This journal club presentation summarized the PRIME II randomized controlled trial which evaluated the efficacy of postoperative whole-breast radiotherapy for women aged 65 years or older with early-stage, hormone receptor-positive breast cancer treated with breast-conserving surgery and adjuvant endocrine therapy. The results showed that radiotherapy achieved a significant but relatively small reduction in local breast recurrence at 5 years compared to no radiotherapy. However, the 5-year rate of recurrence was low enough that omission of radiotherapy could be considered for select low-risk patients based on tumor characteristics and patient preferences. Treatment decisions require individualization based on prognostic factors and risk-benefit assessment.

1. JOURNAL CLUB
Dr Bharti Devnani
Moderator- Dr Sushma Agrawal

2. OVERVIEW OF PRESENTATION
 Disease burden overall and in elderly
 Background of the study
 Present study
 Discussion and Review of literature
 Conclusion

3. 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.

4. DISEASE BURDEN IN ELDERLY

5. 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

6. WHY AVOID RADIATION IN THESE PATIENTS??

7. 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

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

9.  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??

10. 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.

11. 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

12. MATERIALS AND METHODS

13. Study design
 Phase 3 randomised controlled trial
 76 specialist cancer centres and district or
regional hospitals in four countries (the UK, Greece,
Australia & Serbia)

14. 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.

15. 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.

16. 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 therapy
Tamoxifen 20mg for 5 yrs
Others forms allowed

17. 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.

18. End points
 Primary endpoint
IBTR
 Secondary endpoints
Regional recurrence,
C/L breast cancer,
Distant metastases,
DFS & OS
 Unplanned analysis based on hormone status

19. 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

20. RESULTS

21. Randomization
1:1
2003-2009

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

25.  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)

26.  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.

27. SALVAGE SURGERY

28. 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 radiotherapy
p=0・026); however, the number of patients in this analysis is small

29. 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

30. DISCUSSION AND REVIEW OF
LITERATURE

31. CALGB Potter et al Fyles et al Italian
Tinterri et
al
PRIME II
No of pts 636 869 769 749 1326
Year 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

32. CALGB Potter et al Fyles et al Italian
Tinterri et
al
PRIME II
Arm Sx+ Tam
Sx+Tam+R
T
Sx+ Tam or
AI
Sx+Tam or
AI +RT
Sx+Tam
Sx+Tam
+RT
Sx
Sx+ RT
Sx+HT
Sx+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 Gy
10 Gy
40-50Gy
10-15 Gy
SS <0.001 <0.001 0.001 0.07 0.002
Hormone Tamoxifen Tam or AI Tam No Tam or AI

33. T1NOMO
70 years
Hormone
positive

34. 9% v/s 2%

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

36. After a median follow-up of 53 months
IBTR 3% v/s 1% (p=0.07).
OS = NS diff
T-2.5 cm
55-75years
Receptor
status-Any
EIC –
Negative
LVI-Negative

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

41. 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

42. 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..]

43. THANK YOU!!

45.  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.

46. HOWEVER
Treatment should be individualized based on
 Grade
 LVSI
 Biological profile-hormone and Her-2
 Proliferative index
 Comorbidities
 Patient preferences
 Risk benefit ratio