Kevin S. Hughes, MD, FACS Co-Director, Avon Comprehensive Breast Evaluation Center Massachusetts General Hospital Associate Professor of Surgery Harvard Medical School Surgeon The Newton-Wellesley Hospital Breast Center Is Post-Lumpectomy Radiation Necessary in Older Patients?

1.9 cm, ER+, clinical N0 Cancer Lumpectomy Plus Radiation/Boost Tamoxifen Sentinel Node Chemotherapy BRCA testing

1.9 cm, ER+, clinical N0 Cancer Lumpectomy Plus Radiation/Boost Tamoxifen Sentinel Node Chemotherapy BRCA testing Lumpectomy Plus Radiation/Boost Tamoxifen/AI Sentinel Node Chemotherapy BRCA testing

CALGB 9343 Comparison of Lumpectomy Plus Tamoxifen With and Without Irradiation in Women 70 or Older with Clinical Stage I, ER+ Breast Carcinoma Kevin S. Hughes, Lauren A. Schnaper, Constance Cirrincione, Donald Berry, Beryl McCormick, Hyman B. Muss, Clifford Hudis, Eric Winer, Barbara L. Smith Cancer and Leukemia Group B Radiation Therapy Oncology Group Eastern Cooperative Oncology Group

CALGB 9343 ELIGIBILITY Age  70 ELIGIBILITY Age  70Clinically Node Negative Lumpectomy, Negative Margin Tumor size  2 cm Node Negative Lumpectomy, Negative Margin Tumor size  2 cm ER Positive or Indeterminate STRATIFICATION Age < 75  75 Axillary Dissection Yes No RadiationTamoxifen Tamoxifen RANDOMIZERANDOMIZERANDOMIZERANDOMIZE

CALGB 9343 Opened July 15, 1994 Closed February 26, patients –Eligible 631 –Ineligible 5 –Canceled/Never treated 11 Median follow-up 12 years

Patient characteristics RT+Tam Tam Total treated Age > (56%)172 (54%) ER Positive308 (97%)310 (97%) Size < 2cm295 (93%)296 (93%) No Ax dissection 200 (63%)203 (64%)

IBTR (Ipsilateral Breast Tumor Recurrence) 91% 98%

Ipsilateral cancer risk 40 and under RT 70 above no RT LCIS

Radiation decreases local recurrence by ~7% Does it do anything else?

No RT Mastectomy Lumpectomy IBTR 27 RT IBTR

Actuarial survival for given ages at entry D. Berry 8/28/11

Ultimate Outcome

Breast Recurrence Less Ultimate Mastectomy Same Second primary cancer Same Distant metastasis Same Death Same Death Other CausesSame Death from breast cancerSame 22 women With modern margins and AI’s, RT will likely have even less benefit CONCLUSION: In older women, the benefits of radiation after lumpectomy are small

1.9 cm, ER+, clinical N0 Cancer Lumpectomy Plus Radiation/Boost Tamoxifen Sentinel Node Chemotherapy BRCA testing Lumpectomy Plus Radiation/Boost Tamoxifen/AI Sentinel Node Chemotherapy BRCA testing

1.9 cm, ER+, clinical N0 Cancer Lumpectomy Plus Radiation + Boost Tamoxifen Sentinel Node Chemotherapy Lumpectomy Tam/AI

When does this woman…become this woman?

Breast Recurrence Less Ultimate Mastectomy Same Second primary cancer Same Distant metastasis Same Death Same Death Other CausesSame Death from breast cancerSame 22 women Study is mature: 12 years Median, Half of patients dead With modern margins and AI’s, RT will likely have even less benefit CONCLUSION: In older women, the benefits of radiation after lumpectomy are small

1.9 cm, ER+, clinical N0 Cancer Lumpectomy Plus RT/Boost Tamoxifen Sentinel Node Chemotherapy BRCA testing Agreement: Elderly women need less treatment Lumpectomy OR Tam/AI OR Tam/AI/RT

1.9 cm, ER+, clinical N0 Cancer Lumpectomy Plus Radiation + Boost Tamoxifen Sentinel Node Chemotherapy BRCA testing Agreement: Elderly women need less treatment Lumpectomy OR Tam/AI OR Tam/AI/RT Continued discussion: Who are the elderly?

Conclusions Every elderly woman does not need –lumpectomy,sentinel node,RT+Boost,Tam/AI,Chemo Breast irradiation provides less benefit with age Breast irradiation plus Tam/AI is often excessive Question: Who are the elderly? Elderly women need individualized treatment

Axillary recurrence TamRTTam No ax dissection Ax Recurrence0 6 (3%)

Breast Recurrence Less Ultimate Mastectomy Same Second primary cancer Same Distant metastasis Same Death Same Death Other CausesSame Death from breast cancerSame Benefits of RT are small N (% at 10 yeas) N (% at 10 years) 22 women Study is mature: 12 years Median, Half of patients dead With modern margins and AI’s, RT will likely have even less benefit

In older women, the benefits of radiation after lumpectomy are small Breast recurrence ~7% Radiate 319 women to avoid 21 in breast recurrences Ultimate breast preservationNS Second primary cancerNS Distant metastasesNS Death breast cancerNS Death from any causeNS 21 women Omitting Radiation in women 70 and above with Clinical Stage I breast cancer is a reasonable alternative for our patients

Managing the elderly If mastectomy needed –Preop chemo or endocrine possible & needed Yes=>Try No=>Do Mastectomy (With sentinel node) If breast preservation possible –Clinically positive node Lumpectomy/Axillary dissection –Tumor ER- or over 2 cm Lumpectomy/Sentinel node –If Clinical Stage I and ER+ If chemotherapy a possibility –Do sentinel node If chemotherapy NOT a possibility –Sentinel node optional (Not encouraged)

No RT IBTR 20 RT IBTR 4

No RT Mastectomy Lumpectomy IBTR 20 RT IBTR

In older women, the benefits of radiation after lumpectomy are small Breast recurrence ~7% Radiate 319 women to avoid 21 in breast recurrences Ultimate breast preservationNS Second primary cancerNS Distant metastasesNS Death breast cancerNS Death from any causeNS 21 women

CONCLUSION: In older women, the benefits of radiation after lumpectomy are small Breast recurrence ~7% Radiate 319 women to avoid 21 in breast recurrences Ultimate breast preservationNS Second primary cancerNS Distant metastasesNS Death breast cancerNS Death from any causeNS 21 women Study is mature: 12 years Median, Half of patients dead With modern margins and AI’s, RT will likely have even less benefit

Axillary recurrence

CALGB 9343: All Patients Dead Breast 2 % Dead Other 27% Alive 71%

Morbidity statistically inferior in RT arm Physician assessment Patient assessment 4 monthsCosmesisPain TendernessFibrosis Skin color changes Breast edema 1 year CosmesisPain TendernessFibrosisSkin color changes Breast edema Fibrosis 2 years Skin color changesSkin color changes Breast edemaCosmesis Fibrosis 4 yearsNo differencesNo differences

Benefit of RT LocoRegional recur5.9% Ultimate Breast Preservation0 % Distant Metastases0 % Death Breast Cancer0 % Death Any Cause0 %

Benefit of RT LocoRegional recur5.9% Ultimate Breast Preservation0 % Distant Metastases0 % Death Breast Cancer0 % Death Any Cause0 % 5 YR results verified at 8.2 YRS

Early 1990’s: Was RT always needed after conservative surgery? Possible groups –Elderly –Small tumors –Tamoxifen

Summary of Randomized Trials: Lumpectomy + Tam vs Lumpectomy + Tam + RT NSABPCanadianCALGBScottishAustrian B-21FylesHughesStewartPotter AgeAny50 and over70 and overAny Size<1 cm< 5 cm< 2 cm< 4 cm< 3 cm Tamoxifen2 / 3 armsyes PopulationSmall tum / younger large tum / older Small tum / older Large tum / younger Large tum / younger # of pts1, Median FU8 y 6 y3.5 y

Summary of Randomized Trials: Lumpectomy + Tam vs Lumpectomy + Tam + RT NSABPCanadianCALGBScottishAustrian B-21FylesHughesStewartPotter Tam16.5%11.5%7%25%3.1% Tam + RT2.8%3.8%1%3%0.2%

Summary of Randomized Trials: Older Women NSABP B-21 Canadian Fyles CALGB Hughes Age>70>60> 70 Size< 1cm < 2cm # of pts Tam7%4.8%7% Tam + RT0 %4.2%1%

Can we Vs should we?

Managing the elderly  Lumpectomy ≤ 2 cm & ER+  Adjuvant treatment  RT plus Tam/AI  Tam/AI  RT  Sentinel node  IF chemo being considered > 2 cm &/or ER-  Sentinel node plus RT  Mastectomy

Treating breast cancer in the elderly differently makes medical sense Or is discrimination

I can’t define elderly, but I know it when I see it. Paraphrase of Supreme Court Decision Potter Stewart Miller VS California, 1973 Miller VS California, 1973

2004: Median 5 Yr Hughes NEJM, 2004

Mastectomy Lumpectomy IBTR Lumpectomy + RT Local recurrence does not preclude breast preservation

GOALS  Prevent Breast Recurrence  Prevent Axillary Recurrence  Prevent Systemic Recurrence  Preserve the Breast  Minimize Treatment

Mission of the American Academy of Pediatrics change the custom of treating children as miniature adults

Mission of the American Academy of Pediatrics change the custom of treating children as miniature adults The mission of Geriatric Oncology should be similarly described.

CALGB 9343: All Patients Dead Breast 2 % Dead Other 27% Alive 71%

CALGB 9343: Deceased Dead Breast 6 % Dead Other 94%

For older women… these hazards would exceed the estimated benefits Breast Cancer Trialists’ Collaborative Group Lancet 2000; 355: 1757–70 …if …radiotherapy regimens … can … yield most of the benefit while avoiding most of the hazard, 20- year survival could be moderately improved …

NEJM 2004: Median 5 Yr Hughes NEJM, 2004 Criticism FU too short Curves will separate Need longer FU!

Can we? Should we? Patient factors are dependent on physiologic age Tumor factors are dependent on chronologic age

FEMALE POPULATION (in thousands) USA - November 1, 1998 Age Group 138,

Biologic factors in older patients Doubling Time by Xeromammography Cancer Research 46:970,1986 Spratt et al Cancer Research 46:970,1986

Histopathology of Breast Cancer in Relation to Age CJ Fisher, et al, Guy’s Hopital BrJCa 75:593,1997

Superimpose Yrs

Can we…? Patient factors Dependent on physiologic age

New Approach to Geriatric Oncology Should we…? –Will the patient live long enough to benefit? Does less aggressive cancer increase the time needed to show benefit? –Does tumor response abrogate the need for multimodality therapy?

Decreased local recurrence Biologic factors

Decreased local recurrence Decreased time at risk

Decreased local recurrence Tamoxifen

Local recurrence does not preclude breast preservation

IBTR (Ipsilateral Breast Tumor Recurrence)

SECOND PRIMARY CANCER TamRTTam TOTAL36 (12%)33 (9%) Breast1210 Leukemia12 MDS01 Lymphoma43 Colorectal65 Epiglottis10 Peritoneum01 GI,NOS10 Liver02 Pancreas01 Spleen10 Bladder10 Endometrium31 Lung47 Melanoma20

Initial Approach to Geriatric Oncology Can we…? –Can we do the same surgery? –Can we use the same drugs? –Can we radiate?

Women could now choose breast preservation or mastectomy

Can we…? Patient factors Dependent on physiologic age

In Breast Recurrence from another trial

STANDARD THERAPY

Cancer May 15;47(10): Survival following breast cancer surgery in the elderly. Herbsman H, Feldman J, Seldera J, Gardner B, Alfonso AE. Herbsman HFeldman JSeldera JGardner BAlfonso AE “there is little justification for avoiding conventional operative treatment in elderly patients with breast cancer solely on the basis of advanced age.” Early papers on cancer in the elderly evaluated the question: ‘Can we?”

Should we? Patient factors Dependent on physiologic age Tumor factors Dependent on chronologic age

Can we? Should we? Patient factors Dependent on physiologic age Tumor factors Dependent on chronologic age

NSABP B - 06 Lumpectomy + Axillary Dissection Lumpectomy + Axillary Dissection Mastectomy Mastectomy n n IBTR 40.9% 12.4% N/A IBTR 40.9% 12.4% N/A Survival 65% 71% 68% Survival 65% 71% 68% Lumpectomy + Axillary Dissection & RT Lumpectomy + Axillary Dissection & RT vs

Early 1990’s: Did any group NOT need RT after conservative surgery? –Elderly –Small tumors –Tamoxifen

RADIATION AFTER AGE 70 No change in survival Decreased local recurrence Biologic factors in patients over 50 Decreased time at risk Tamoxifen Local recurrence does not preclude breast preservation

RT: No change in survival Authorn Follow-up RT No RT Authorn Follow-up RT No RT Fisher Years 71% 65% Liljegren381 5 Years 91% 87.1% Veronesi567 4 Years No Difference Clark837 3 Years 91-96% 90-96%

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 Early Breast Cancer Trialists’ Collaborative Group, Lancet 2005; 366: 2087–2106 By contrast, more than half the 15-year breast cancer mortality (and much more than half of any such treatment effects on breast cancer mortality) occurred after the first 5 years. Some local treatment comparisons (eg, axillary clearance vs effective axillary radiotherapy; mastectomy vs BCS plus effective radiotherapy; post-mastectomy radiotherapy in nodenegative disease) involved little (10%) absolute difference in the 5-year risk of local recurrence and, in aggregate, these comparisons also involved little difference in 15-year breast cancer mortality (figure 5, upper panel).

Decreased local recurrence MILAN TRIAL III Quandrantectomy and Axillary Dissection Only Age n Local Recurrence  45 years 6311 (17.5%) (8.7%) >55 years (3.8%)

NEJM 351: 963, 2004 Fyles (Princess Margaret) Age at diagnosis#Local Relapse 50–59 yr –69 yr ≥70 yr3253.2

Decreased Time at Risk

NSABP B MONTH ANALYSIS IBTR1.9% 4.3% IBTR1.9% 4.3% TamoxifenPlacebo Decreased local recurrence: Tamoxifen

No RT Mastectomy Lumpectomy IBTR RT IBTR

Concerns regarding this study Patients randomized to receive no radiation would be inappropriately under-treated

No RT IBTR 28 RT IBTR 6

Concerns regarding this study Patients randomized to receive no radiation would be inappropriately under-treated Patients randomized to receive radiation therapy would be inappropriately over-treated

In Breast Recurrence from another trial

Recurrence Rates after Treatment of Breast Cancer with Standard Radiotherapy with or without Additional Radiation Bartelink, N Engl J Med 2001; 345: Tam 70 and above Lumpectomy, RT/Boost 40 or younger

Ipsilateral breast from another study AtypiaIpsilateral 5 year riskIpsilateral 10 year risk Type ADH (n=1233) ALH (n=851) LCIS (n=595) Borderline (n=370)

LCIS AtypiaIpsilateral 5 year riskIpsilateral 10 year risk Type ADH (n=1233) ALH (n=851) LCIS (n=595) Borderline (n=370)