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The Effect of Radiotherapy on Local Regional Recurrence among Patients with Pathologic Complete Response to Neoadjuvant Chemotherapy in Breast Cancer
Reviewer: Samuel Swisher-McClure, MD
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: November 3, 2010
Authors: C. E. Fasola, K. D. Godette, M. W. McDonald, R. M. O'Regan, A. B. Zelnak, J. C. Landry, M. A. Torres.
Affiliations: Emory University School of Medicine, Atlanta, GA. Department of Radiation Oncology, Winship Cancer Institute of Emory University, Atlanta, GA. Department of Radiation Oncology, Indiana University School of Medicine, Indianapolis, IN. Department of Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA. Department of Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA. Department of Radiation Oncology, Winship Cancer Institute of Emory University, Atlanta, GA.
- Neoadjuvant chemotherapy is increasingly used in the management of locally advanced breast cancer and in select Stage I, II tumors.
- The NSABP B-18 trial randomized 1,523 women with breast cancer to either 4 cycles of AC chemotherapy pre-operatively vs. post-operatively. After 9 years of follow-up, both groups were found to be equivalent in terms of disease free survival (DFS), distant metastasis free survival (DMFS), and overall survival (OS).
- Retrospective data demonstrates that pathologic complete response (pCR) after neoadjuvant chemotherapy is an important prognostic indicator
- A study published by Kuerer et al. (JCO, 1999) analyzed outcomes in 372 patients with locally advanced breast cancer receiving neoadjuvant chemotherapy with AC x4. Five-year OS was found to be significantly higher in patients with a pCR vs. those with less than pCR (89 vs. 64%).
- Post-mastectomy radiation therapy (PMRT) has been shown to reduce local regional recurrence rates (LRR) and improve overall survival (OS) in multiple randomized trials (Danish 82b NEJM 1997, Danish 82c Lancet 1999, British Columbia Trial JNCI 2005).
- NCCN guidelines recommend PMRT for patients with T3 disease or ? 4 positive axillary lymph nodes. The management of patients with 1-3 positive axillary lymph nodes remains an area of controversy and the suggestion has been to enroll such patients on clinical trials when possible.
- However, indications for PMRT following pCR to neoadjuvant chemotherapy remain to be defined.
- The aim of this study was to evaluate the rates of LRR among pCR patients treated with breast conserving therapy (BCT) or mastectomy with or without radiation (XRT) after neoadjuvant chemotherapy.
- This was a retrospective observational cohort study that examined outcomes of women with breast cancer treated with neoadjuvant chemotherapy and surgery with or without XRT from March 1997 to January 2010.
- In total, 378 patients with breast cancer were analyzed.
- All patients received neoadjuvant chemotherapy consisting of doxorubicin-based (92%) or taxane-based (8%) regimens.
- Patients then underwent either breast conserving surgery followed by XRT (n = 168, 45%) or modified radical mastectomy (n =207, 55%) with (n = 144, 70%) or without PMRT (n = 63, 30%).
- Pathology was reviewed at Emory University Hospital and pCR was defined by the MD Anderson Cancer Center definition of no residual invasive disease within the tumor specimen or axillary lymph nodes.
- Median follow-up time was 41 months.
- All analyses were performed using SAS software, version 9.2 (SAS Institute, Cary, NC).
- Characteristics of the Study population
- Median age at diagnosis was 49 years (range: 22-84).
- The clinical stage at diagnosis was I in 4 (1%), IIA in 122 (36%), IIB in 103 (30%), IIIA in 87 (25%), IIIB in 25 (7%) and IIIC in 4 (1%) patients.
- A greater proportion of patients within the BCT group had stage II disease while a greater proportion of patients within the mastectomy group had stage III disease.
- There was also a greater proportion of ER/PR – tumors within the PMRT group compared to the no PMRT group.
- Otherwise the two groups were balanced with respect to age and tumor grade.
- Of the 378 patients, 72 (19%) achieved a pCR to neoadjuvant chemotherapy, 40 (56%) of whom were treated with BCT and 32 (44%) with mastectomy (n = 22 in PMRT group, n = 10 in non-PMRT group).
- Mastectomy patients who achieved pCR did significantly better at 3 years than those who did not.
- DFS 91% vs. 65%, p = 0.007
- OS 100% vs. 72%, p =0.003
- BCT patients who achieved pCR compared to those who did not had no difference in observed outcomes at 3 years.
- Local control (LC) 97% vs. 93%, p = 0.8
- DFS 86% vs. 81%, p = 0.5
- OS 90% vs. 95%, p = 0.8.
- Among all mastectomy patients, XRT improved local control (95% vs. 83%, p = 0.06) with the most common site of recurrence being chest wall (n = 5, 56%) followed by axilla (n = 2, 22%) and supraclavicular fossa (n = 2, 22%).
- The clinical stage of mastectomy patients who did not receive XRT and experienced a LRR was IIA in 2 (22%), IIB in 5 (56%), IIIA in 1(11%) and IIIB in 1(11%).
- Among pCR post mastectomy patients, XRT was associated with a trend towards improved outcomes at 3 years.
- LC 100% vs. 89%, p = 0.3
- DMFS 100% vs. 78%, p = 0.08
- Mastectomy patients who achieve a pCR to neoadjuvant chemotherapy have high rates of local regional recurrence and may benefit from radiation therapy.
- Further studies regarding the role of radiation therapy in mastectomy patients following neoadjuvant chemotherapy are needed.
- This is a retrospective observational study that examines clinical outcomes in women treated with neoadjuvant chemotherapy followed by BCT or mastectomy with or without PMRT.
- The data suggest that although women who have a pCR after neoadjuvant chemotherapy have a better prognosis than those who do not, the addition of PMRT following was associated with a trend towards improved local control and DMFS.
- This suggests that for women with locally advanced breast cancer at initial presentation, PMRT should remain the standard of care even when a path CR is achieved with neoadjuvant chemotherapy.
- A more detailed assessment of axillary lymph node involvement prior to the initiation of systemic therapy either with MRI, axillary ultrasound and FNA biopsy, or sentinel lymph node biopsy may be helpful in determining the need for PMRT in advance.
- The limitations of this study include:
- The retrospective nature of the data, which creates the potential for a selection bias when comparing cohorts of patients who were treated with or without PMRT.
- The relatively small sample size with a total of 32 patients who had a pCR and were then treated either with or without PMRT. This limits the statistical power of the study to detect differences between the patient cohorts.
- Ultimately, this clinical question would need to be evaluated in a prospective randomized trial in order to obtain more definitive data to guide treatment decisions.