96% increase in LR at 5 years (SS). On continuous modeling, HR 1.005 per day (SS). Starting >6 weeks associated with LN+, comorbidity, low income, Hispanic/non-white, residence outside southern states
 * Conclusion: Continuous relationship between interval to RT and local recurrence in older women


 * Florence; 2009 PMID 18715726 -- "Radiotherapy timing in 4,820 patients with breast cancer: university of florence experience." (Livi L, Int J Radiat Oncol Biol Phys. 2009 Feb 1;73(2):365-9. Epub 2008 Aug 18.)
 * Retrospective. 4,820 patients, postop RT. surgery to start RT grouped <60 days, 61-120 days, 121-180 days, and >180 days
 * Outcome: Timing of RT not significant on multivariate analysis. Independent risk factors for poor outcome age, SM, and boost
 * Conclusion: Timing of RT itself doesn't affect local recurrence


 * British Columbia; 2008 (1989-2003) - PMID 19018080 &mdash; "Intervals Longer Than 20 Weeks From Breast-Conserving Surgery to Radiation Therapy Are Associated With Inferior Outcome for Women With Early-Stage Breast Cancer Who Are Not Receiving Chemotherapy." (Olivotto IA, J Clin Oncol. 2009 Jan 1;27(1):16-23. Epub 2008 Nov 17.)
 * Retrospective. 6428 patients, T1-2 N0-1. No chemotherapy. Intervals evaluated were <4, 4-8, 8-12, 12-16, 16-20, and >20 weeks. 23% patients >12 weeks interval. Median f/u 7.5 yrs.
 * Outcome: No significant difference in recurrence for groups treated with a surgery-to-RT interval up to 20 weeks. Increased relapse rate for interval >20 weeks vs 4-8 week reference group: 10-year LR 6% vs. 10% (HR 2.0, p=0.2), DM 9% vs. 23% (HR 1.9, SS), BCSS 93% vs. 82% (HR 2.1, SS)
 * Subset analysis: Similar HR for N0 subset, and patients not treated with hormone therapy. Patients treated >20 weeks still better local control compared to no RT at all (HR 2.3, p=0.08)
 * Conclusion: RT should start within 20 weeks of BCS; there is no impact on local control but significant benefit to distant control and breast cancer specific survival.


 * Cornell / SEER; 2008 (1991-99) PMID 18932243 -- "Correlates and effect of suboptimal radiotherapy in women with ductal carcinoma in situ or early invasive breast cancer." (Gold HT, Cancer. 2008 Dec 1;113(11):3108-15.)
 * SEER. DCIS or Stage I, women aged 66+. Of 7791 pts undergoing RT, 16% had delay in RT (>8 weeks post surgery if no chemo or >4 weeks post chemo), 3% had incomplete RT
 * More likely to experience subsequent breast event if had delay in RT (OR 1.14). Those with incomplete RT had higher overall mortality (OR 1.32). Longer RT delays (>12 weeks, or >8 weeks with chemo) had a strongly negative impact on evens (OR 3.94 for DCIS, 2.77 for invasive).
 * Conclusion: RT should be facilitated to ensure completion and timeliness.


 * British Columbia; 2000 (1989-93) - PMID 10661343 &mdash; "Effect of time interval between breast-conserving surgery and radiation therapy on ipsilateral breast recurrence." Froud PJ et al. Int J Radiat Oncol Biol Phys. 2000 Jan 15;46(2):363-72.
 * 1962 pts. No chemotherapy, but tamoxifen allowed.
 * Median f/u 71 mo. IBR in 3.9%. No significant difference in IBR for surgery to RT intervals, even after adjusting for tamoxifen use and tumor grade.


 * UT-Memphis, 1995 (1974-89) - PMID 8625076 &mdash; "Delaying the initiation of intact breast irradiation for patients with lymph node positive breast cancer increases the risk of local recurrence." Hartsell WF et al. Cancer. 1995 Dec 15;76(12):2497-503.
 * 474 pts. 84 pts with chemo for N+.
 * Median f/u 62 mo. 5-yr breast recurrence 2% ("early RT" - < 120 days) and 14% ("delayed RT" - > 120 days). No difference in OS or DFS.

Reviews:
 * 2003: PMID 12560449 - "Does delay in starting treatment affect the outcomes of radiotherapy? A systematic review." Huang J et al. J Clin Oncol. 2003 Feb 1;21(3):555-63.
 * 5 yr LRR higher in pts treated more than 8 wks after surgery (odds ratio 1.62).

Boost dose may overcome

 * JCRT, 1994 (1968-1985) - PMID 8083111 &mdash; " The relation between the surgery-radiotherapy interval and treatment outcome in patients treated with breast-conserving surgery and radiation therapy without systemic therapy." Nixon AJ et al. Int J Radiat Oncol Biol Phys. 1994 Aug 30;30(1):17-21.
 * 673 pts, node negative, no chemo or hormonal therapy. All pts received a boost with > 60 Gy. 5-year breast failure rate was 13% for SRI of 0-4 weeks, 8% for 5-8 wks, 2% for 9-12 wks.

Effect of margins

 * Hartsell, 1995 - PMID 8625076 &mdash; "Delaying the initiation of intact breast irradiation for patients with lymph node positive breast cancer increases the risk of local recurrence." Hartsell WF et al. Cancer. 1995 Dec 15;76(12):2497-503.
 * In pts with negative margins (>2 mm) low risk of local failure if SRI 120 days. If margins close, positive, or unknown, lower risk for early radiotherapy (6%) vs delayed (24%).


 * JCRT - see discussion at Sequencing chemotherapy and radiotherapy (Recht, 1996) which discusses effect of margin status

Irradiation after breast augmentation

 * M.D.Anderson 1990 - PMID 2298621 - 11 pts followed 3-16 yrs after RT
 * Conclusions: 1) Better cosmetic outcome after RT for pts free of fibrotic changes in the augmented breast before RT, 2) 45 Gy to the whole breast preferred over higher doses, 3) irradiation immediately after reconstruction led to poorer cosmetic results.

Irradiation after breast reconstruction

 * Memorial Sloan Kettering 2004 (1995-2001) - PMID 15108879 - 156 pts (81 pts irradiated, 75 controls)
 * 68% of RT group developed capsular contracture vs 40% controls. Cosmesis good to excellent in 80% vs 88% (N.S.).


 * Mayo (Scottsdale) 2004 - PMID 15289733 - 15 pts, TRAM flaps
 * 13 of 15 had cosmesis rated as good or better


 * Fox Chase, 2004 (1987-2002) - PMID 15234042 &mdash; "Low complication rates are achievable after postmastectomy breast reconstruction and radiation therapy." Anderson PR et al. Int J Radiat Oncol Biol Phys. 2004 Jul 15;59(4):1080-7.
 * 85 pts. Tissue expander + implant, 50 pts; TRAM, 35 pts. Reconstruction first in 70 pts (RT at a median of 7 mos post-surgery), RT first in 15 (median interval 13 mos).


 * MDACC, 2001 (1988-98) - PMID 11420508 &mdash; "Comparison of immediate and delayed free TRAM flap breast reconstruction in patients receiving postmastectomy radiation therapy." Tran NV et al. Plast Reconstr Surg. 2001 Jul;108(1):78-82.
 * 32 pts with immediate TRAM followed by RT, 70 with TRAM following RT.
 * No difference in early complications between groups. More late complications (87% vs 8%) for immediate reconstruction vs delayed group.

RT following TRAM:
 * Cleveland Clinic, 2000 (1985-99), PMID 10889371 &mdash; "The acute effects of postoperative radiation therapy on the transverse rectus abdominis myocutaneous flap used in immediate breast reconstruction." Hanks SH et al. Int J Radiat Oncol Biol Phys. 2000 Jul 15;47(5):1185-90.
 * 25 pts.
 * Conclusion: Postmastectomy radiation for TRAM flap reconstruction is well tolerated and is not associated with an increased incidence of acute side effects. Radiation technique and the use of preradiation chemotherapy do not appear to be correlated with an increased incidence of acute side effects.

RT Utilization

 * Multi-Institutional/SEER; 2010 (2005-2007) PMID 20351324 -- "Patterns and Correlates of Adjuvant Radiotherapy Receipt After Lumpectomy and After Mastectomy for Breast Cancer." (Jagsi R, J Clin Oncol. 2010 Mar 29. [Epub ahead of print])
 * Survey respondents and matched SEER data. For BCS, strong indications (LN+ or T3-T4) or weak indications (elderly). For mastectomy, strong indications (LN+ or T3-T4) or weak indications (T1N1, T2N1 or T3N0)
 * Outcome: Strong indications for RT actually received it BCS 96% vs mastectomy 78% (SS). Weak indications for RT actually received it BCS 80% vs mastectomy 47% (SS)
 * Predictors for RT: surgery type, indication strength, age, comorbidity, income, patient desire to avoid RT, level of surgeon involvement, and SEER site
 * Conclusion: RT after BCS high, lower after mastectomy