- Email: [email protected]
Surgery of the Intact Primary Tumor for Patients Presenting With Metastatic Breast Cancer: Palliation or Cure?
menopausal hormone users in a screened population. J Clin Oncol 21:4314-4321, 2003. 21. Ross RK, Paganini-Hill A, Wan PC, et al: Effect of hormone replacement therapy on breast cancer risk: Estrogen versus estrogen plus progestin. J Natl Cancer Inst 92:328-332, 2000. 22. Olsson HL, Ingvar C, Bladstrom A: Hormone replacement therapy containing progestins and given continuously increases breast carcinoma risk in Sweden. Cancer 97:1387-1392, 2003.
Surgery of the Intact Primary Tumor for Patients Presenting With Metastatic Breast Cancer: Palliation or Cure? Gildy V. Babiera, MD Traditionally, surgical removal of the primary tumor has been considered palliative for patients who have metastatic breast cancer at initial diagnosis. Because stage IV disease is considered incurable, surgery of the primary tumor has heretofore focused on improving quality of life through so-called “toilet” mastectomy for ulceration, bleeding, infection, or pain. However, this traditional view was challenged by Khan and colleagues,1 who were the first to publish findings from the largest retrospective review at the time of a series of patients from the National Cancer Database of the American College of Surgeons. Their findings showed that surgical removal of the primary tumor with negative margins was associated with improved overall survival compared with treatment that did not involve resection of the tumor. This study suggested that surgical removal of the primary tumor, even in patients with advancedstage disease, should be undertaken not just for palliation, but also with the possibility of cure. Considering the impact of such a proposal, it is not surprising that criticisms of this study abounded. Most obviously, as a retrospective analysis, the results were subject to all of the selection biases associated with these types of studies. Moreover, although surgeons are clearly willing to operate on patients whom they judge to have some chance of a better outcome, their willingness to operate on those with a less certain future may be less. In addition, the time between the identification of metastatic disease and surgery of the intact primary breast tumor was not entirely clear in this study; some patients may have had surgery before metastases were identified, and no distinc-
23. Chen WY, Manson JE, Hankinson SE, et al: Unopposed estrogen therapy and the risk of invasive breast cancer. Arch Intern Med 166:1027-1032, 2006. 24. Beral V, Million Women Study collaborators: Breast cancer and hormone-replacement therapy in the Million Women Study [published erratum appears in Lancet 362:1160, 2003]. Lancet 362:419-427, 2003.
tion was made between patients who had had surgery early in the course of the disease and those who had lived with metastatic disease for many years before the surgery was performed. Further, concerns were raised regarding the potential inaccuracies associated with use of a large national cancer database in which the data were not cross-verified. However, in the interval since Khan and colleagues published their findings, 2 studies2,3 have been published, including 1 from our group at The University of Texas M. D. Anderson Cancer Center. This study supports the notion that resection of the primary tumor may improve the outcome of patients with stage IV disease compared with those who do not undergo such resection. To address some of the criticisms associated with the study reported by Khan and colleagues, the M. D. Anderson group limited the study to patients treated only at a single National Comprehensive Cancer Center, derived from a verified database, by surgeons who shared a similar surgical philosophy.2 Most importantly, the time between the diagnosis of metastatic disease and surgical removal of the primary tumor was clearly noted for all patients, and only patients with synchronous metastases and intact primary tumors were evaluated. Moreover, to eliminate other biases, patients who also underwent surgical removal of metastases (eg, brain, lung, and liver metastases) were eliminated from the analysis because such surgery may improve outcomes. In this context, we reported a trend toward extended overall survival time and a statistically significant increase in metastatic progression-free survival time for patients who underwent surgical resection of the intact primary tumor compared with those who did not. However, the median followup time was relatively short (32.1 months), and the median survival duration in both the surgically resected and nonresected groups had not been reached at the time of publication. In another recent investigation, Rapiti and colleagues3 noted similar results. In their retrospective review of patients with
®
Breast Diseases: A Year Book Quarterly Vol 17 No 3 2006
217 217
metastatic breast cancer identified from the Geneva Cancer Registry, these investigators found that patients with stage IV disease who underwent margin-negative resection of the intact primary breast tumor experienced a 40% reduction in risk of death from breast cancer compared with patients who did not receive surgery. This study too was limited by its retrospective nature; however, the authors tried to eliminate many potential biases by excluding patients with short survival time, delayed metastatic disease, and more advanced tumors. So what have we learned from these studies? Most obviously, all 3 studies poked holes in the traditional thinking that surgery is only for palliation for patients who present with an intact primary tumor and metastatic disease. However, the studies also left open the distinct possibility that the association between surgery and improved outcome may have resulted from the fact that those selected for surgery would have done well regardless of whether they had surgery or not because of their intrinsic responsiveness to systemic therapy. Clearly, defining the role of surgery for such patients will require a prospective, randomized clinical trial. The time for such a trial has probably come. Because the accrual of patients for such a study may be difficult given the small population these patients represent, such a trial will necessitate a multi-institutional effort. In addition to redefining the role of surgery, the studies of Khan and collegues,1 Babiera and colleagues,2 and Rapiti and colleagues3 also suggested some interesting aspects of tumor biology. First, removal of the primary tumor in patients with synchronous metastatic disease did not seem to accelerate the growth of metastatic deposits away from the breast, as has been suggested by animal models of other cancer types such as lung cancer.4 Second, these studies suggested that some subpopula-
218 218
®
Breast Diseases: A Year Book Quarterly Vol 17 No 3 2006
tion of patients with stage IV cancer will do well. It is critical that such patients be identified early so that aggressive treatment such as surgery can maximize their survival. For this to happen, clinicians must partner with basic and translational scientists to understand the unique biology of metastatic breast cancer and to develop molecular and genetic profiles that distinguish patients with good or bad prognoses. Surgeons can assist in these studies by framing the appropriate questions and by providing the necessary tissue to the basic scientists who deal with the molecular aspects of breast cancer and its therapies. Ultimately, the integration of surgery, basic science, and medical and radiation oncology is paramount to finding a cure for breast cancer.
References 1. Khan SA, Stewart AK, Morrow M: Does aggressive local therapy improve survival in metastatic breast cancer? Surgery 132:620-626, 2002. 2. 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 13:776782, 2006. 3. 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 May 15 [Epub ahead of print], 2006. 4. O’Reilly MS, Holmgren L, Shing Y, et al: Angiostatin: A novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell 79:315-28, 1994.
Surgery of the Intact Primary Tumor for Patients Presenting With Metastatic Breast Cancer: Palliation or Cure? Gildy V. Babiera, MD Traditionally, surgical removal of the primary tumor has been considered palliative for patients who have metastatic breast cancer at initial diagnosis. Because stage IV disease is considered incurable, surgery of the primary tumor has heretofore focused on improving quality of life through so-called “toilet” mastectomy for ulceration, bleeding, infection, or pain. However, this traditional view was challenged by Khan and colleagues,1 who were the first to publish findings from the largest retrospective review at the time of a series of patients from the National Cancer Database of the American College of Surgeons. Their findings showed that surgical removal of the primary tumor with negative margins was associated with improved overall survival compared with treatment that did not involve resection of the tumor. This study suggested that surgical removal of the primary tumor, even in patients with advancedstage disease, should be undertaken not just for palliation, but also with the possibility of cure. Considering the impact of such a proposal, it is not surprising that criticisms of this study abounded. Most obviously, as a retrospective analysis, the results were subject to all of the selection biases associated with these types of studies. Moreover, although surgeons are clearly willing to operate on patients whom they judge to have some chance of a better outcome, their willingness to operate on those with a less certain future may be less. In addition, the time between the identification of metastatic disease and surgery of the intact primary breast tumor was not entirely clear in this study; some patients may have had surgery before metastases were identified, and no distinc-
23. Chen WY, Manson JE, Hankinson SE, et al: Unopposed estrogen therapy and the risk of invasive breast cancer. Arch Intern Med 166:1027-1032, 2006. 24. Beral V, Million Women Study collaborators: Breast cancer and hormone-replacement therapy in the Million Women Study [published erratum appears in Lancet 362:1160, 2003]. Lancet 362:419-427, 2003.
tion was made between patients who had had surgery early in the course of the disease and those who had lived with metastatic disease for many years before the surgery was performed. Further, concerns were raised regarding the potential inaccuracies associated with use of a large national cancer database in which the data were not cross-verified. However, in the interval since Khan and colleagues published their findings, 2 studies2,3 have been published, including 1 from our group at The University of Texas M. D. Anderson Cancer Center. This study supports the notion that resection of the primary tumor may improve the outcome of patients with stage IV disease compared with those who do not undergo such resection. To address some of the criticisms associated with the study reported by Khan and colleagues, the M. D. Anderson group limited the study to patients treated only at a single National Comprehensive Cancer Center, derived from a verified database, by surgeons who shared a similar surgical philosophy.2 Most importantly, the time between the diagnosis of metastatic disease and surgical removal of the primary tumor was clearly noted for all patients, and only patients with synchronous metastases and intact primary tumors were evaluated. Moreover, to eliminate other biases, patients who also underwent surgical removal of metastases (eg, brain, lung, and liver metastases) were eliminated from the analysis because such surgery may improve outcomes. In this context, we reported a trend toward extended overall survival time and a statistically significant increase in metastatic progression-free survival time for patients who underwent surgical resection of the intact primary tumor compared with those who did not. However, the median followup time was relatively short (32.1 months), and the median survival duration in both the surgically resected and nonresected groups had not been reached at the time of publication. In another recent investigation, Rapiti and colleagues3 noted similar results. In their retrospective review of patients with
®
Breast Diseases: A Year Book Quarterly Vol 17 No 3 2006
217 217
metastatic breast cancer identified from the Geneva Cancer Registry, these investigators found that patients with stage IV disease who underwent margin-negative resection of the intact primary breast tumor experienced a 40% reduction in risk of death from breast cancer compared with patients who did not receive surgery. This study too was limited by its retrospective nature; however, the authors tried to eliminate many potential biases by excluding patients with short survival time, delayed metastatic disease, and more advanced tumors. So what have we learned from these studies? Most obviously, all 3 studies poked holes in the traditional thinking that surgery is only for palliation for patients who present with an intact primary tumor and metastatic disease. However, the studies also left open the distinct possibility that the association between surgery and improved outcome may have resulted from the fact that those selected for surgery would have done well regardless of whether they had surgery or not because of their intrinsic responsiveness to systemic therapy. Clearly, defining the role of surgery for such patients will require a prospective, randomized clinical trial. The time for such a trial has probably come. Because the accrual of patients for such a study may be difficult given the small population these patients represent, such a trial will necessitate a multi-institutional effort. In addition to redefining the role of surgery, the studies of Khan and collegues,1 Babiera and colleagues,2 and Rapiti and colleagues3 also suggested some interesting aspects of tumor biology. First, removal of the primary tumor in patients with synchronous metastatic disease did not seem to accelerate the growth of metastatic deposits away from the breast, as has been suggested by animal models of other cancer types such as lung cancer.4 Second, these studies suggested that some subpopula-
218 218
®
Breast Diseases: A Year Book Quarterly Vol 17 No 3 2006
tion of patients with stage IV cancer will do well. It is critical that such patients be identified early so that aggressive treatment such as surgery can maximize their survival. For this to happen, clinicians must partner with basic and translational scientists to understand the unique biology of metastatic breast cancer and to develop molecular and genetic profiles that distinguish patients with good or bad prognoses. Surgeons can assist in these studies by framing the appropriate questions and by providing the necessary tissue to the basic scientists who deal with the molecular aspects of breast cancer and its therapies. Ultimately, the integration of surgery, basic science, and medical and radiation oncology is paramount to finding a cure for breast cancer.
References 1. Khan SA, Stewart AK, Morrow M: Does aggressive local therapy improve survival in metastatic breast cancer? Surgery 132:620-626, 2002. 2. 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 13:776782, 2006. 3. 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 May 15 [Epub ahead of print], 2006. 4. O’Reilly MS, Holmgren L, Shing Y, et al: Angiostatin: A novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell 79:315-28, 1994.