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Abstract & Commentary
Synopsis: Currently available data that correlate pathologic features identified at the time of mastectomy with increased risk of locoregional recurrence of breast cancer are derived from chemotherapy-naïve patients. This study retrospectively assessed whether such features remain important in patients who received neoadjuvant chemotherapy, and they determined that, regardless of pathologic response, patients with locally advanced breast cancer might benefit from postmastectomy irradiation.
Source: Buchholz TA, et al. J Clin Oncol. 2002;20: 17-23.
Neoadjuvant chemotherapy preceding mastectomy has been explored in various clinical trials over the past several years. Two of the potential advantages to this approach are early treatment of micrometastatic disease, and facilitation of breast conservation in patients with large breast tumors. Given that recommendations regarding adjuvant breast radiotherapy are derived from chemotherapy-naïve patients status postmastectomy, Buchholz and colleagues sought to evaluate whether up-front chemotherapy might alter the indications for radiotherapy or perhaps eliminate the need for it altogether. Their retrospective review of data accumulated from consecutive neoadjuvant chemotherapy trials conducted from 1974-1998 at the M.D. Anderson Cancer Center (MDACC) involved the 150 patients who opted out of postmastectomy radiotherapy among 970 participants.
There were no cases of inflammatory carcinoma among the 150 patients. Twenty percent of participants were younger than 40 years old, 59% were 40-60 years old, and 21% were older than 60 years. Forty-eight percent of patients were estrogen-receptor positive. The breakdown by stage was: 1% stage I, 43% stage II, 23% stage III, and 7% stage IV. The median number of lymph node samples per patient was 15. There were 121 patients (81%) who received adriamycin-based chemotherapy (FAC or VACP), and 29 (19%) received paclitaxel as a single agent. Ninety-two percent of patients received adjuvant chemotherapy, and one third received adjuvant tamoxifen. Median follow-up was measured from the time of diagnosis, and was 4.1 years (r, 1.5-17.7).
Fifteen patients (10%) manifested a complete pathologic response to neoadjuvant chemotherapy. Sixty-two patients (41%) had negative lymph nodes at the time of mastectomy, 28% had 1-3 + lymph nodes (LNs), 20% had 4-9 + LNs, and 7% had > 10 +LNs. Forty-seven percent of patients (n = 70) developed a recurrence, including 23% (n = 35) with locoregional recurrences (LR) and 42% (n = 63) with distant metastases (DM). Among the former, 23 of 35 had isolated locoregional recurrences, and the rest had both LR and DM. Actuarial overall survival was 57% at 5 years, and 40% at 10 years. Actuarial LR was 27% at 5 and 10 years. For patients who presented with clinically negative axillary nodes that were confirmed to be pathologically negative, the LR rate was 3%. In patients with clinically negative but pathologically positive axillary nodes, the LR rate was 14%. For clinically positive, pathologically negative nodes, the LR rate was 63%, and for clinically/pathologically positive nodes, the LR rate was 32%. There was no statistical difference in locoregional recurrence rates for patients with pathologic complete responses in comparison to the rest of the group.
In multivariate analysis, there were 3 factors that correlated with LR. Those were: clinical stage IIIB or higher presentations; > 4 involved LNs at the time of axillary dissection; and use of tamoxifen. Higher stage patients had higher LR rates (P < .001) as did patients with > 4 involved LNs (P = .008). Patients taking tamoxifen had lower LR rates (P = .001).
Buchholz et al concluded that a complete pathologic response to neoadjuvant chemotherapy does not preclude the need for postmastectomy radiation. Both clinical and pathologic findings must be considered when deciding whether there is a role for postmastectomy radiotherapy. Downstaged patients still have a significant risk of locoregional recurrence absent adjuvant radiotherapy.
This retrospective analysis of patients treated with neoadjuvant chemotherapy followed by mastectomy alone is the first time we have seen data regarding locoregional recurrences following omission of postmastectomy radiotherapy. The major thrust of the article addressed the question of whether postchemotherapy pathologic findings should change the way we make recommendations regarding postmastectomy radiotherapy. The typical factors which mitigate in favor of postmastectomy radiotherapy are: primary tumor size > 5 cm; > 4 positive LNs; inflammatory features; and positive surgical margins. These and similar factors were identified by these same researchers from MDACC in a previously published paper reporting their experience with local failures in a series of 1000 women treated with adjuvant chemotherapy after mastectomy without radiotherapy.1 The Danish Breast Cancer Cooperative Groups and British Columbia trials published in 1997 said much the same thing. An updated analysis of the Danish DBCG 82b and c trials reiterated their conclusion that adjuvant systemic therapy does not prevent local recurrences.2
The multivariate analysis reported by Buchholz et al found that tamoxifen protected women against locoregional recurrences. This was the only treatment-related factor found to be important. Patients who used tamoxifen had a 7% rate of LR, while the others had a 36% rate of LR. In the Dutch DBCG 82c randomized trial where adjuvant tamoxifen alone was compared with tamoxifen plus postoperative radiotherapy, there was a 35% LR rate in the tamoxifen arm vs. an 8% LR rate in the combined arm (P < .001).3 Therefore, while tamoxifen may play a role in prevention of LR, radiotherapy remains the mainstay in the postmastectomy population.
For now, while the optimal chemotherapy regimen and delivery sequence is being explored, the MDACC results offer us the first confirmation that our present standards for determining who receives postmastectomy radiotherapy are valid even after neoadjuvant chemotherapy. This is best appreciated by the fact that patients with a complete pathologic response had a statistically similar rate of LR as the other patients in the study.
I am not aware of any ongoing randomized trials that omit radiotherapy in mastectomy patients with locally advanced breast cancer, so studies like this one may be very important sources of data in terms of the decision-making process.
Dr. Kaplan is Acting Chairman, Department of Radiation Oncology, Cleveland Clinic Florida, Ft. Lauderdale, FL; Medical Director, Boca Raton Radiation Therapy Regional Center, Deerfield Beach, FL.
1. Katz A, et al. J Clin Oncol. 2000;18:2817-2827.
2. Overgaard M, et al. Rays. 2000;25:325-330.
3. Overgaard M, et al. Lancet. 1999;353:1641-1648.