Kevin S. Hughes, MD, FACSCo-Director, Avon Comprehensive Breast Evaluation CenterMassachusetts General Hospital

Associate Professor of SurgeryHarvard Medical School

SurgeonThe Newton-Wellesley Hospital Breast Center

Is Post-Lumpectomy Radiation Necessary in Older Patients?

1.9 cm, ER+, clinical N0 CancerLumpectomyPlusRadiation/BoostTamoxifenSentinel NodeChemotherapy BRCA testing

1.9 cm, ER+, clinical N0 CancerLumpectomyPlusRadiation/BoostTamoxifenSentinel NodeChemotherapyBRCA testing

LumpectomyPlusRadiation/BoostTamoxifen/AISentinel NodeChemotherapyBRCA testing

CALGB 9343Comparison 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 BRadiation Therapy Oncology GroupEastern Cooperative Oncology Group

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

Radiation

Tamoxifen

Tamoxifen

CALGB 9343Opened July 15, 1994Closed February 26, 1999

647 patients Eligible 631 Ineligible 5 Canceled/Never treated 11

Median follow-up 12 years

Patient characteristicsRT+Tam TamTotal treated 317 319

Age >75 176 (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 risk40 and under RT

70 above no RT

LCIS

Radiation decreases local recurrence by ~7%

Does it do anything else?

No RTMastectomyLumpectomyIBTR27RTIBTR641810

Actuarial survival for given ages at entryD. Berry8/28/11

Ultimate Outcome

22 womenWith modern margins and AIs, RT will likely have even less benefitCONCLUSION: In older women, the benefits of radiation after lumpectomy are small

Breast RecurrenceLessUltimate MastectomySameSecond primary cancerSameDistant metastasis SameDeathSameDeath Other Causes SameDeath from breast cancer Same

1.9 cm, ER+, clinical N0 CancerLumpectomyPlusRadiation/BoostTamoxifenSentinel NodeChemotherapyBRCA testing

LumpectomyPlusRadiation/BoostTamoxifen/AISentinel NodeChemotherapyBRCA testing

1.9 cm, ER+, clinical N0 CancerLumpectomyPlusRadiation + BoostTamoxifenSentinel NodeChemotherapy

LumpectomyTam/AI

When does this womanbecome this woman?

22 womenStudy is mature: 12 years Median, Half of patients dead

With modern margins and AIs, RT will likely have even less benefitCONCLUSION: In older women, the benefits of radiation after lumpectomy are small

Breast RecurrenceLessUltimate MastectomySameSecond primary cancerSameDistant metastasis SameDeathSameDeath Other Causes SameDeath from breast cancer Same

1.9 cm, ER+, clinical N0 CancerLumpectomyPlusRT/BoostTamoxifenSentinel NodeChemotherapy BRCA testing

Agreement: Elderly women need less treatmentLumpectomyORTam/AI ORTam/AI/RT

1.9 cm, ER+, clinical N0 CancerLumpectomyPlusRadiation + BoostTamoxifenSentinel NodeChemotherapyBRCA testing

Agreement: Elderly women need less treatment

LumpectomyORTam/AI ORTam/AI/RTContinued discussion: Who are the elderly?

Conclusions

Every elderly woman does not need lumpectomy,sentinel node,RT+Boost,Tam/AI,ChemoBreast irradiation provides less benefit with ageBreast irradiation plus Tam/AI is often excessive

Question: Who are the elderly?

Elderly women need individualized treatment

Axillary recurrence

TamRTTam317319No ax dissection200203Ax Recurrence0 6 (3%)

Benefits of RT are smallN (% at 10 yeas) N (% at 10 years)22 womenStudy is mature: 12 years Median, Half of patients dead

With modern margins and AIs, RT will likely have even less benefit

Breast RecurrenceLessUltimate MastectomySameSecond primary cancerSameDistant metastasis SameDeathSameDeath Other Causes SameDeath from breast cancer Same

In older women, the benefits of radiation after lumpectomy are smallBreast recurrence ~7%Radiate 319 women to avoid 21 in breast recurrencesUltimate breast preservationNSSecond primary cancerNSDistant metastasesNSDeath breast cancerNSDeath from any causeNS21 womenOmitting Radiation in women 70 and above with Clinical Stage I breast cancer is a reasonable alternative for our patients

Managing the elderlyIf mastectomy neededPreop chemo or endocrine possible & neededYes=>TryNo=>Do Mastectomy (With sentinel node)If breast preservation possibleClinically positive nodeLumpectomy/Axillary dissectionTumor ER- or over 2 cmLumpectomy/Sentinel node If Clinical Stage I and ER+If chemotherapy a possibilityDo sentinel nodeIf chemotherapy NOT a possibilitySentinel node optional (Not encouraged)

No RTIBTR20RTIBTR4

No RTMastectomyLumpectomyIBTR20RTIBTR44119

In older women, the benefits of radiation after lumpectomy are smallBreast recurrence ~7%Radiate 319 women to avoid 21 in breast recurrencesUltimate breast preservationNSSecond primary cancerNSDistant metastasesNSDeath breast cancerNSDeath from any causeNS21 women

CONCLUSION: In older women, the benefits of radiation after lumpectomy are smallBreast recurrence ~7%Radiate 319 women to avoid 21 in breast recurrencesUltimate breast preservationNSSecond primary cancerNSDistant metastasesNSDeath breast cancerNSDeath from any causeNS21 womenStudy is mature: 12 years Median, Half of patients dead

With modern margins and AIs, RT will likely have even less benefit

Axillary recurrence

RT & Tam

Tam

317

319

No ax dissection

200

203

Ax Recurrence

0

4 (2%)

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

Morbidity statistically inferior in RT arm Physician assessment Patient assessment4 monthsCosmesisPainTendernessFibrosisSkin color changes Skin color changesBreast edemaBreast edema

1 year CosmesisPainTendernessFibrosisSkin color changesSkin color changesBreast edema Fibrosis

2 years Skin color changesSkin color changesBreast edemaCosmesisFibrosis

4 yearsNo differencesNo differences

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

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

5 YR results verified at 8.2 YRS

Early 1990s: Was RT always needed after conservative surgery?Possible groupsElderlySmall tumorsTamoxifen

Summary of Randomized Trials:Lumpectomy + Tam vs Lumpectomy + Tam + RT

NSABPCanadianCALGBScottishAustrianB-21FylesHughesStewartPotterAgeAny50 and over70 and overAnyAnySize

Summary of Randomized Trials:Lumpectomy + Tam vs Lumpectomy + Tam + RT

NSABPCanadianCALGBScottishAustrianB-21FylesHughesStewartPotterTam16.5%11.5%7%25%3.1%Tam + RT2.8%3.8%1%3%0.2%

Summary of Randomized Trials:Older Women

NSABPB-21CanadianFylesCALGB HughesAge>70>60 > 70Size< 1cm< 1cm< 2cm# of pts100193636Tam7%4.8%7%Tam + RT0 %4.2%1%

Can we Vs should we?

Managing the elderlyLumpectomy 2 cm & ER+Adjuvant treatmentRT plus Tam/AITam/AIRTSentinel nodeIF chemo being considered

> 2 cm &/or ER-Sentinel node plus RTMastectomy

Treating breast cancer in the elderly differently makes medical sense

Or

is discrimination

I cant define elderly, but I know it when I see it.Paraphrase of Supreme Court DecisionPotter Stewart Miller VS California, 1973

2004: Median 5 YrHughes NEJM, 2004

MastectomyLumpectomyIBTRLumpectomy + RTLocal recurrence does not preclude breast preservation

GOALSPrevent Breast RecurrencePrevent Axillary RecurrencePrevent Systemic RecurrencePreserve the BreastMinimize 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 PatientsDead Breast 2 %Dead Other 27%Alive 71%

CALGB 9343: DeceasedDead Breast 6 %Dead Other 94%

For older women these hazards would exceed the estimated benefits Breast Cancer Trialists Collaborative GroupLancet 2000; 355: 175770if 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 YrHughes NEJM, 2004CriticismFU too shortCurves will separateNeed longer FU!

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

FEMALE POPULATION (in thousands) USA - November 1, 1998Age Group138,2005-910-14

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

Age

Ax -

Ax +

35-39

51-65

38-49

50-54

112-140

84-105

70-74

131-192

99-145

Histopathology of Breast Cancer in Relation to AgeCJ Fisher, et al, Guys HopitalBrJCa 75:593,1997

(39

40-49

50-69

(70

Node +

60%

54%

48%

42%

Lymphovascular Invasion

41%

35%

27%

27%

Superimpose 5 + 8.2 Yrs

Can we? Patient factors Dependent on physiologic age

New Approach to Geriatric OncologyShould 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 recurrenceBiologic factors

Decreased local recurrenceDecreased time at risk

Decreased local recurrenceTamoxifen

Local recurrence does not preclude breast preservation

IBTR (Ipsilateral Breast Tumor Recurrence)

SECOND PRIMARY CANCER

TamRTTamTOTAL36 (12%)33 (9%)Breast1210Leukemia12MDS01Lymphoma43Colorectal65Epiglottis10Peritoneum01GI,NOS10Liver02Pancreas01Spleen10Bladder10Endometrium31Lung47Melanoma20

Initial Approach to Geriatric OncologyCan 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. 1981 May 15;47(10):2358-63. Survival following breast cancer surgery in the elderly.Herbsman H, Feldman J, Seldera J, Gardner B, Alfonso 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 ageTumor factors Dependent on chronologic age

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

NSABP B - 06Lumpectomy + Axillary DissectionMastectomy n 719 731 713 IBTR 40.9% 12.4% N/A Survival 65% 71% 68%Lumpectomy + Axillary Dissection & RTvsvs

Early 1990s: Did any group NOT need RT after conservative surgery?ElderlySmall tumorsTamoxifen

RADIATION AFTER AGE 70

No change in survival Decreased local recurrenceBiologic factors in patients over 50Decreased time at riskTamoxifen Local recurrence does not preclude breast preservation

RT: No change in survival

Authorn Follow-up RT No RT Fisher930 10 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 ofsurgery for early breast cancer on local recurrence and15-year survival: an overview of the randomised trialsEarly Breast Cancer Trialists Collaborative Group, Lancet 2005; 366: 20872106By contrast, more than half the 15-yearbreast cancer mortality (and much more than half of anysuch treatment effects on breast cancer mortality)occurred after the first 5 years. Some local treatmentcomparisons (eg, axillary clearance vs effective axillaryradiotherapy; mastectomy vs BCS plus effectiveradiotherapy; post-mastectomy radiotherapy in nodenegativedisease) involved little (10%) absolutedifference in the 5-year risk of local recurrence and, inaggregate, these comparisons also involved littledifference in 15-year breast cancer mortality (figure 5,upper panel).

Decreased local recurrence MILAN TRIAL IIIQuandrantectomy and Axillary Dissection Only Age n Local Recurrence 45 years 6311 (17.5%) 46-55104 9 (8.7%) >55 years 106 4 (3.8%)

NEJM 351: 963, 2004 Fyles (Princess Margaret)

Decreased Time at Risk

NSABP B-14 53 MONTH ANALYSIS IBTR1.9% 4.3% Tamoxifen Placebo Decreased local recurrence: Tamoxifen

No RTMastectomyLumpectomyIBTR

RTIBTR

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

No RTIBTR28RTIBTR6

Concerns regarding this studyPatients 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; 345:1378-1387

Tam 70 and aboveLumpectomy, RT/Boost 40 or younger

Ipsilateral breast from another studyAtypiaIpsilateral 5 year riskIpsilateral 10 year riskTypeADH(n=1233)0.0273540.08439ALH(n=851)0.053390.114086LCIS(n=595)0.0537810.096924Borderline(n=370)0.040020.08236

LCISAtypiaIpsilateral 5 year riskIpsilateral 10 year riskTypeADH(n=1233)0.0273540.08439ALH(n=851)0.053390.114086LCIS(n=595)0.0537810.096924Borderline(n=370)0.040020.08236

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