It has traditionally been accepted in oncology that once patients have measurable stage IV disease, removal of the primary tumor is unlikely to improve survival. Indeed, this has been likened to closing the barn doors after the horses have left. In this setting, surgery has been considered to be palliative, or to prevent symptoms due to uncontrolled local tumor growth. It is with this in mind that patients with both a primary tumor in the breast and documented metastatic disease are generally not considered for lumpectomy or mastectomy. In her article, Dr. Khan argues that this widely held belief may be a misconception, and that removal of the primary tumor may indeed improve survival.
Dr. Khan presents compelling data that aggressive local therapy in such patients is associated with longer survival—but is this cause or effect? The evidence for this comes from studies that retrospectively reviewed patients with stage IV disease and compared those patients who underwent extirpation of the primary tumor with those who did not.[1-5] Dr. Khan argues that these data support the design and implementation of a prospective, randomized trial to definitively answer this question.
Tangibles and Intangibles
Retrospective, historically controlled clinical research contains inherent biases. Simply because similar, statistically significant results were obtained across several studies representing diverse geographic and cultural populations does not make them more credible. Repeating an inherently biased study 4 or 5 or even 100 times would almost by definition give you the same statistically significant results, especially when the bias is related to patient selection.
Patients deemed less likely to succumb quickly to their disease are offered surgery on the primary tumor more commonly than are less healthy appearing patients. Although most authors have stratified patients by known prognostic factors such as age, site of metastatic disease, type of systemic therapy, or comorbidities, this information is not always available. Even when it is, numerous intangibles may still have led to surgery in one subset of patients over another.
We believe it is also likely that publication bias affects this analysis. In general, investigations that results in negative findings are often less likely to be reported. For example, a presentation of these Surveillance, Epidemiology, and End Results (SEER) data at the 2007 Society of Surgical Oncology meeting prompted a response that in another study, when patients were stratified by the site of their metastases, the advantage of surgery largely disappears. However, this report has not been published.
The 'Gold Standard'
The hallmark of evidence-based medicine is the prospective, randomized clinical trial. Dr. Khan argues that such a trial is not only feasible but of potential benefit. While we are generally quite supportive of prospective, randomized trials, we are not sure that Dr. Khan's estimates are realistic.
First, we have grave concerns about the feasibility of such a trial. Dr. Khan estimates that approximately 7,000 patients are seen in the United States with simultaneous new primary tumors and distant metastases. If we estimate that approximately one-half of these women would not be eligible for this type of study due to confounding factors, then only 3,500 patients would be available for entry. Randomization to highly diverse treatment arms, such as surgery vs observation, has always presented accrual problems, since doctor and patient biases are so strong.
1. Khan SA, Stewart AK, Morrow M: Does aggressive local therapy improve survival in metastatic breast cancer? Surgery 132:620-627, 2002.
2. Rapiti E, Verkooijen HM, Vlastos G, et al: Complete excision of primary breast tumor improves survival of patients with metastatic breast cancer at diagnosis. J Clin Oncol 24:2743-2749, 2006.
3. Babiera GV, Rao R, Feng L, et al: Effect of primary tumor extirpation in breast cancer patients who present with stage IV disease and an intact primary tumor. Ann Surg Oncol 13:776-782, 2006.
4. Gnerlich J, Jeffe DB, Deshpande AD, et al: Surgical removal of the primary tumor increases overall survival in patients with metastatic breast cancer: Analysis of the 1988-2003 SEER data (abstract). Ann Surg Oncol 2007 (epub ahead of print).
5. Blanchard DK, Bhatia P, Hilsenbeck SG, et al: Does surgical management of stage IV breast cancer affect outcome? Breast Cancer Res Treat 100(suppl 1):S118, 2006.
6. Bosworth T: Data may support breast cancer removal in stage IV disease. General Surgery News 34(5):1, 2007.
7. Li F, Tiede B, Massague J, et al: Beyond tumorigenesis: Cancer stem cells in metastasis. Cell Res 17:3-14, 2007.
8. Allan AL, Vantyghem SA, Tuck AB, et al: Tumor dormancy and cancer stem cells: Implications for the biology and treatment of breast cancer metastasis. Breast Dis 26:87-98, 2006-2007.
9. Smalley M, Ashworth A: Stem cells and breast cancer: A field in transit. Nat Rev Cancer 3:832-844, 2003.
10. Flanigan RC, Salmon SE, Blumenstein BA, et al: Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal-cell cancer. N Engl J Med 345:1655-1659, 2001.
11. Bloom HJ: Proceedings: Hormone-induced and spontaneous regression of metastatic renal cancer. Cancer 32:1066, 1973.
12. Dadian G, Riches PG, Henderson DC, et al: Immunological parameters in peripheral blood of patients with renal cell carcinoma before and after nephrectomy. Br J Urol 74:15-22, 1994.
13. Sabel MS, Nehs MA: Immunologic approaches to breast cancer treatment. Surg Oncol Clin N Am 14:1-31, 2005.
14. Peeters CFJM, de Waal RMW, Wobbes T, et al: Outgrowth of human liver metastases after resection of the primary colorectal tumor: A shift in the balance between apoptosis and proliferation. Int J Cancer 119:1249-1253, 2006.
15. Fisher B, Gunduz N, Coyle J, et al: Presence of a growth-stimulating factor in serum following primary tumor removal in mice. Cancer Res 49:1996-2001, 1989.
16. Camphausen K, Moses MA, Wolf-Dietrich B, et al: Radiation therapy to a primary tumor accelerates metastatic growth in mice. Cancer Res 61:2207-2211, 2001.
17. Coffey JC, Wang JH, Smith MJF, et al: Excisional surgery for cancer cure: therapy at a cost. Lancet Oncol 4:760-768, 2003.
18. Oliver RT: Does surgery disseminate or accelerate cancer? Lancet 346:1506-1507, 1995.
19. Demicheli R, Valagussa P, Bonadonna G: Does surgery modify growth kinetics of breast cancer micrometastases? Br J Cancer 17:490-492, 2001.