EDITORIAL
“The Beginning of Wisdom is the Definition of Terms” – Socrates
S
ocrates was right about writing, at least sometimes, wherein the written word can give the illusion of knowledge when none exists. Or, at best, words are mere reflections of concepts, as opposed to the real thing. In this exciting era when the secrets of tumor biology are being unlocked, we continue to use words in the clinical literature that mean different things to different people. We have dragged some of these clumsy definitions still in use today through a quagmire of miscommunication that began long before the first patient enrolled in a breast conservation trial. In this issue of The Breast Journal, Shaikh et al. analyzed their outcomes that attempt to rise above two of these variably defined clinical issues—multicentricity and local recurrence. The takeaway message is reflected in the title – “Multifocal and multicentric breast cancer is associated with increased local recurrences regardless of surgery type”. Acknowledging that definitions have “greatly varied in the literature,” these investigators assumed a pragmatic approach. Rather than attempting to distinguish multifocal from multicentric disease, the two groups of patients were studied together. Multifocal was defined as multiple areas of disease within the same quadrant, while multicentric involved at least two quadrants, or greater than a 5.0 cm separation between areas of disease. While this definition is widely utilized, it has also been criticized on the basis of “quadrants” which do not exist in anatomic reality (score one for Socrates). There are several scenarios that expose this definition as inadequate, including boundary tumors that end up in two quadrants in the pathology lab, or those tumors that can be distinguished as “diffuse”. Perhaps, a better approach to defining “multicentricity” would be a variable
Address correspondence and reprint requests to: Alan Hollingsworth, MD, Mercy Hospital – OKC - Mercy Women’s Center, 4300 McAuley Blvd., Oklahoma City, OK 73120, USA, or e-mail: [email protected] DOI: 10.1111/tbj.12370 © 2015 Wiley Periodicals, Inc., 1075-122X/15 The Breast Journal, Volume 21 Number 2, 2015 119–120
90-degree arc, rather than a fixed quadrant based on a clock dial. But this approach still suffers from the pie-shaped wedge that narrows to a point the closer one gets toward the nipple-areola complex, culminating in those pesky sub-areolar and central tumors, which can touch four quadrants simultaneously even when unifocal. In recognizing the difficult distinction between multifocal and multicentric, the authors chose to erase the blurred lines by grouping the two presentations together as a single entity. This effectively solves one problem, but simultaneously creates another in distinguishing “multifocal” from “unifocal,” given that the vast majority of breast cancers prove to be multifocal when enough sections are taken for histology. Holland’s landmark work in this area revealed only 37% of 282 invasive cancers were truly unifocal (1), though outcomes were not the intent of this histologic study of mastectomy specimens. Remarkably close to Holland’s 37%, however, was Tot’s large-format histology study of 500 consecutive breast cancer cases where 34% of cases could be categorized as unifocal (2). Here, outcomes were reported. Notably, true unifocal cancers demonstrated lymph node metastases in 34%, whereas a multifocal pattern (not affecting stage) was associated with lymph node involvement in 48%, and in patients with diffuse invasion, 60% had positive lymph nodes. Extending this cohort to 574 patients and measuring 10-year disease-specific cumulative survival (3) revealed highly significant differences (p < 0.0001) with unifocal disease (89.6%), multifocal (76.0%), and diffuse invasive (63.6%). Although not all comparable analyses have demonstrated such remarkable outcomes, it still raises questions once again about the need to refine the breast cancer staging system and its implications, both with regard to local tumor mapping and systemic recommendations. Multifocal/multicentric disease comes in a wide variety of presentations, clinically and pathologically. The hope, of course, is that molecular medicine with
120 • editorial
targeted therapies will render these manifold presentations obsolete. And, this hope can be considered as the presumptive truth, as long as one does not include time as a variable. If the past 60 years (since the revolution in biologic theory began in Dr. Bernard Fisher’s animal lab), are an indicator, we will be contending with these same unsettled issues for several decades still. Eventually, biologic staging will supersede anatomic staging, but there are visionaries today who seem blinded to the present, acting as though we are fully immersed in the future. The same goes for “local recurrence” with regard to precise definitions. Returning to the original concepts in Fisher Theory, a tumor recurrence within the breast parenchyma was considered so inconsequential that these patients were originally scored as “cosmetic failures,” rather than treatment failures (4). After clinical implications became more evident, the terminology was later changed from “cosmetic failure” to ipsilateral breast tumor recurrence (IBTR), but the formal definition of local recurrence excluded IBTR, and was utilized only for treatment failures in the “chest wall and operative scar” (5). Regional treatment failures included ipsilateral axillary, internal mammary, and supraclavicular nodes. It is with these definitions of local and regional treatment failures where the three limbs of the B-06 trial (and other trials) showed equivalency. So, when informed consent includes the information that “mastectomy and conservation have the same local recurrence rate,” the physician following the NSABP lead should be talking about chest wall/regional nodes, but the patient might be hearing “breast”. If IBTR (a.k.a. in-breast tumor recurrence) is added to “locoregional recurrence,” then the two approaches are not equal, as IBTR can only occur in the conservation group. Even with the reduced IBTR rate of today compared to the era of B-06, if these numbers are added to the original definition of “local and regional recurrence,” equivalency is lost. As the decades have passed, we have grown casual in these definitions. Perhaps, a recurrence presenting as a solitary chest wall nodule after mastectomy has similar biology and comparable outcomes to IBTR, but how will this be confirmed? The current trend, away from the NSABP distinction (and outcome data), has been to describe local recurrence as “chest wall and breast” while regional is “nodal”. In the current
article by Shaikh, this is how patients were divided. The authors are not alone. In the CALOR trial (6), recently confirming the long-held belief that chemotherapy is indicated after “isolated locoregional recurrence,” the stratification was into “local” (chest wall, scar, skin, or breast) and “regional” (axilla or ipsilateral internal mammary nodes). Accrual has been a limiting factor here, but a study design that places IBTR and chest wall recurrence into the same stratum will not be able to answer specific outcome questions about IBTR as a distinct clinical problem. If we rewrite the original definitions and include IBTR with chest wall and regional node recurrences, then we cannot claim that conservation is equal to mastectomy in all respects. There will be more “local recurrences” in the conservation group. A good informed consent must be precise on this issue—survival is equal, chest wall, and regional control is equal, but IBTR only occurs in the conservation group. Combining IBTR and chest wall into a single entity precludes the use of the word “equal,” unless we move from Socrates to Orwell, claiming that “all local therapies are equal, but some are more equal than others”. Alan Hollingsworth, MD Mercy Hospital – OKC - Mercy Women’s Center Oklahoma City Oklahoma REFERENCES 1. Holland R, Veling SH, Mravunac M, Hendriks JH. Histologic multifocality of Tis, T1-2 breast carcinomas. Implications for clinical trials of breast-conserving surgery. Cancer 1985;56:979–90. 2. Tot T. Clinical relevance of the distribution of the lesions in 500 consecutive breast cancer cases documented in large-format histology. Cancer 2007;110:2551–60. 3. Tot T, Gere M, Pekar G, et al. Breast cancer multifocality, disease extent, and survival. Hum Pathol 2011;42:1761–9. 4. Fisher B, Bauer M, Margolese R, et al. Five-year results of a randomized clinical trial comparing total mastectomy and segmental mastectomy with or without radiation in the treatment of breast cancer. New Engl J Med 1985;312:665–73. 5. Fisher B, Redmond C, Poisson R, et al. Eight-year results of a randomized clinical trial comparing total mastectomy and lumpectomy with or without irradiation in the treatment of breast cancer. New Engl J Med 1989;320:822–8. 6. Aebi S, Gelbar S, Anderson SJ, et al. Chemotherapy for isolated locoregional recurrence of breast cancer (CALOR): a randomized trial. Lancet Oncol 2014;15:156–63.
Copyright of Breast Journal is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
“The Beginning of Wisdom is the Definition of Terms” – Socrates
S
ocrates was right about writing, at least sometimes, wherein the written word can give the illusion of knowledge when none exists. Or, at best, words are mere reflections of concepts, as opposed to the real thing. In this exciting era when the secrets of tumor biology are being unlocked, we continue to use words in the clinical literature that mean different things to different people. We have dragged some of these clumsy definitions still in use today through a quagmire of miscommunication that began long before the first patient enrolled in a breast conservation trial. In this issue of The Breast Journal, Shaikh et al. analyzed their outcomes that attempt to rise above two of these variably defined clinical issues—multicentricity and local recurrence. The takeaway message is reflected in the title – “Multifocal and multicentric breast cancer is associated with increased local recurrences regardless of surgery type”. Acknowledging that definitions have “greatly varied in the literature,” these investigators assumed a pragmatic approach. Rather than attempting to distinguish multifocal from multicentric disease, the two groups of patients were studied together. Multifocal was defined as multiple areas of disease within the same quadrant, while multicentric involved at least two quadrants, or greater than a 5.0 cm separation between areas of disease. While this definition is widely utilized, it has also been criticized on the basis of “quadrants” which do not exist in anatomic reality (score one for Socrates). There are several scenarios that expose this definition as inadequate, including boundary tumors that end up in two quadrants in the pathology lab, or those tumors that can be distinguished as “diffuse”. Perhaps, a better approach to defining “multicentricity” would be a variable
Address correspondence and reprint requests to: Alan Hollingsworth, MD, Mercy Hospital – OKC - Mercy Women’s Center, 4300 McAuley Blvd., Oklahoma City, OK 73120, USA, or e-mail: [email protected] DOI: 10.1111/tbj.12370 © 2015 Wiley Periodicals, Inc., 1075-122X/15 The Breast Journal, Volume 21 Number 2, 2015 119–120
90-degree arc, rather than a fixed quadrant based on a clock dial. But this approach still suffers from the pie-shaped wedge that narrows to a point the closer one gets toward the nipple-areola complex, culminating in those pesky sub-areolar and central tumors, which can touch four quadrants simultaneously even when unifocal. In recognizing the difficult distinction between multifocal and multicentric, the authors chose to erase the blurred lines by grouping the two presentations together as a single entity. This effectively solves one problem, but simultaneously creates another in distinguishing “multifocal” from “unifocal,” given that the vast majority of breast cancers prove to be multifocal when enough sections are taken for histology. Holland’s landmark work in this area revealed only 37% of 282 invasive cancers were truly unifocal (1), though outcomes were not the intent of this histologic study of mastectomy specimens. Remarkably close to Holland’s 37%, however, was Tot’s large-format histology study of 500 consecutive breast cancer cases where 34% of cases could be categorized as unifocal (2). Here, outcomes were reported. Notably, true unifocal cancers demonstrated lymph node metastases in 34%, whereas a multifocal pattern (not affecting stage) was associated with lymph node involvement in 48%, and in patients with diffuse invasion, 60% had positive lymph nodes. Extending this cohort to 574 patients and measuring 10-year disease-specific cumulative survival (3) revealed highly significant differences (p < 0.0001) with unifocal disease (89.6%), multifocal (76.0%), and diffuse invasive (63.6%). Although not all comparable analyses have demonstrated such remarkable outcomes, it still raises questions once again about the need to refine the breast cancer staging system and its implications, both with regard to local tumor mapping and systemic recommendations. Multifocal/multicentric disease comes in a wide variety of presentations, clinically and pathologically. The hope, of course, is that molecular medicine with
120 • editorial
targeted therapies will render these manifold presentations obsolete. And, this hope can be considered as the presumptive truth, as long as one does not include time as a variable. If the past 60 years (since the revolution in biologic theory began in Dr. Bernard Fisher’s animal lab), are an indicator, we will be contending with these same unsettled issues for several decades still. Eventually, biologic staging will supersede anatomic staging, but there are visionaries today who seem blinded to the present, acting as though we are fully immersed in the future. The same goes for “local recurrence” with regard to precise definitions. Returning to the original concepts in Fisher Theory, a tumor recurrence within the breast parenchyma was considered so inconsequential that these patients were originally scored as “cosmetic failures,” rather than treatment failures (4). After clinical implications became more evident, the terminology was later changed from “cosmetic failure” to ipsilateral breast tumor recurrence (IBTR), but the formal definition of local recurrence excluded IBTR, and was utilized only for treatment failures in the “chest wall and operative scar” (5). Regional treatment failures included ipsilateral axillary, internal mammary, and supraclavicular nodes. It is with these definitions of local and regional treatment failures where the three limbs of the B-06 trial (and other trials) showed equivalency. So, when informed consent includes the information that “mastectomy and conservation have the same local recurrence rate,” the physician following the NSABP lead should be talking about chest wall/regional nodes, but the patient might be hearing “breast”. If IBTR (a.k.a. in-breast tumor recurrence) is added to “locoregional recurrence,” then the two approaches are not equal, as IBTR can only occur in the conservation group. Even with the reduced IBTR rate of today compared to the era of B-06, if these numbers are added to the original definition of “local and regional recurrence,” equivalency is lost. As the decades have passed, we have grown casual in these definitions. Perhaps, a recurrence presenting as a solitary chest wall nodule after mastectomy has similar biology and comparable outcomes to IBTR, but how will this be confirmed? The current trend, away from the NSABP distinction (and outcome data), has been to describe local recurrence as “chest wall and breast” while regional is “nodal”. In the current
article by Shaikh, this is how patients were divided. The authors are not alone. In the CALOR trial (6), recently confirming the long-held belief that chemotherapy is indicated after “isolated locoregional recurrence,” the stratification was into “local” (chest wall, scar, skin, or breast) and “regional” (axilla or ipsilateral internal mammary nodes). Accrual has been a limiting factor here, but a study design that places IBTR and chest wall recurrence into the same stratum will not be able to answer specific outcome questions about IBTR as a distinct clinical problem. If we rewrite the original definitions and include IBTR with chest wall and regional node recurrences, then we cannot claim that conservation is equal to mastectomy in all respects. There will be more “local recurrences” in the conservation group. A good informed consent must be precise on this issue—survival is equal, chest wall, and regional control is equal, but IBTR only occurs in the conservation group. Combining IBTR and chest wall into a single entity precludes the use of the word “equal,” unless we move from Socrates to Orwell, claiming that “all local therapies are equal, but some are more equal than others”. Alan Hollingsworth, MD Mercy Hospital – OKC - Mercy Women’s Center Oklahoma City Oklahoma REFERENCES 1. Holland R, Veling SH, Mravunac M, Hendriks JH. Histologic multifocality of Tis, T1-2 breast carcinomas. Implications for clinical trials of breast-conserving surgery. Cancer 1985;56:979–90. 2. Tot T. Clinical relevance of the distribution of the lesions in 500 consecutive breast cancer cases documented in large-format histology. Cancer 2007;110:2551–60. 3. Tot T, Gere M, Pekar G, et al. Breast cancer multifocality, disease extent, and survival. Hum Pathol 2011;42:1761–9. 4. Fisher B, Bauer M, Margolese R, et al. Five-year results of a randomized clinical trial comparing total mastectomy and segmental mastectomy with or without radiation in the treatment of breast cancer. New Engl J Med 1985;312:665–73. 5. Fisher B, Redmond C, Poisson R, et al. Eight-year results of a randomized clinical trial comparing total mastectomy and lumpectomy with or without irradiation in the treatment of breast cancer. New Engl J Med 1989;320:822–8. 6. Aebi S, Gelbar S, Anderson SJ, et al. Chemotherapy for isolated locoregional recurrence of breast cancer (CALOR): a randomized trial. Lancet Oncol 2014;15:156–63.
Copyright of Breast Journal is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
