ROLE OF NEOADJUVANT CHEMORADIATION IN LOCALLY ADVANCED BREAST CANCER

1. NEOADJUVANT CHEMORADIATION IN BREAST CANCER:
CHERRY PICKING from evidence
DR KANHU CHARAN PATRO
MD,DNB[RADIATION ONCOLOGY],MBA,FAROI,PDCR,CEPC
1/19/2021 1

2. If someone cherry-picks things, they choose
the best ones from a group of them, often in a
way that other people consider unfair
CHERRY-PICKS
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3. 1/19/2021 3
My topic is like this

4. Usual sequence
NACT
SURGERY
RADIATION+1/19/2021 4

5. • Neoadjuvant systemic therapy improves surgical outcomes
• New therapeutic approaches that result from neoadjuvant trials
ideally demonstrate benefits in terms of pathologic complete
response and event-free and overall survival.
• Downstaging with neoadjuvant therapy enables more women to
undergo breast conservation with lumpectomy and breast
radiotherapy.
• Locoregional cancer outcomes comparable to mastectomy are
expected from breast conservation in appropriately selected
patients after neoadjuvant therapy.
• Postmastectomy radiotherapy appears to be of most benefit after
neoadjuvant therapy in those with extensive clinical stage III breast
cancer (T3–4, N2–3).
• Tailoring the extent of locoregional therapy necessary for those
who downstage to pathologically node negative after neoadjuvant
therapy is evolving and clinical trials are ongoing.
Key points in NACT practice
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6. Flipping the sequence
NACT+RT
SURGERY
+/-HT1/19/2021 6

7. Flipping the result
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I will not leave the white house
Can we change our practice?

8. But Why?
• NOT HAPPY WITH RESULT?
• NOT HAPPY WITH TOXICITY?
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9. NOT HAPPY WITH RESULT?
• NON RESPONDERS?
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10. NOT HAPPY WITH TOXCITY?
• CAPSULAR CONTRACTURE?
• VOLUME LOSS?
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11. EXTRAPOLATING FROM OTHER?
•Rectal cancer
•Sarcoma
•Esophagus carcinoma
•Lung cancer
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12. What are the available evidence?
• Retrospective studies
• Pilot studies
• Phase ll data
• Metanalysis of those studies
• No proper prospective studies
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13. RETROSPECTIVE STUDY
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14. GPS TRACKING OF
STUDY
STUDY CENTRE Department of Radiation Oncology, Gustave Roussy,
France
STUDY PERIOD Between 1970 and 1984
TYPE RETROSPECTIVE STUDY
END POINTS ANALYSED 1. Locoregional control,
2. Disease-free survival (DFS)
3. Overall survival(OS)
4. Pathological complete remission (PCR)
5. Predictors thereof
6. Immediate safety.
PATIENTS 187 patients with a median age of 49
MEDIAN FOLLW UP 32 YEARS
TREATMENT PROTOCOL Hypofractionated RT to the whole breast, ipsilateral
supraclavicular fossa and axilla the internal mammary
(45 Gy TO 50Gy/18 # of 2.5 Gy/34 days) systematically
followed by a MRM with an AD
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15. TREATMENT DETAILS
RADIATION DETAILS 1. RT, performed with a Cobalt-60 unit,
2. Whole breast, ipsilateral supraclavicular fossa and
the axilla, delivered 45 Gy in 18 fractions of 2.5 Gy,
one fraction a day, 4 days a week.
3. The ipsilateral internal mammary chain received a
total dose of 45 TO 55 Gy
SURGERY DETAILS 1. A modified radical mastectomy (MRM) with an AD
was systematically performed at least 4 weeks after
the completion of radiotherapy, whatever the
tumours response.
CHEMOTHERAPY
DETAILS
1. No patient received preoperative chemotherapy or
endocrine therapy.
2. Postoperative chemotherapy (CMF or anthracycline-
based regimens) was prescribed according to
institutional guidelines at that time
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16. ELIGIBLE PATIENT
DETAILS
T SATGE 1. T2 tumours with a clinical doubling time of less than 6 months
2. Inoperable T3 bulky tumours
3. Non-inflammatory T4 tumours
N STAGE 1. Palpable fixed N2 axillary nodes
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17. Pathological analysis
Pathology 1. Retrospectively, the hormone receptor (HR) status assessed by
immunohistochemistry and the HER2 status assessed by
immunohistochemistry on the biopsy and mastectomy
specimens were centrally reviewed.
2. Missing data were due to exhausted histological specimens.
3. The cut-off for HR positivity was 10% of positive tumour cells
exhibiting nuclear staining.
4. HER2 positivity was defined as a score of 3
5. A pCR at surgery was defined as the absence of invasive or in
situ carcinoma in the breast (ypT0) and axillary nodes (ypN0)
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18. Follow up DETAILS
Follow up 1. The 30-day morbidity and mortality following surgery were
collected from patient files and defined as any event
requiring medical intervention.
2. Toxicities were classified according to the CTCAE V4.03 .
3. The patients had a clinical follow-up every 6 months for 5
years, and annually thereafter.
4. A mammography was performed once a year.
5. Follow-up data were last updated in June 2014.
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19. Statistical analysis-1
1. The median follow-up was calculated with the inverted Kaplan Meier method .
2. Tumor event rates were calculated from the first day of radiotherapy to the
date of diagnosis of the event (local or regional recurrence, or contralateral BC,
or distant metastasis).
3. DFS and OS were calculated from the initiation of radiotherapy to the
ipsilateral locoregional relapse, distant metastases or death, or censored at the
last follow-up. In the univariate analysis,
4. They used the log-rank test for binary and nominal variables to obtain p-
values, and we performed a trend test in Cox models for ordinal variables.
5. Concerning DFS and OS, we considered interaction with time and age for each
explanatory variable using proportional hazard Cox models.
6. Each model was stratified on age [<40 years old; 40-50; 50-60; 60-70 and 70].
7. Interactions with time of follow-up [5 years and >5 years] and age [<50 and 50]
were considered separately. If both were significant, they were then jointly
considered.
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20. Statistical analysis-2
1. Proportional hazard Cox models were used in the multivariate analysis to
study time to LRR; DFS and OS. For time to LRR, variable selection was
stepwise
2. The significant interactions were taken into account in the multivariable
analysis.
3. All Cox models were stratified on age.
4. The relationship between a pCR and preoperative factors was analyzed with
Pearson c square or Fisher (if the number of patients was small) tests for
categorical variables and the ANOVA test for continuous variables.
5. A logistic regression model was used to study pCR outcomes.
6. All analyses were performed using SAS 9.1e9.3 (SAS Institute Inc., Cary, North
Carolina).
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21. Patient characterstics
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22. • The whole breast, ipsilateral supraclavicular fossa and
the axilla internal mammary chain received a dose of 45
Gy over 34 days with 2.5 Gy per fraction.
• An MRM with an AD was performed after a median
interval of 34 days following the completion of RT
• Postoperative chemotherapy was administered to 58
(31%) patients.
• Ovarian suppression for premenopausal patients was
performed with pelvic RT (12 Gy in four fractions or 15
Gy in six fractions).
• For postmenopausal patients, only 15 (8%) had received
endocrine therapy (tamoxifen) from 1981 after a
biochemical determination of HR
Treatment details
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23. • A pCR (ypT0-ypN0) was achieved in 18 patients
(10%).
• Among those with triple-negative breast cancer
(TNBC - 35), nine achieved a pCR (26%).
• The entire population underwent an AD, with a
median of 10 nodes removed
• A total of 112 patients (60%) had pathological nodal
involvement including 51 patients (27%) with
extracapsular spread (ECS).
• In the multivariate analysis, the TN status was the
only significant predictive factor for a pCR
(OR=5.49, 95% CI [1.87-16.1], p =0.002).
Pathological findings
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24. • The 30-day postoperative complication rate was
19% (n =36).
• Grade 2 dehiscence of the suture occurred in
seven patients (4%). Grade 3 skin necrosis
occurred in eight patients (4%), and nine (5%)
patients required a second surgical procedure for
grade 3 infection or haematoma.
• 10 patients (5%) developed a grade 2 lymphocele.
• During the early postoperative period, one patient
(0.5%) experienced a myocardial infarction and
one patient (0.5%) died 3 days after surgery due to
a pulmonary embolism
Toxicity findings
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25. • 15 patients (8%) developed an LRR: chest wall (n = 8) (4%),
axillary nodes (n = 3) (2%) and supraclavicular (2%) nodes.
• The 5-, 10-, 20- and 30-year locoregional control rates were
94%, 91%, 89% and 89%, respectively.
• No LRR occurred after 10 years.
• More local relapses occurred among TN tumours versus non-
TN tumours (HR Z 3.00, 95% CI [0.80-11.18], p =0.09) in the
univariate analysis.
• In the multivariate analysis, the TN status adjusted on the pN
status was correlated with an LRR (HR = 4.92, 95% CI
[1.16=20.86]; p = 0.03).
• 5 patients developed a contralateral BC (25-year rate: 2.7%).
Local control
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26. • The median DFS of the whole population
was 8 years
• The 10-, 20- and 30-year DFS rates were,
respectively, 47%, 35% and 27%.
• In the multivariate analysis, the independent
negative prognostic factor was pathological
node involvement (ypN0 versus ypN + ECS
versus ypN + ECS+; HR Z 1.57, 95% CI
[1.19-2.06], p = 0.002).
Disease-free survival
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27. • Median OS was 12 years
• 10-, 20- and 30-year OS rates of 55%, 41%
and 25%, respectively
• In the univariate analysis, only the
histological grade and pathological node
involvement were significant.
• In the multivariate analysis, only pathological
node involvement exerted a significant
negative prognostic impact
Overall survival
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28. Overall survival.
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29. Overall survival with nodal
involvement
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30. Long-term Locoregional
control.
This study • 9% of LRR at 10 years
Danish Breast Cancer
Cooperative Group 82b-c trials
• 18-year LRR rate of 8% without distant
metastases was reported with RT versus
14% without RT
EBCTCG meta-analysis, • the LRR rate at 10 years after a mastectomy
plus AD was 26% without locoregional RT
versus 8.1% with RT in pN+, and
respectively 3% and 1.6% in pN0
Conclusion • Rates appear quite similar despite the
worst local prognostic factors in the current
series
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31. Locoregional control.
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32. pCR
This study • 19% of postoperative toxicities
• (10%) achieved a pCR
• pCR was achieved in 26% of TNBC representing half of the
patients with a pCR
• TNBC might be more radiosensitive based on higher pCR
rates
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33. Cautionary notes
1. Although these results should be interpreted with caution because of
potential biases
2. This PreopRT strategy, combined or not with chemotherapy, could be
interesting in specific subpopulations such as TNBC and warrants further
investigation in future trials.
3. Identification and independent validation of gene expression signatures
associated with radiosensitivity could define subpopulations benefiting from
PreopRT alone or combined with systemic treatments
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34. 1/19/2021 34

35. In short summary
1. (SEER) database
2. United States from 1972 to 2012
3. 250,195 female patients
4. Early-stage breast cancer who received RT before
5. Improve disease-free survival without reducing overall survival
6. Partial and complete mastectomies were performed in 94.4% and 5.6% of
patients
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36. Portugal
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37. In short summary
1. This study confirms that NART is an effective downsizing treatment in
inoperable LABC, allowing surgical resection regardless of systemic treatment
performed.
2. There was no correlation between intrinsic subtypes and response, but the
luminal B HER2+ and basal-like have worse prognosis, with a 5 years PFS of
56% and 0% and a 5 years OS of 26% and 18%, respectively
3. Had pCR, 31 (41%)
4. Subgroup analysis showed that pR >90% is correlated with a better OS
(p=0.004).
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38. 1/19/2021 38

39. In short summary
1. GenesisCare Victoria, the Alfred and the Austin hospital
2. Forty-seven LABC patients
3. All patients initially underwent NACT, followed by NART (median dose 50.4 Gy
in 28 fractions) to the breast
4. 13 patients pCR
5. Postsurgical toxicities were graded using Clavien-Dindo classification.
6. This review demonstrated that SR is a safe technique, which has not lead to an
increase in surgical complication rates. Cosmetic outcome has not been
affected by NART. SR can achieve a shorter, simpler reconstructive journey for
patients.
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40. 1/19/2021 40

41. 1/19/2021 41

42. 1/19/2021 42

43. In short summary
1. The majority of the studies used whole-breast radiotherapy with 50 Gy,
conventionally fractionated, and waited 6–8 weeks before surgery.
2. The IBR methods were varied, with both implant and autologous
reconstructions.
3. No intraoperative complications occurred, and the postoperative complication
rates ranged from 3 to 36%.
4. The partial and total flap loss rates were very low.
5. Studies reporting cosmetic outcomes rated the majority of cases as good or
excellent. The pathologic complete response rates ranged from 17 to 55%, and
the locoregional recurrence rates were low (B 10%), with a short follow-up
period
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44. 1/19/2021 44
MD ANDERSON PROTOCOL

45. Brazil1/19/2021 45

46. This study • After neoadjuvant chemotherapy, patients normally receive either
conservative breast surgery or mastectomy followed by radiation
therapy. Some patients achieve a complete response after neoadjuvant
chemotherapy.
• Considering that radiation therapy is an effective treatment for
subclinical microscopic disease, the question arises whether breast
surgery before radiation therapy can be avoided in the subgroup of
patients with complete response after neoadjuvant chemotherapy.
ARM • Radiation: Radiation therapy Radiation therapy to the breast with or
without regional nodal area is performed within 12 weeks after
completion of chemotherapy with conventional dose (25x200cGy).
Additional boost of 16 Gy in the primary involved tumor region.
• Techniques: 3D conformal radiation therapy or intensity modulated
radiation therapy (IMRT).
• Standard systemic treatment for patients with hormonal positive receptor
(hormone therapy for at least 5 years) and HER2 positive (trastuzumab for
1 year)
End point • IBTR is defined from the date from complete response of neoadjuvant
chemotherapy to the date of any ipsilateral locoregional recurrence or
death.
Result • 2025
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47. NeoRad
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48. NeoRad
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49. • Accrual completed
• Locally advanced breast
cancer
• Concurrent chemo
• CMF<CAF<CEF-old
• Triweekly paclitaxel
• 50Gy/25#
• Results awaited
Indian trial
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50. Take home message
1. Not a standard of care
2. Non responders after neoadjuvant chemo can be tried
3. TNBC
4. If you are planning a good reconstruction and cosmesis
5. Chemo unsuitable patients due to medical comorbidity
6. But needs more prospective trials and results from
pending trials
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51. Acknowledgment
1. Dr Pooja N Patel
2. Dr Bhawana Parikh and team
3. Dr Vivek Bansal
4. Audience
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