The Explanation Behind the Observation?

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.[6] 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.

For example, the American College of Surgeons Oncology Group Z0011 study (axillary lymph node dissection [ALND] vs no ALND for a positive sentinel lymph node) and the Radiation Therapy Oncology Group 9915 study (postmastectomy external-beam radiotherapy vs observation for one to three positive lymph nodes) addressed admittedly important questions in much larger and distinct populations, but both were closed due to poor accrual. Therefore, we estimate that only 5% of patients might accept the proposed randomization, and at best, only about 175 patients per year might enter such a trial, assuming universal participation by all of the cooperative groups.

Endpoints would also be problematic. In this case, survival is the only valid endpoint. Given the vast heterogeneity of tumor burden, disease biology, and available systemic therapies, this trial would have to be enormous to ensure reliable statistical analysis to avoid alpha and beta errors.

These considerations also raise the issue of cost. At a time when research dollars are at a premium, clinical trialists' groups have had severe budgeting restrictions and randomized trials are being discontinued due to a lack of funding, one wonders whether mounting such a trial to address an issue that affects a relatively small population is worth the expense.

Why Might Removal of the Primary Improve Survival?

Before proceeding with a costly and risky randomized trial, there are important questions to ask. If there is a reason other than selection bias to explain these results, what could it be? This central issue is absent from Dr. Khan's review. Why would the removal of one foci of cancer, in the face of many others, prolong survival? Asking this question highlights the many unknowns regarding the complex interactions between the primary tumor, the metastases, and the host. There are several possible explanations:

• Continued Dissemination of Disease-One possibility is that the presence of the primary tumor is a continuous source of metastases. This would presume that systemic spread from the metastatic lesions is less likely. Is this concordant with the present stem-cell theory of breast cancer? The presumption would be that-at least in some patients-the cancer stem cells are restricted to the primary tumor. If it is stem cells that spread from the primary tumor to distant sites, where they continue to give rise to malignant cells with metastatic potential, then it seems unlikely that removal of the primary tumor would improve survival. How the stem cell theory fits into the scheme of breast cancer progression and metastasis has not been well defined.[7-9] Further investigation of stem cells in metastases may shed light on this clinical observation.

• Immunologic Factors-Another possibility is that removal of the primary tumor leads to increased immune recognition and control of metastatic disease by components of the immune system. To support her argument, Dr. Khan uses the example of renal cell carcinoma (RCC), where in a prospective randomized trial, nephrectomy improved survival in stage IV patients undergoing immunologic therapy.[10] Spontaneous regression of RCC metastases do occur after nephrectomy, suggesting an immunologic process associated with tumor debulking.[11] This may be mediated by changes in lymphocyte phenotypes, diminished immunosuppression or cytokine-mediated changes in NK cell activity.[12]

Could these same changes be responsible for an improved survival in stage IV breast cancer after removal of the primary tumor? Renal cell carcinoma (along with melanoma) is uniquely associated with the immune system, and metastatic RCC is typically resistant to conventional chemotherapy. Breast cancer, however, is quite the opposite, with excellent response rates to systemic therapy but no strong evidence for being a particularly immunogenic tumor. Immunotherapy, while demonstrating a significant impact on RCC, has had little success in the treatment of breast cancer.[13] However, there is much we don't know regarding breast cancer and the immune system, and more research is certainly warranted.

• Growth Factors Secreted by the Primary Tumor-A third explanation lies in the possible control over distant growth exerted by the primary tumor. Tumors produce and secrete any number of factors that influence the surrounding stroma, vasculature, and components of the immune system. These factors allow for the growth of the primary tumor, but may also have effects on distant disease. If the primary tumor releases growth factors essential to the other sites of disease, then it is feasible that removal of the primary could have a beneficial effect on the patient, depriving metastatic foci of essential factors.

Could this be at play in the results reviewed by Dr. Khan? This would actually contradict the present data. Evidence suggests that primary tumors secrete antiangiogenic and growth inhibitors that help to control the growth of distant sites of disease.[14-16] Removal of the primary tumor may in fact increase the growth kinetics of distant disease by taking away a source of antiangiogenic and antiproliferative mediators.[17-19]

Conclusions

The superb review by Dr. Khan highlights how much we don't know regarding the associations, if any, between primary tumors and distant metastases. More information is needed on how primary tumors develop and spread, how stem cells function, how cancer evades the immune system, and how factors secreted by the tumor affect both the host and distant sites of disease. We are accustomed to going from "bench to bedside," translating preclinical data to the clinic. However, there are times when it is prudent to go from "bedside to bench," attempting to explain clinical observations through basic science. We suggest that this is one of those times. If we believe that the results of these retrospective reviews are not due to bias, then it is incumbent upon us to examine the science behind the observation.

Before proceeding with a randomized trial, it may be more prudent to focus on the correlative science, which might provide leads to a more efficient prospective trial. Do stem cells metastasize and do distant sites of disease have the same potential to generate metastases? By what mechanisms does surgery on the primary tumor influence the components of the immune system? What factors are secreted by the primary tumor, and how does this impact distant disease? We may be better off designing a prospective study of patients with stage IV undergoing surgery, and correlating their outcome with changes in serum growth factors, cytokines, antibodies, infiltration of the distant sites by lymphocytes, or any number of other possible mediators of this effect. In this way we may not only better understand the biology behind the theory, but better select which patients may benefit from surgery in the face of stage IV disease.

-Michael S. Sabel, MD, FACS
-Daniel Hayes, MD

References:

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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 Oncol24:2743-2749, 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 Oncol13:776-782, 2006.

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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.

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19. Demicheli R, Valagussa P, Bonadonna G: Does surgery modify growth kinetics of breast cancer micrometastases? Br J Cancer 17:490-492, 2001.