Kenny Guida, DMP, DABR March 21 st, 2015

Kenny Guida, DMP, DABR March 21 st, 2015

Breast Cancer Treatment planning and delivery Hypofractionation Trials Hybrid Planning History Techniques RTOG 1005 Trial Hybrid-VMAT Research project

3D Tangents Hard Wedges Not as popular these days Increase dose to contralateral breast Hot spots EDW, Virtual Wedge Limited in field size Collimator rotation and MLCs Field-in-Field Increasingly popular technique Use of multiple subfields can yield homogenous plan and reduce hotspots

3D Boost Wedge Pair Cone-down tangents 3 Field in some cases Electron Boost Single field Treat to % IORT Boost If positive margins, deliver WBRT postoperatively

Free breathing Use of 2+ cm of flash compensates for patient motion associated with breathing when treating patient with tangents Breathold becoming more popular these days effort to reduce heart dose in some patients Setup Wing board or Breast board Prone breast board seeing more implementation Imaging 2D matching with MV portal imaging 3D matching with OBI available on many linacs

Whole Breast 200cGy x 25 fx 180cGy x 25 fx 180cGy x 28 fx Boost 200cGy x 5 fx 200cGy x 8 fx

ASTRO 2013 Choosing Wisely Don t initiate whole breast radiotherapy as a part of breastconservation therapy in women 50 with early-stage invasive breast cancer without considering shorter treatment schedules.

Possibility of treating patients to a lower total dose in fewer fractions, but with increased dose per fraction as compared to the clinical norm Benefits: Patient convenience Shorter duration Lower cost for entire treatment Favorable rates of late effects and loco-regional tumor control

Potential holdups Early stage T1-T2, N0 (maybe N1) No chemotherapy Patient size Few trials with 10 years of follow up Not as much information and data available as standard fractionation Reimbursement system in US Conventional fraction efficacy Early and late effects? Prescribed dose and fractionation What works best? Trials in Canada/UK/US have different Rx doses, number of fractions, and boost/no boost

Typical Treatment Regimens: Canada (OCOG) 4272cGy in 16fx UK START A 4160cGy or 3900cGy in 13fx START B 4000cGy in 15fx Other Italy 4000cGy in 15fx WB + 300cGy x 3fx boost

Ontario Clinical Oncology Group OCOG 4250cGy in 16fx vs 5000cGy in 25fx 1234 patients HF vs CF N0, negative margins, invasive breast cancer with breast-conserving surgery Small to moderately sized breasts Shortened course did not compromise local tumor control 10 year risk of local recurrence was 6.2% with Hypofraction compared to 6.7% with conventional fractionation No observed differences in terms of overall survival or death due to breast cancer

RT after surgery, chemotherapy and endocrine treatment followed if prescribed Boost dose given at physician discretion START A UK 3900cGy or 4160cGy in 13fx vs 5000cGy in 25fx Moderate or marked breast induration, telangiectasia, and edema were significantly less common in 3900cGy group Normal tissue effects did not differ between 4160 and 5000cGy groups START B UK 40Gy in 15fx over 3 weeks for HF arm Small but significant improvement in rates of disease-free survival, mets, and overall survival when compared to CF Breast shrinkage, telangiectasia, and edema were significantly less common in 4000cGy group

Phase III Trial of Accelerated Whole Breast Irradiation with Hypofractionation plus Concurrent Boost vs. Standard Whole Breast Irradiation plus Sequential Boost for Early Stage Breast Cancer Patient population: Stage 0, I, II Breast cancer resected by lumpectomy ± neoadjuvant systemic therapy Arm 1: Standard fractionation WBRT 50Gy (25Fx x 2Gy) Optional hypofraction 42.7Gy (16Fx x 2.67Gy) Sequential boost 12Gy (6Fx x 2Gy) Optional boost of 14Gy (7Fx x 2Gy) Arm 2: Hypofractionation WBRT 40.05Gy (15Fx x 2.67Gy) Concurrent boost to 48Gy - 7.95Gy (15Fx x 53cGy)

Goals of the protocol Evaluation of biological equivalence for both the whole breast and boost dose to the breast tissue Major focus - lumpectomy bed (highest risk for recurrence is area immediately around the lumpectomy site) Comparison of early and late stage toxicity after standard and hypofractioned courses Late effects include telangiectasia, breast shrinkage, and fibrosis How dose hypofractionation with a boost affect cosmesis?

Is tumor bed boost needed? Canada no boost UK and US generally includes tumor bed boost Especially for younger patients and patients with close margins 85% of American and 75% of European physicians deliver boost dose even with negative margins What is the optimal method? Still unanswered by hypofractionated protocols Concomitant boost of 50cGy/fx and sequential boost of 300cGy x 3fx proven effective Slight increase in acute and late skin toxicity

Can hypofractionation be used for patients with large breasts? Canada excludes patients with separation of over 25cm Vicini patients with large breast volumes (>1600cc) saw more acute skin toxicity Harsolia 59% of patients with large breast volumes (>1600cc) developed G2 and G3 skin reactions Ciammella significant correlation between acute skin toxicity and breast volume (P = 0.01504)

Is there a way to deliver WB plus a boost while reducing hotspots? Technique suitable for all patients Technique that integrates boost, based on European trials and RTOG 1005 IMRT / VMAT could be that solution but we generally see an increase in low dose spray outside of the target region Could lead to secondary malignancies Breathing motion could be an issue What if we combine the best aspects of 3D and IMRT

Described by Charles Mayo as a technique that combines static and IMRT beams treated concurrently The prescribed dose is delivered via static fields and IMRT, with a split favoring the static fields more Separate prescriptions needed in treatment planning for static and IMRT beams, a Plan Sum can add the components together

Inverse optimization in Hybrid IMRT planning Can offer the potential of increased conformity Planner has ability to set constraints on PTVs and OARs during planning process Saved optimization guidelines can be used on whole subsets of patients to speed up the planning process Can reduce planning time Mayo suggests optimization time of 10-15 mins Yields consistent results Can be useful for difficult anatomy Large separation, OAR in field, non uniform shape, etc.

Mayo (UMass): Compared wedged-field tangents, FIF, IMRT-only tangents, and 4 and 6 field hybrid plans 4-field hybrid conventional open field tangents plus 2 IMRT tangents Comparable to FIF in dosimetry, but significantly faster planning time 6-field hybrid conventional open field tangents plus 4 IMRT tangents 2 IMRT fields aligned with tangents, 2 anterior oblique IMRT fields Created the most conformal dose distribution, however low dose spray increased for surrounding normal tissue

Mayo (UMass): Mayo, et. al. Hybrid IMRT Plans-Concurrently treating conventional and IMRT beams for improved breast irradiation and reduced planning time. IJROBP. 2005. Pages 922-932.

Mayo, et. al. Hybrid IMRT Plans-Concurrently treating conventional and IMRT beams for improved breast irradiation and reduced planning time. IJROBP. 2005. Pages 922-932.

Asbury (University of Maryland): Static tangents in conjunction with IMRT beams using same beam angles as tangents IMRT beams were inversely optimized 2 separate Rx s for static and IMRT fields Benefits: Help achieve desired dose coverage and reduce hotspots in breast Suitable for patients that are more difficult to plan with tangential fields (ex wide separation, non-uniform shape, deep lumpectomy beds)

Technique: Use of static tangents and VMAT arcs to deliver a simultaneously integrated boost to the lumpectomy bed while delivering a uniform dose throughout the breast Potential benefits: Increased conformity Reduce hotspots Adaptable for all patients Ease of planning

Scheme Contouring Lots of contouring OARs GTVs CTVs PTVs Plan the tangents first Generate a VMAT plan Optimize with tangent plan as the Base Dose

Contouring GTV Lumpectomy excision cavity volume, clips, seroma CTVs Lumpectomy GTV + 1cm expansion, excludes 5mm skin contour, should not cross midline Breast apparent glandular tissue visualized on CT, exclude 5mm skin contour, follow RTOG Breast Atlas guidelines PTVs Lumpectomy CTV + 7mm expansion (excludes heart) Breast CTV + 7mm expansion PTV eval Lumpectomy PTV eval exclude part outside of breast, exclude 5mm skin contour Breast PTV eval exclude 5mm skin contour, posteriorly no deeper than anterior surface of ribs For DVH analysis only OARs: Heart Lungs (ipsilateral and contralateral) Contralateral breast Thyroid

Planning the Tangents Determine optimal beam angles Avoid entry/exit into contralateral breast Shape MLCs 5mm aperture for the breast PTV Add 2cm or more for flash Determine beam energy Depending on anatomy and separation Can incorporate high energy photons into tangents Plan with only 6MV for VMAT

Planning the Tangents Determining the appropriate weight of the tangents A good starting point is to have 2400cGy (60% WB dose) adequately cover the breast PTV eval Can use plan normalization to cover the breast PTV eval with adequate dose If plan sum with VMAT is subpar, one can increase weight of tangential plan

VMAT Planning Use of 2 Arcs Increase conformity and yield more homogenous dose within breast PTV Arc angles went from one tangent angle to the other Base Dose Planning Use tangent plan as base dose Allows VMAT to fill in the cracks Enables coverage of Breast PTV and simultaneously boosts Lumpectomy PTV

Slappa da bass, mon!

Varian Eclipse Can optimize an IMRT or VMAT plan from an existing dose Can be another plan or same plan Plan can be 3D, IMRT, or VMAT Can be employed in either DVO or PRO algorithms Precalculated dose distributions taken into account during optimization process Fill in gaps from previous plan in plan sum Improve homogeneity in tumor volumes Improve conformity

VMAT Optimization Set PTV and OAR goals Helper contours Breast-Lumpectomy Helps increase homogeneity in breast and enable lumpectomy simultaneously-integrated boost Interactive optimization Helpful in determining ability to meet constraints Allows one to optimize on fly Can change constraints during optimization

Delivery Integrated boost will require separate plan to be moded up at treatment machine Delivery time for tangents should be similar between FiF and static fields Arc delivery should also be comparable to boost fields Delivery time for 2 or 3 boost fields with wedges or EDW would be similar to 2 partial arcs

Other Caveats QA IMRT QA would be required for VMAT fields Increase in workload for physicists, unless they are already performing QA for FiF plans QA device for VMAT would be needed ArcCheck, EPID, Matrixx RMM Decisions regarding RMM would need to be made Monitor each patient If 4DCT is available, it could be helpful to determine amount of motion Consider on a patient-by-patient basis

Ideal Breast PTV eval D 95 95% WB Rx Dose (3800cGy) D 30 Lump Rx Dose (4800cGy) D 50 108% WB Rx Dose (4320cGy) Lumpectomy PTV eval D 95 95% Lump Rx Dose (4560cGy) D 5 110% Lump Rx Dose (5280cGy) D max 115% Lump Rx Dose (5520cGy) Acceptable Breast PTV eval D 90 90% WB Rx Dose (3600cGy) D 35 Lump Rx Dose (4800cGy) D 50 112% WB Rx Dose (4480cGy) Lumpectomy PTV eval D 95 90% Lump Rx Dose (4320cGy) D 10 110% Lump Rx Dose (5280cGy) D max 120% Lump Rx Dose (5520cGy)

Ideal Heart left D 5 < 1600cGy D 30 < 800cGy Mean < 320cGy Heart - right D max < 1600cGy D 10 < 800cGy Mean < 320cGy Acceptable Heart left D 5 < 2000cGy D 35 < 800cGy Mean < 400cGy Heart - right D max < 2000cGy D 15 < 800cGy Mean < 400cGy

Ideal Ipsilateral Lung D 15 < 1600cGy D 35 < 800cGy D 50 < 400cGy Contralateral Lung D 10 < 400cGy Acceptable Ipsilateral Lung D 20 < 1600cGy D 40 < 800cGy D 55 < 400cGy Contralateral Lung D 15 < 400cGy

Ideal Contralateral Breast D max < 240cGy D 5 < 144cGy Thyroid D max < 96cGy Acceptable Contralateral Breast D max < 384cGy D 5 < 240cGy Thyroid D max < 144cGy

Retrospective study 9 patients previously treated with FiF+3D boost 5 Left, 4 Right PTV eval volume ranged from 448cc to 1560cc (average = 938cc) Played by the RTOG 1005 rules MLC shaping for tangents PTV coverage OAR sparing All Hybrid-VMAT plans planned with set of tangents and 2 partial arcs 6X and 18X used on tangents 6X used for ARCs

Ideal Acceptable Total Structure Volume Goal Volume Goal Hybrid FiF+3D > 95% 3800 > 90% 3600 4013 3990 Breast < 30% 4800 < 35% 4800 4517 4704 PTVeval < 50% 4320 < 50% 4480 4288 4377 CI95.95 to 2.0 CI95.85 to 2.5 1.22 1.49 Lumpectomy PTVeval Heart (Left) Heart (Right) Ipsilateral Lung > 95% 4560 > 95% 4320 4767 4769 < 5% 5280 < 10% 5280 5036 5078 max pt dose 5520 max pt dose 5760 5140 5154 CI95.95 to 2.5 CI95.9 to 3 1.54 2.27 < 5% 1600 < 5% 2000 841 671 <30% 800 <35% 800 390 164 mean 320 mean 400 370 201 0% 1600 0% 2000 977 374 <10% 800 <15% 800 405 131 mean 320 mean 400 229 47 < 15% 1600 < 20% 1600 1260 907 < 35% 800 < 40% 800 589 291 < 50% 400 < 55% 400 357 158 Contralateral Lung < 10% 400 < 15% 400 215 71 Contralateral dmax 240 dmax 384 277 207 Breast < 5% 144 < 5% 240 138 66 Thyroid dmax 96 dmax 144 104 57

Ideal Acceptable Total Structure Volume Goal Volume Goal Hybrid FiF+3D > 95% 3800 > 90% 3600 4013 3990 Breast < 30% 4800 < 35% 4800 4517 4704 PTVeval < 50% 4320 < 50% 4480 4288 4377 CI95.95 to 2.0 CI95.85 to 2.5 1.22 1.49 Lumpectomy PTVeval > 95% 4560 > 95% 4320 4767 4769 < 5% 5280 < 10% 5280 5036 5078 max pt dose 5520 max pt dose 5760 5140 5154 CI95.95 to 2.5 CI95.9 to 3 1.54 2.27

Ideal Acceptable Total Structure Volume Goal Volume Goal Hybrid FiF+3D < 5% 1600 < 5% 2000 841 671 Heart (Left) <30% 800 <35% 800 390 164 mean 320 mean 400 370 201 0% 1600 0% 2000 977 374 Heart (Right) <10% 800 <15% 800 405 131 mean 320 mean 400 229 47 < 15% 1600 < 20% 1600 1260 907 Ipsilateral Lung < 35% 800 < 40% 800 589 291 < 50% 400 < 55% 400 357 158 Contralateral Lung < 10% 400 < 15% 400 215 71 Contralateral Breast dmax 240 dmax 384 277 207 < 5% 144 < 5% 240 138 66 Thyroid dmax 96 dmax 144 104 57

Hybrid FiF + 3D

Hybrid FiF + 3D

Hybrid FiF+3D

Hybrid-VMAT improves: Conformity! CI 95 for both the breast and lumpectomy PTV eval volumes dropped considerably with this approach Less normal tissue receiving high dose and less breast tissue receiving boost dose Lumpectomy CI 95 dropped from 2.27 to 1.54 with hybrid VMAT Breast CI 95 dropped from 1.49 to 1.22 with hybrid VMAT

Hybrid-VMAT improves: Planning time Inverse optimization allows for one to import pre-set goals for dose-volumes and weighting Simply loading optimization gets process rolling quickly No setting up FiF simply set tangents, select energy and weight beams to your liking No determining best 3D boost approach, boost taken care of during VMAT optimization More experience less planning time and better results

Hybrid-VMAT drawbacks: Low dose spray What is acceptable? See higher volumes of lung and heart receiving more low dose Plans met acceptable DVH goals at the minimum, set by RTOG Possible increase in secondary cancer risk due to low dose spray associated with VMAT RMM issues Insurance coverage Plan is more complex to deliver

Free breathing What about FLASH? Can create a flash structure to optimize to Respiratory Motion Management Can perform respiratory gating Minimize variation of breast motion via DIBH and ABC Tsai, et. al. - could cut up arcs into smaller arcs to deliver during a breathhold to control motion Can monitor breathing motion from 4D CT scan to determine magnitude of motion

Introduction of VMAT beams could increase risk of secondary cancers More low dose spray associated with VMAT than tangential beam delivery More beam on time increase in head leakage and collimator scatter Abo-Madyan, et. al. reported secondary cancer risk after 3D or FiF delivery for breast cancer was about 34% lower than IMRT or VMAT using linear modeling About 50% lower when using linear-exponential model

Hypofractionation has a future in radiation therapy for breast cancer in the US Still no best practice for lumpectomy boost when delivering hypofractionation No boost, cone down, or SIB? Hybrid planning can yield very conformal plans that meet clinical tolerances Could be a useful tool in treating WB + SIB in the future

VU Softball Champs 2011

Phase I and II Studies safety and efficacy Freedman 2007 WB 225cGy x 20 (4500cGy), SIB 280cGy x 20 (5600cGy) IMRT acceptable treatment modality No grade 3 skin toxicity, all grade 2 and lower resolved in 6 weeks post treatment 5 year local recurrence was 1.4% Chadha 2009 4005 cgy to whole breast in 15 fx 4500cGy to boost volume concomitantly Conventional whole breast irradiation No grade 3 toxicities

Phase I and II Studies safety and efficacy Formenti 2007 4005cGy to whole breast in 15 fx 4800cGy to boost volume concomitantly IMRT acceptable treatment modality Grade 1-2 dermatitis in 67% of patients 2 Grade 3 toxicites 1 skin, 1 fatigue Breast pain grade 1 8%, grade 2 2% 1 regional node recurrence

3 Phase I and II Studies safety and efficacy Ciamella Italy 2014 212 patients on trial T1-T2, N0-N1 267cGy x 15 + possible boost Boost of 300cGy x 3 for patients with high risk factors (age < 50, close margins) Cosmesis good or excellent in 92% of patients Acute skin toxicity of G1 (79%), G2 (12%), G3 (1 patient) Late skin toxicity of G1 or G2 in <20%, no G3, corresponded with boost delivery

Compared to IMRT plans, Hybrid plans for lung and esophageal patients were seen to reduce lung dose (V20, V13, and V5) Hybrid planning also reduced potential magnitude of motion-induced dose distribution deviations