Refining Radiotherapy for Early Breast Cancer: The Challenges. David Dodwell Radiotherapy in Practice Sheffield Hallam University October 2010

Refining Radiotherapy for Early Breast Cancer Current practice Toxicity Prediction of benefit Partial breast radiotherapy Ongoing trials Choices

Radiotherapy for early breast cancer – plenty of demand Increased incidence Increased breast screening Changing surgical techniques Increasing indications Better risk-benefit ratio

Radiotherapy for early breast cancer – plenty of demand Following lumpectomy – almost always For DCIS - commonly Following mastectomy - often After neo-adjuvant chemotherapy - usually

Following lumpectomy

Preliminary results. Not for publication or citation 7EBCTCG Fifth Cycle BCS ± RT in N-ve disease Prognostic factors and 5-year local recurrence risk

Tamoxifen alone in older patients? 636 patients >70years Tam vs Tam + RT Node negative, ER+ Hughes et al SABCS 2006

Following lumpectomy for DCIS

Preliminary results. Not for publication or citation 20EBCTCG Fifth Cycle Radiotherapy after breast conserving surgery in women with carcinoma in situ (CIS±RT) 4100 women in 5 trials, started median follow-up 8.7 years, 295 deaths Surgery: BCS - Clear margins not always required Radiotherapy: Whole breast

Preliminary results. Not for publication or citation 21EBCTCG Fifth Cycle. CIS±RT RECURRENCE (CIS and invasive) BREAST CANCER MORTALITY

Preliminary results. Not for publication or citation 22EBCTCG Fifth Cycle Radiotherapy after carcinoma in situ (CIS±RT) Conclusions In these trials, radiotherapy reduced recurrence by about 10% Radiotherapy had no effect on mortality from breast cancer

Variation in radiotherapy given to DCIS cases treated with breast-conserving surgery

After mastectomy

Preliminary results. Not for publication or citation 25EBCTCG Fifth Cycle Radiotherapy after Mastectomy with Axillary Clearance (Mast+AC+RT vs. Mast+AC) women in 26 trials, started –Years 0-9: 5000 deaths in woman-years –Years 10+: 2000 deaths in woman-years Radiotherapy –All trials: axilla and/or supraclavicular fossa –Most trials: chest wall and internal mammary chain

Preliminary results. Not for publication or citation 26EBCTCG Fifth Cycle Mast+AC+RT vs. Mast+AC Year 2000 NIH consensus conference: RT recommendations after mastectomy, axillary clearance and pathology (p) of nodes (N): pN0 : no RT pN4+ : RT pN1-3: more uncertainty

Preliminary results. Not for publication or citation 27EBCTCG Fifth Cycle Mast+AC+RT vs. Mast+AC Isolated local recurrence by pathological nodal status (pN) pN0pN1-3 pN4+ 49 events in 1277 women 399 events in 3316 women 487 events in 2813 women

Preliminary results. Not for publication or citation 28EBCTCG Fifth Cycle Mast+AC+RT vs. Mast+AC Breast cancer mortality by pathological nodal status (pN) pN0 pN1-3 pN events in 1354 women 1552 events in 3344 women 1986 events in 2876 women

Preliminary results. Not for publication or citation 29EBCTCG Fifth Cycle Mast+AC+RT vs. Mast+AC Any death by pathological nodal status (pN) pN0 pN1-3 pN events in 1354 women 1934 events in 3344 women 2134 events in 2876 women

Preliminary results. Not for publication or citation 30EBCTCG Fifth Cycle Mast+AC+RT vs. Mast+AC Conclusions In N0 disease, RT did not reduce mortality from breast cancer in these trials and 15-year overall survival was poorer with RT than without it. On average in these old RT trials, 15-year breast cancer mortality was reduced, and 15-year overall survival was improved both for N1-3 and N4+ disease

Radiotherapy after neoadjuvant chemotherapy? To the breast post BCS If positive nodes post remaining post Mx/ANC If pre-chemotherapy staging (+SLNB) suggests nodal involvement (irrespective of response) post Mx/ANC Buchholz 2008

Preliminary results. Not for publication or citation 32EBCTCG Fifth Cycle With better RT regimens the proportional reduction in breast cancer mortality may be more than in these trials If absolute recurrence risks are lower nowadays, absolute gains from RT may be correspondingly lower More study still needed of RT benefits at 10 years, 20 years, and beyond General RT recommendations and individual RT choices should depend not only on these old trials but also on many other considerations Remarks on benefits of RT

Toxicity

EBCTCG 2006 Overview, PROVISIONAL RESULTS

RT given vs. no RT given NON-BREAST-CANCER MORTALITY 15-yr mortalityAbsolute AgeRTControl15-yr loss (se) Logrank p <505.3 %4.6%0.7 % (0.6) %11.6 %1.7 % (1.0) %26.4 %3.0 % (1.5) %55.0 %5.7% (5.0)>0.1 EBCTCG 2006: PROVISIONAL RESULTS

Variability in heart dose Heart dose (Gy) Right 6 MV breast tangential pair Left 6 MV breast tangential pair Right 6 MV direct IMC field Left 6 MV direct IMC field Target and field arrangement Taylor et al. Int J Radiat Oncol Biol Phys (in press)

Mean dose (Gy) YearHeartLeft anterior descending artery Right coronary artery Circumflex coronary artery Sweden 1970s* Sweden 1990s* UK Reduction in dose to cardiac structures from left tangential radiotherapy * Taylor et al. Int J Radiat Oncol Biol Phys (in press)

EBCTCG 2006: PROVISIONAL RESULTS

Summary Breast radiotherapy prevents breast cancer deaths Radiotherapy can cause death from heart disease Current regimens still deliver some heart doses Dose-response relationships may predict cardiac hazard Improve understanding of radiation-induced heart disease

Prediction of benefit

Genomic profiling Cheng 2008

Outcome after PMRT by ER/PR/HER-2 Kyndi et al 2008

Can we improve patient selection? At present by avoiding RT (or modifying RT) at a ‘low’ level of recurrence risk +/- high competing mortality risks In future my improved understanding of recurrence risk + better predictive ability

Radiotherapy for early breast cancer – a success story After breast conservation 95-98% local control 1% serious morbidity 60-80% ‘good’ cosmesis

Radiotherapy for pharyngeal cancer 35% local control 15% serious morbidity 20-40% 5 year survival

Partial Breast Radiotherapy

Rationale For APBI  Time and Inconvenience of BCT  Time and Inconvenience of BCT Improve Documented Underutilization of BCTImprove Documented Underutilization of BCT Potentially Reduce Acute and Chronic ToxicityPotentially Reduce Acute and Chronic Toxicity Improve Quality of Life of PatientsImprove Quality of Life of Patients Eliminate Scheduling Problems With Systemic ChemotherapyEliminate Scheduling Problems With Systemic Chemotherapy

Scientific Rationale - APBI - Two types of local failure can develop after standard breast conserving therapy (BCT):Two types of local failure can develop after standard breast conserving therapy (BCT): –Recurrence of index lesion (True Recurrence/Marginal Miss) –Development of a new cancer (Elsewhere Failure) Major effect of post-lumpectomy RT:Major effect of post-lumpectomy RT: –Reduce risk of recurrence in tumor bed region (TR/MM) Recurrences away from tumor bed (‘Elsewhere’ Failures):Recurrences away from tumor bed (‘Elsewhere’ Failures): –It is not clear if the development of these new cancers is impacted by whole breast RT

Rationale for Whole Breast Irradiation Pathologic Justification:Pathologic Justification: –Older pathologic data from mastectomy specimens –30-40% of cases with occult areas of disease elsewhere in the breast –Whole breast RT theoretically given in an attempt to ‘treat’ these additional sites of disease In addition to the index lesionIn addition to the index lesion

Catheter Based Brachytherapy Kuske template

Published Interstitial APBI Data Guy’s Hospital (n=27) 1987Guy’s Hospital (n=27) 1987 Florence, Italy (n=115)Florence, Italy (n=115) Oschner Clinic (n=300)Oschner Clinic (n=300) London Regional Cancer Center (n=39)London Regional Cancer Center (n=39) William Beaumont Hospital (n=199)William Beaumont Hospital (n=199) Orebro Medical Center (n=45)Orebro Medical Center (n=45) Virginia Commonwealth University (n=59)Virginia Commonwealth University (n=59) National Institute of Oncology – Hungary (n=245)National Institute of Oncology – Hungary (n=245) University of Kansas (n=24)University of Kansas (n=24) RTOG (n=99)RTOG (n=99) Massachusetts General Hospital (n=48)Massachusetts General Hospital (n=48) Tufts/Brown University (n=79)Tufts/Brown University (n=79) German/Austrian Trial (n=156)German/Austrian Trial (n=156) William Beaumont Hospital (199) 2008William Beaumont Hospital (199) 2008

Interstitial Experience - Selected APBI Studies - RTOG 95-17:RTOG 95-17: –Phase I/II PBI Trial –12 institutions –99 patients enrolled –Median f/u: 6.14 yrs –5-yr actuarial local recurrence rate: 4% –Int J Radiat Oncol Biol Phys William Beaumont Hospital:William Beaumont Hospital: –199 patients (LDR/HDR brachytherapy) –Median follow-up: 8.6 yrs –10-yr actuarial local recurrence: 3.8% –Int J Radiat Oncol Biol Phys 68 (2): 341-6, 2007

WBH Data: Matched:Pair Analysis - 12 Year Actuarial Outcome - APBI vs. WBRT 12 Year Outcome MeasureAPBI (n=199)WBRT (n=199)p IBTR5 %4 %0.5 Clonally Distinct / Elsewhere2 % 0.6 Clonally Related / TRMM3 %2 %0.6 Contralateral Failure6 %8 %0.2 Regional Nodal Failure2 %0.5 %0.3 Distant Metastases Free Survival95 %90 %0.08 Freedom From Failure91 %87 %0.4 Cause-Specific Survival95 %93 %0.3 Cosmesis (excellent/good)99%96%0.1 5 yr DFS after IBTR75 %67 %0.1

Published APBI Results - Catheter Based Brachytherapy -

Balloon Catheter ‘MammoSite’ MammoSite device (Cytyc Surgical Products) Inflatable Balloon Placed In Lumpectomy Cavity At Surgery HDR brachytherapy 34 Gy in 10 fractions FDA clearance May 2002 Since 2002, > 40,000 cases treated

TARGIT trial very early results suggest equivalence to conventional WBRT

3D Conformal External Beam Radiotherapy - APBI -

Radiotherapy for early breast cancer – ongoing trials To identify benefits in intermediate risk groups – SUPREMO To optimise dose/volume according to risk – IMPORT To minimize inconvenience - TARGIT

High volume Already very successful Statistically challenging Is it a funding priority?

Technical developments? or A better biological understanding?

Or improving service delivery – addressing unequal access & variability in practice?