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praeoperative Chemotherapie des Mamma - Karzinoms |
| allgemeines |
|
Gepardo |
GEPARDO, GEPARDUO, GEPARTRIO,
GEPARQUADRO, GEPARQUINTO GeparQUINTO GeparSixto GeparSepto
GeparOcto GeparOLA
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CALGB 40603 (Alliance) |
Carboplatin and/or bevacizumab to neoadjuvant once-perweek paclitaxel followed by dose-dense doxorubicin and cyclophosphamide(5) |
AZURE |
praeoperative Chemotherapie +- Biphosphonat |
| NSABP B-18 |
praeoperative Chemotherapie des Mammakarzinoms |
| CREATE-X |
Adjuvant Capecitabine for Breast Cancer
after Preoperative Chemotherapy |
| NSABP B-27 |
praeoperative Chemotherapie des Mammakarzinoms: 4x AC versus 4x
AC -> 4x Tax versus 4x AC -> OP -> 4x Tax |
| Quellen |
1.) Fisher B, et al.:
Effect of preoperative chemotherapy on local-regional disease in women with
operable breast cancer: findings from National Surgical Adjuvant Breast and
Bowel Project B-18.
JCO 15(1997):2483-2493
2.) Fisher B, et al.:
Effect of preoperative chemotherapy on the outcome of women with operable breast
cancer.
JCO 16(1998):2672-2685
3.) Bear HD, et al.:
The effect on tumor response of adding sequential preoperative docetaxel to
preoperative doxorubicin and cyclophosphamide: preliminary results from National
Surgical Adjuvant Breast and Bowel Project Protocol B-27.
JCO 21(2003):4165-4174
4.) Bear HD, et al.:
Sequential preoperative or postoperative docetaxel added to preoperative
doxorubicin plus cyclophosphamide for operable breast cancer: National Surgical
Adjuvant Breast and Bowel Project Protocol B-27.
JCO 24(2006):2019-2027
5.) Sikov WM, Berry DA, Perou CM, et al.:
Impact of the addition of carboplatin and/or bevacizumab to neoadjuvant once-perweek paclitaxel followed by dose-dense doxorubicin and cyclophosphamide on pathologic complete response rates in stage II
to III triple-negative breast cancer: CALGB 40603 (Alliance).
J Clin Oncol 2015; 33: 13-21.
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Mamounas et al.
Predictors of locoregional recurrence after neoadjuvant
chemotherapy: Results from combined analysis of National Surgical Adjuvant
Breast and Bowel Project B18 and B27.
J Clin Oncol 2012. (1)
Early randomized trials evaluating neoadjuvant, or preoperative, chemotherapy hoped to demonstrate an improvement in overall survival by targeting subclinical metastatic disease at an earlier time point.
Although survival outcomes were ultimately found to be equivalent in these studies 2, 3, 4, significant increases in the rates of breast-conserving therapy due to tumor downstaging were noted.
This effect, in conjunction with the opportunity to observe “real-time” disease response, promoted the widespread adoption of this clinical tool.
For example, in a subset of patients with biologically aggressive disease (estrogen receptor/progesterone receptor/HER2-, HER2+), chemotherapy response can be profound and is associated with better survival outcomes.
In contrast, the link between chemotherapy response and locoregional outcomes remains relatively uncertain.
Pathologic features that have classically been associated with a higher risk of locoregional recurrence (LRR) are the same features that predict for a more significant chemotherapy response.
Therefore, in the absence of robust data, this biomarker has not been routinely adopted as a determinant of radiation benefit.
However, in the November 2012 issue of the Journal of Clinical Oncology, Mamounas and colleagues report the highest-quality data available to date on this issue, from the National Surgical Adjuvant Breast and Bowel Project (NSABP)
B18 and B27 randomized trials.
Although locoregional outcomes were not a primary study endpoint, data on LRR as a first event were gathered prospectively to inform the primary endpoint of relapse-free survival.
Patients on these trials had operable cT1-T3, N0-1 breast tumors and were treated with chemotherapy (doxorubicin/cyclophosphamide [AC] alone or followed by neoadjuvant/adjuvant docetaxel) before lumpectomy (64%) or mastectomy (36%) and axillary node dissection.
Nodal status before chemotherapy was determined clinically and was not pathologically confirmed.
Patients undergoing lumpectomy received radiation to the whole breast (without directed treatment to the regional nodes), and those who underwent mastectomy received no radiation.
Of note, 29% of the patients in B27 had T3 tumors, and 27%-30% of patients in both trials were clinically node positive.
In fact, almost 50% of the 2346 women in B27 could have been considered for postmastectomy radiation therapy on the basis of clinical stage.
Presumably, a substantial additional portion was pathologically node positive. However, at the time these trials were initiated, NSABP protocol dictated no postmastectomy radiation therapy
because the available data were concerning for increased morbidity with radiation therapy and predated the documentation of a survival benefit.
This consistent approach makes the B18 and B27 datasets particularly useful for documenting rates of LRR in the absence of radiation.
Ten-year LRR for the entire patient cohort was 11.1% (8.4% local; 2.7% regional),
10.3% for those treated with lumpectomy and breast radiation, and
12.6% for patients treated with mastectomy and no radiation.
Locoregional recurrence rates were significantly reduced, from 12.2%-14.3% in the 2 AC arms to 8.5% (neoadjuvant, P=.02) or 9.5% (adjuvant, P=.08) with the addition of neoadjuvant/adjuvant
docetaxel, respectively.
In the small number of patients undergoing mastectomy with pathologic complete response, only 1 recurrence was seen in 94 patients, regardless of tumor size and clinical nodal status.
Age, clinical T stage, clinical N stage, and pathologic response were all independent predictors of LRR on multivariate analysis.
This is the first evidence of what will become a common theme from this dataset—both clinical and pathological stage remain
relevant in estimating LRR risk. The authors subsequently expand on this theme
with additional subgroup analyses that ultimately result in 2 LRR nomograms, 1
for patients treated with breast-conserving therapy and 1 for those treated with
mastectomy. From these nomograms, 4 essential groups emerge. First, there are
clinically node-negative patients with a robust chemotherapy response, who seem
to have a low risk of LRR. The numbers are small, but this group’s minimal risk
suggests that there may be little benefit from regional nodal or postmastectomy
radiation therapy. At the other end of the spectrum, there are clinically
node-positive patients with residual nodal involvement after chemotherapy, who
seem to have a substantial LRR risk, across the spectrum of age and tumor size.
These patients seem to have sufficient risk to be offered locoregional radiation.
Finally, there are 2 groups with intermediate risk: clinically node-positive
patients with a robust chemotherapy response, in whom chemotherapy response may
serve to identify a lower risk of LRR, and clinically node-negative patients
with residual nodal disease after chemotherapy, who may have higher LRR risks
than previously appreciated in the adjuvant chemotherapy era. Of note, the B18
and B27 trials included only operable breast cancer, and patients with more
advanced nodal and primary disease were not included, so the results should not
be extrapolated to these groups. Indeed, evidence from other sources has
suggested that individuals presenting with locally advanced disease have
substantial risk of LRR even when they have brisk response to neoadjuvant
chemotherapy (5). The results of the present study are relevant for decision
making in the population of patients similar to those enrolled on these studies,
particularly those who present with cN1 disease but are later found to be ypN0.
In summary, this landmark trial has the potential to significantly alter the way
that we think about risks of LRR and therefore, benefit from radiation therapy.
Certainly this trial was not intended to test the utility of radiation therapy
on the basis of chemotherapy response, but it nevertheless provides strong
preliminary data that set the agenda for further research in this area. To
provide level I evidence for decision making in this complex situation, the
national cooperative groups have come together to design 2 complementary
randomized trials. Both trials, which are in the final phases of development,
focus on patients with clinical T1-3, N1 disease who undergo neoadjuvant
systemic therapy. One trial will evaluate, in the potentially low-risk subset of
patients in whom neoadjuvant chemotherapy eradicates axillary nodal disease, the
role of postmastectomy radiation therapy or regional nodal radiation therapy. In
this study, which will be led by the (NSABP, RTOG - Radiation Therapy Oncology
Group, GOG - Gynecologic Oncology Group) committee formed by the recent merger
of the NSABP and Radiation Therapy Oncology Group’s breast committees, patients
with needle biopsy confirmation of axillary involvement before commencement of
neoadjuvant systemic therapy will be enrolled if they experience a complete
pathologic response in the axilla (ypN0) at the time of surgery. Patients who
receive mastectomy will be randomly assigned to postmastectomy radiation therapy
to the chest wall and regional nodes (undissected level III axillary/infraclavicular,
supraclavicular, and internal mammary nodes) or no radiation therapy. Patients
who receive breast-conserving surgery will be randomly assigned to breast plus
regional nodal radiation therapy (undissected level III axillary/infraclavicular,
supraclavicular, and internal mammary nodes) or breast radiation therapy alone.
Thus, this study will provide high-quality evidence to inform patients’
decisions regarding radiation therapy in this increasingly common situation.
Moreover, it may, if it shows little benefit to radiation therapy, establish
neoadjuvant chemotherapy as an approach that can not only improve rates of
breast conservation but also allow for the individualization of radiation
therapy in patients with node-positive disease. The other trial will evaluate
radiation therapy versus surgery for axillary management in the higher-risk
subset of patients with residual axillary disease, who in the study by Mamounas
et al had a risk of LRR exceeding 10%. In this study, to be led by the Alliance
group formed by the merger of the American College of Surgeons Oncology Group,
Cancer and Leukemia Group B, and North Central Cancer Treatment Group, patients
will undergo sentinel lymph node biopsy after completion of neoadjuvant
chemotherapy and will, if the sentinel node is positive, be randomly assigned to
completion axillary lymph node dissection versus directed radiation to the full
axilla. All patients will receive radiation to the breast (after breast
conservation) or chest wall (after mastectomy) and other regional nodal basins (undissected
level III axillary/infraclavicular, supraclavicular, and internal mammary nodes).
Thus, the study by Mamounas et al is an important contribution that has allowed
for the rational design of randomized trials that will provide more definitive
evidence regarding radiation therapy recommendations in the growing population
of patients who receive neoadjuvant chemotherapy. Only through such detailed and
thoughtful analyses of existing data may we achieve our ultimate goals of
appropriately individualizing radiation therapy to maximize benefit and minimize
morbidity and burden. Back to Article Outline References Mamounas EP, Anderson
SJ, Dignam JJ, et al. Predictors of locoregional recurrence after neoadjuvant
chemotherapy: Results from combined analysis of National Surgical Adjuvant
Breast and Bowel Project B18 and B27. J Clin Oncol. 2012;30:3960–3966 View In
Article CrossRef Rastogi P, Anderson SJ, Bear HD, et al. Preoperative
chemotherapy: Updates of National Surgical Adjuvant Breast and Bowel Project
Protocols B-18 and B-27. J Clin Oncol. 2008;26:778–785 View In Article CrossRef
Mauriac L, MacGrogan G, Avril A, et al. Neoadjuvant chemotherapy for operable
breast carcinoma larger than 3 cm: A unicentre randomized trial with a 124-month
median follow-up. Institut Bergonié Bordeaux Groupe Sein (IBBGS). Ann Oncol.
1999;10:47–52 View In Article MEDLINE CrossRef van der Hage JA, van de Velde CJ,
Julien JP, et al. Preoperative chemotherapy in primary operable breast cancer:
Results from the European Organization for Research and Treatment of Cancer
trial 10902. J Clin Oncol. 2001;19:4224–4237 View In Article McGuire SE,
Gonzalez-Angulo AM, Huang EH, et al. Postmastectomy radiation improves the
outcome of patients with locally advanced breast cancer who achieve a pathologic
complete response to neoadjuvant chemotherapy. Int J Radiat Oncol Biol Phys.
2007;68:1004–1009
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