As reported in the Society of Thoracic Surgeons, and multiple other outlets, a newly published study by several surgeons in Germany shows that surgical removal of metastatic breast cancer that has spread to the lungs may improve overall patient survival. The study, by Meimarakis et al. was published in the April 2013 issue of the Annals of Thoracic Surgery.
The Meimarakis study included 81 patients over a twenty-five year period. The study looked at the overall survival time in breast cancer patients with a pulmonary metastasis. The study began in 1992, and data was collected retrospectively to 1982.
Poor median survival despite advances in chemotherapy
Current survival time in these patients ranges from 12 to 24 months. However, the authors note that in up to 23% of these patients, the sole metastatic lesion is in the lung or pleural space. In these patients with pulmonary metastasis alone, the majority survived less than 22 months after diagnosis, despite chemotherapy. The 10 year survival has been previously reported as a dismal 9% in this population in prior studies conducted as M. D. Anderson (Meimarakis, et. al, 2013).
Role of pulmonary metastatectomy in advanced breast cancer
Unlike pulmonary metastatectomy for colon cancer, metastatectomy has been used sparingly in this population and with no clear-cut criteria to distinguish which breast cancer patients would benefit from surgery, surgery in addition to chemotherapy, versus chemotherapy alone.
Aim of study
The authors, at Ludwig-Maximilian University in Munich, Germany attempt to address this deficiency by investigating surgical, pathological and demographic factors that impact survival in this patient population to help determine which candidates would benefit the most from surgical intervention.
The authors looked at a multitude of factors such as presence and type of hormone receptor, histological type, size of both primary and metastatic lesions, the number of metastatic lesions, surgical grade/ resectability and the laterality of these lesions. They also collected and compared additional markers such as CEA, LDH and CA 15-3.
These factors and their impact on survival were analyzed using statistical analysis, Kaplan-Meier estimators, log-rank tests as well as matched pair analysis of 2 year survival (metastectomy vs. standard therapy only). These factors included data from pathological specimens and tumor typing (Meimarakis, 2013).
What makes this study particularly interesting and noteworthy, is the operative inclusions. While patients with local residual disease, additional (non-lung) metastases or recurrent primary breast tumors were excluded, patients with contralateral lung lesions were not.
Selected patient demographics
Total number of patients: 81
Median age: 58.2 (range 28.2 to 76.3)
Breast cancers: Histological types
64.1% invasive ductal carcinoma, 17.2 % with ductal carcinoma in situ? and 18.7% other breast cancer.
Number and size of metastatic lesions:
61 (75.3%) lesions were less than 3 cm in size.
20 (24.7%) of lesions were 3 cm or greater.
The majority (51 (63%) of patients presented with a solitary lung lesion, whereas 30 (37. %) presented with two or more lesions.
Operative procedures
Meimarakis et al. performed a total of 92 operations. These included 71 patients who underwent one procedure, 9 patients for two procedures and 1 patient with three procedures.
All of the patients undergoing more than one procedure had contralateral surgery for newly occurring metastases. (The authors re-operated on patients within 4 to 6 weeks for synchronous metastatic lung lesions.) This is important to remember when reviewing the primary article since the terminology ‘re-do’ operations and repeat operations can be confusing. However, after clarifying with the primary author, there were no completion procedures (i.e. wedge converted to lobectomy based on final pathology) and no returns to the operating room for surgery due to complications. There was no return to the operating room for any procedures on the same side as the original procedure. Thus for clarification, no “re-do” procedures.
All patients underwent resection via anterolateral thoracotomy. However, patients with peripheral, previously unbiopsied nodules were initially approached via VATS with conversion to anterolateral thoracotomy for positive intraoperative pathology.
67 operations were wedge resection, with an additional 10 segmental resections. The remainder of procedures included 7 lobectomies, 7 pneumonectomies and 1 bilobectomy.
Median operating room time was 83 minutes, with a fairly lengthy hospitalization stay (median 9 days, with a range of 3 – 63 days.) Complication rate was 7.6% (3 patients with pneumonia, 4 patients with atelectasis).
Limitations of Study
The median follow-up was only 27.2 months. At the end of this period, 27 of the 81 patients (33.3%) had died. While the published study was lengthy and detailed (10 pages with multiple charts and graphs) much of this was related to discussion regarding receptor status, and existing literature. A clearer, more streamlined algorithmic approach or scoring system utilize to their findings would be more helpful to readers in determining the likelihood of successful outcomes with surgical resection, and for encouraging replication of their research.
Results
Despite the limited number of patients with multiple metastatic lung lesions in this study, the underlying rules of surgical resection remain consistent. Patients who did the best, with the longest overall survival time were patients with complete surgical resection (R0). While patients with a completely resection of a single metastasis lived longer than patients with complete resection of multiple metastases, the R0 patients with multiple metastases had greater median survival than all patients with incomplete resection, regardless of the degree of residual (R1, R2) disease (microscopic or gross disease).
Receptor positive patients with better outcomes
As seen in multiple studies, tumor types were a crucial factor in long-term outcomes; whether estrogen receptor positive (ER+), human growth factor receptor 2 positive (HER2+), progesterone receptor+ (PR+).
Median survival of all patients after metastatectomy was 82.4 months with the greatest median survival time in the 31 patients with + hormone receptor tumors (HR+) at 127.4 months (range 33.2 to 221.6 months). In comparison, the 8 patients with HER+ had a mean survival of 66 months and only 27 months median survival for the 14 triple negative patients)*.
These findings regarding longevity and tumor receptors are similar to those reported by Welter et. al (2008) and others, but the patients from this larger study demonstrated greater longevity, which gives weight to continued study in this area.
In Meimarakis’ work, the presence of pleural infiltration or lymphangiosis carcinomatosis denoted a reduced longevity (32.1 and 34.5 months). This may serve as a better marker of systemic disease for future classification and treatment of advanced breast cancer.
Implications: For breast cancer patients, the discovery of a metastatic lung lesion advances the stage of the disease, drastically changing current treatment options. Most breast cancer patients diagnosed with metastatic disease are not considered surgical candidates even if complete surgical resection is technically feasible.
Meimarakis’s study is one of the larger studies to date, using a large number of prospective patients versus retrospective chart review. This gives a more comprehensive look at a multitude of factors and patient demographics. It serves as an excellent framework for future study in this area.
But, more interesting to our readers is the low incidence of post-operative complications (7 operations; 3 patients with pneumonia, 4 patients with atelectasis).
None of the patients died post-operatively. There were no ‘take backs’ for post-operative complications such as bleeding, prolonged air leak or post-operative infections despite the fact that almost 10% (8 patients) underwent significantly larger procedures such as pneumonectomy or bilobectomy and that all patients underwent thoracotomies versus the smaller VATS procedures. There was no difference in outcomes in this set of patients by procedure (wedge versus pneumonectomy) though Meimarakis notes that “there is a trend to worse survival in case of pneumonectomy during R1/ R2 resection (considering the whole database [Munich Cancer Registry] i.e not only in this group of patients with breast cancer.”
As outcomes appeared independent of the surgical procedure itself; based solely on resectability and tumor type, even larger scale resections such as pneumonectomy may be worthy of consideration during preoperative surgical evaluation, particularly in patients with favorable tumor types with good potential for complete resection.
Future considerations
Using the work of Meimarakis and similar researchers, development of an algorithmic approach may be beneficial to thoracic surgeons and others who encounter pulmonary metastases from breast cancer outside of larger research facilities.
Related case reports: We previously reported a case of metastatic breast cancer that was discovered at the time of surgery, despite the use of multiple imaging and diagnostic modalities. However, in that case, the patient also had local metastases to bone (ribs), which were also resected.
*Please see original article for further detail on patient characteristics and outcomes.
While the data (statistics, patient outcomes) is from the original research of Meimarakis et al., the commentary has been written by writers at Cirugia de Torax and may not reflect the thoughts, considerations and experiences of the primary researchers.
Reference Article
Meimarakis, G., Ruttinger, D., Stemmler, J., Crispin, A., Weidenhagen, R., Angele, M., Fertman, J., Hatz, R. A. & Winter, H. (2013). Prolonged overall survival after pulmonary metastatectomy in patients with breast cancer. Annals of thoracic surgery, April 2013, 1170-1180. [Free full text not available.]
Additional Information
TNM Classification Help: Manual for Cancer Staging
Kycler, W. & Laski, P. (2012). Surgical approach to pulmonary metastases from breast cancer. Breast J. 2012 Jan-Feb;18(1):52-7. doi: 10.1111/j.1524-4741.2011.01176.x. Epub 2011 Nov 20. [no free full text available]. Retrospective data review of 33 patients who underwent pulmonary metastatectomy (1997 – 2002) at the Great Poland Cancer Center, in Poznan, Poland.
Welter S, Jacobs J, Krbek T, Tötsch M, Stamatis G. (2008). Pulmonary metastases of breast cancer. When is resection indicated? Eur J Cardiothorac Surg. 2008 Dec;34(6):1228-34. doi: 10.1016/j.ejcts.2008.07.063. Epub 2008 Sep 27 [free text available]. A review of 47 cases of metastatic breast cancer with pulmonary metastatectomy, Essen, Germany.
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