NcXHF

CONTROVERSIES IN BREAST CANCER NEOADJUVANT THERAPY
comes relative to pattern of postmastectomy radiotherapy
use in 106 women who experienced pCR from neoadjuvant
chemotherapy. 26 The majority of cases were clinical
stage III (70%). When the entire group was analyzed, there
was no signifıcant advantage in LRR in the 72 patients who
were irradiated compared with those who received observed
postmastectomy (p 0.40; Table 1). However,
when only the 74 patients with clinical stage III disease
were analyzed, postmastectomy radiotherapy was associated
with a signifıcantly lower 10-year rate of LRR (7.3% in
the patients who were irradiated vs. 33.3% in those who
did not receive radiotherapy postmastectomy; p 0.040)
and better OS (77.3% for the patients who were irradiated
and 33.3% for the patients who were not irradiated, p
0.0016), leading the authors to recommend routine treatment
for patients with clinical stage III disease, even when
achieving a pCR. 26 Two other studies examined cancer
outcomes retrospectively by postmastectomy use in those
who were downstaged to pathologically node-negative
(ypN0) following neoadjuvant chemotherapy. Le Scodan
et al reviewed 1,054 patients with breast cancer treated
with neoadjuvant chemotherapy at Institut Curie and
René Huguenin Hospitals between 1990 and 2004 to fınd
134 that had ypN0 status after neoadjuvant chemotherapy
and mastectomy. 27 Of the 134 eligible patients, 78 (58.2%)
received postmastectomy radiotherapy and 56 (41.8%) did
not. At a median follow-up time of 91.4 months, the 5-year
LRR-free survival and OS rate was 96.2% and 88.3% with
postmastectomy radiotherapy and 92.5% and 94.3% without
postmastectomy radiotherapy, respectively (p not significant),
and no signifıcant changes in cancer outcomes were
found at 10 years. Another retrospective study conducted in
nine Korean institutions, identifıed 417 patients with clinical
stage II-III breast cancer who achieved a ypN0 at surgery after
receiving neoadjuvant chemotherapy between 1998 and 2009.
Of these, 151 patients underwent mastectomy, and 105 (69.5%)
received postmastectomy radiotherapy. There was no signifıcant
benefıt in reducing LRR or improving OS in the radiotherapy
group (Table 1). 28 From these studies, it can be observed that
postmastectomy radiotherapy appears to be of most benefıt after
neoadjuvant therapy in those with extensive clinical stage III
disease (T3–4, N2–3), even when a pCR is observed and when
axillary nodes remain pathologically involved.
PATHOLOGIC RESPONSE TO NEOADJUVANT
THERAPY AS A PREDICTOR OF LRR RISK AND NEED
FOR POSTMASTECTOMY RADIOTHERAPY
Evidence supports that neoadjuvant chemotherapy response
is linked to lower rates of subsequent LRR risk in the absence
of postmastectomy radiotherapy. Mamounas et al 29 analyzed
LRR rates in approximately 3,000 women enrolled onto two
NSABP clinical trials evaluating neoadjuvant chemotherapy
(NSABP B-18 and NSABP B-27). Both protocols specifıed
that patients treated with mastectomy were not allowed to
receive any radiotherapy. The combined analysis of these two
trials provides important insight on the rates, patterns, and
independent predictors of LRR after neoadjuvant chemotherapy
and mastectomy. The 10-year cumulative incidence
of LRR was 12.3% for patients who underwent mastectomy
(local, 8.9%; regional, 3.4%). Independent predictors of LRR
postmastectomy, were clinical tumor size, clinical node status,
and pathologic node status/pathologic breast response.
In particular, those with clinically involved nodes before chemotherapy
who had pathologically node-negative disease
(ypN0) at surgery (with or without pCR in the breast) had a
lower LRR than those who were found to have persistent
nodal metastases pathologically. In a small subset of 102 patients
undergoing mastectomy with clinically positive nodes
before neoadjuvant chemotherapy who were downstaged to
ypN0 afterwards, the risk of chest wall and regional nodal
recurrence was between 0% and 10.8% at 10 years. These LRR
rates fıt into a low-risk category of patients who may not experience
a signifıcant benefıt from postmastectomy radiotherapy,
particularly in terms of improved survival, and could be spared
the associated toxicity. It is important to emphasize that the results
of the combined analysis of NSABP B-18 and B-27 are primarily
applicable to patients with clinical stage I to II disease;
55% of the patients presented with cT1–2N0 disease, 20% with
cT1–2N1 disease, and 6% with cT3N0 disease. Only 9% of the
patients presented with cT3N1 disease.
The combined analysis of NSABP B-18 and B-27 supports
that for patients who have positive nodes before neoadjuvant
chemotherapy, the rate of LRR can be modifıed downward if
the nodes become pathologically node-negative after neoadjuvant
chemotherapy (particularly if there is also pCR in the
breast). These fındings are supported by the outcomes reported
in the retrospective studies in those downstaged to
ypN0 after neoadjuvant therapy as described above. 27,28
However, prospective data are needed to ensure omission of
postmastectomy is safe given the extensive data supporting
its benefıt in improving survival for the treatment of nodepositive
breast cancer. 21,22 The NSABP B-51/Radiation Therapy
Oncology Group (RTOG) 1304 phase III clinical trial
(NCT01872975) 30 is designed to answer whether regional radiotherapy
improves the invasive breast cancer recurrencefree
interval rate (local, regional, and distant recurrences and
deaths resulting from breast cancer) in women who present
with clinical N1 axillary node disease (documented pathologically
by needle biopsy) before neoadjuvant chemotherapy
and then become pathologically node-negative at time of
surgery. After mastectomy, patients are randomly assigned
to no radiotherapy or chest wall and regional nodal radiotherapy,
and after lumpectomy, random assignment is to
breast radiotherapy alone or breast and regional lymph node
radiotherapy.
CONCLUSION
In summary, the neoadjuvant setting provides a wealth of opportunities
to identify better treatment strategies through
clinical trials, evaluate new drugs for effıcacy, and improve
locoregional outcomes for individual patients. However, to
fully realize these opportunities, clinical trials must be de-
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