JOURNAL CLUB

Dr Bharti DevnaniModerator- Dr Sushma Agrawal

OVERVIEW OF PRESENTATION

Disease burden overall and in elderly

Background of the study

Present study

Discussion and Review of literature

Conclusion

DISEASE BURDEN (OVERALL)

GLOBOCON 2012

Perez and Brady’s Principles of Radiation Oncology

Leading cause of cancer death among females, accounting for 23 % (1.38 million) of the total new cancer cases & 14 % (458,400)of the total cancer deaths.

DISEASE BURDEN IN ELDERLY

WHY THIS ISSUE IS IMPORTANT

Rising incidence (particularly in elderly)

Increasing use of breast conservation surgery in elderly women

Increasing life expectancy of women :85-90 years [Western world]

Recurrence rates low (<5%) but increases with increasing duration of follow up

Radiation decreases the risk of local recurrences in these population of patients

WHY AVOID RADIATION IN THESE PATIENTS??

LOW RISK GROUP (AGE IS AN IMP RISK FACTOR)

Conclusion- Radiotherapy may be avoided in patients older than 65. and may be optional in women aged 56-65 years with negative nodes.

Veronesi U et al. Ann Oncol 2001;12:997–1003

Survival benefit only applied if the difference in IBTR was > 10%

Elderly women have fewer local recurrences.

Survival benefit only if IBTR > 10% [EBCTCG]

Tend to have estrogen sensitive tumors so tamoxifen more efficacious.

Mortality is mostly due to non-breast cancer related causes.

Half of the local recurrences can be salvaged by lumpectomy again.(Mastectomy free survival is equal)

WHY AVOID RADIATION IN THESE PATIENTS??

WHY AVOID RADIATION IN THESE PATIENTS??

Availability of radiotherapy facilities

Convenience of patients

Rationalisation of RT division workload

Psychological advantages for the patient

Reducing economical burden to the patients and society.

NEED OF THE PRESENT STUDY Trials (NSABP-21) had shown benefit of addition of radiotherapy to

tamoxifen in BCS patients (LR in BCS+TAM vs. BCS+RT vs. BCS+RT+TAM: 17%, 9%,3%)

CALGB Study showed at 5 years of follow up showed LR risk in RT versus no RT as 1% versus 4% (p<0.001)

Despite the low recurrence rates reported in CALGB trial, the practice changed little [Giordano SH. J Clin Oncol 30:1577-1578, 2012]

Other studies like BASO-II, German Breast Cancer Study Group included patients with younger population (45-75 years)

A need for further study in these subset of patients (elderly low risk group) mandated further studies: PRIME II

MATERIALS AND METHODS

Study design Phase 3 randomised controlled trial 76 specialist cancer centres and district or

regional hospitals in four countries (the UK, Greece, Australia & Serbia)

Inclusion criteria

Age > 65 years T1–T2 (up to 3 cm ) N0 M0 Hormone receptor-positive Clear excision margins (≥1 mm) Hormone treatment (Adjuvant or

Neoadjuvant) Grade III / LVI but not both.

Exclusion criteria

< 65 years

H/o previous in-situ or invasive breast cancer of either breast.

Women with current or previous malignant disease within the past 5 years, other than non-melanomatous skin cancer or carcinoma in situ of the cervix.

HER2 status was not recorded as this marker was not routinely assessed at the start of the trial.

RT dose fractionation Conventional # of 50 Gy/ 25# Hypofractionationated RT 40Gy /15 #

allowed.(No of patients receiving a particular # not

mentioned)Boost Electrons 10-15 Gy Implant 20 Gy to 85% reference isodose)

Hormone therapyTamoxifen 20mg for 5 yrsOthers forms allowed

Follow-up

Follow-up was for 10 years Consisted of annual clinic visits, examination

and mammography for at least 5 years beyond this time, either a clinic visit or a

phone call to the patients’ primary health care doctor to ascertain their health status, in addition to follow-up mammography.

End points

Primary endpoint IBTR

Secondary endpoints Regional recurrence,C/L breast cancer,Distant metastases, DFS & OS

Unplanned analysis based on hormone status

Statistical analysis

Based on null hypothesis

A difference in ipsilateral breast tumour recurrence of at least 3% (2% with radiotherapy and 5% without radiotherapy) at 5 years (80% power, 5% level of signifi cance)

Sample size – 588 per group

RESULTS

Randomization1:1

2003-2009

IBTR

1.3 %(6) v/s 4.1%(26)P=0.002

The absolute risk reduction in ipsilateral breast tumour recurrence at 5 years was 2・9% (95% CI 1・ 1–4・ 8).

The number needed to treat was calculated to be 31・ 8 (95% CI 27・ 4–55・ 0), which equates to an adjusted absolute risk reduction of 3・ 1% (95% CI 1・ 8–3・ 6)

Overall survival at 5 years was identical in the two treatment groups (93.9% v/s 95% p=0.34).

At 5 years, no differences b/w treatment groups

were noted in regional recurrences, distant metastases, contralateral breast cancers, or new cancers .

Breast cancer-free survival at 5 years was 94・5% (95% CI 92・ 5–96・ 5) in women allocated to no radiotherapy and 97・ 6% (96・ 2–99・ 0) in those assigned to whole-breast radiotherapy; the diff erence was attributable mainly to IBTR.

SALVAGE SURGERY

SUBGROUP ANALYSIS

In women with poor oestrogen receptor status, six (9%) of 65 women allocated no radiotherapy had local recurrence compared with none of 55 women allocated to whole-breast radiotherapyp=0・ 026); however, the number of patients in this analysis is small

CONCLUSION OF THIS STUDY

Postoperative whole-breast radiotherapy after breast-conserving surgery and adjuvant endocrine treatment resulted in a significant but modest reduction in local recurrence for women aged 65 years or older with early breast cancer 5 years after randomization.

However, the 5-year rate of ipsilateral breast tumor recurrence is probably low

Omission of radiotherapy may be considered for some patients with due consideration of risk

DISCUSSION AND REVIEW OF LITERATURE

CALGB Potter et al

Fyles et al

Italian Tinterri et al

PRIME II

No of pts 636 869 769 749 1326Year of recruitment

1994-99 1996-2004 92-2000 2001-5 2003-9

Age (yrs) >70 PM (mean 66)

>50 PM (55-75) >65

T size T1 < 3 cm T1, T2 <2.5 cm < 3 cm

Hormone receptor status

ER + + + Any +

Grade __ Gr-1,2 -- Any III/LVSI

CALGB Potter et al

Fyles et al

Italian Tinterri et al

PRIME II

Arm Sx+ TamSx+Tam+RT

Sx+ Tam or AISx+Tam or AI +RT

Sx+TamSx+Tam +RT

SxSx+ RT

Sx+HTSx+HT+RT

Follow-up(Median)

10.5yrs 4.5 5.6 5 yrs 5yrs

LR 9% v/s 2% 6 v/s 2 8 v/s 1 3% v/s 1% 4 v/s 1.3%RT # 45G/25#

14G/7#50+10 40 G/16#

12.5 G/5#50 Gy10 Gy

40-50Gy10-15 Gy

SS <0.001 <0.001 0.001 0.07 0.002Hormone Tamoxifen Tam or AI Tam No Tam or AI

T1NOMO70 yearsHormone

positive

9% v/s 2%

Time to mastectomy , distant metastasis and OS did not differ.

After a median follow-up of 53 months

IBTR 3% v/s 1% (p=0.07). OS = NS diff

T-2.5 cm55-75yearsReceptor status-Any

EIC –Negative

LVI-Negative

PROGNOSTIC FACTORS FOR RECURRENCE Age Tumor size Receptor status Grade Lymph node dissection/positivity LVSI Need of a nomogram to predict local

recurrence??

NCCN GUIDELINES 2015

Radiation therapy may be omitted in patients post BCS if [Category 1]: T1 Node negative => 70 years of age Hormone receptor +ve and receiving hormone

therapy

CONCLUSIONS

Adjuvant endocrine treatment alone is a reasonable therapeutic option after breast conserving surgery for women with:

Age> 65-70 years Grade 1 and 2 (NA to grade III) and no LVSI Node-negative Oestrogen receptor-positive tumours (Receiving

hormone therapy) Up to 3 cm in size

[ Patient`s preference, acceptance of risk..]

THANK YOU!!

Postoperative whole-breast radiotherapy achieved a significant but relatively small reduction in local breast recurrence at 5 years in a population of low-risk older patients with early breast cancer after breast-conserving surgery and adjuvant endocrine treatment.

Postoperative whole-breast radiotherapy after breast-conserving surgery and adjuvant endocrine treatment

resulted in a signifi cant but modest reduction in local recurrence for women aged 65 years or older with early breast

cancer 5 years after randomisation. However, the 5-year rate of ipsilateral breast tumour recurrence is probably low

enough for omission of radiotherapy to be considered for some patients.

HOWEVERTreatment should be individualized based on Grade LVSI Biological profile-hormone and Her-2 Proliferative index Comorbidities Patient preferences Risk benefit ratio