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A historical account of breast cancer surgery: beware of local recurrence but be not radical Charles P Halsted1, John R Benson2 & Ismail Jatoi*,1
ABSTRACT: In the late 19th century, William Halsted proposed the radical mastectomy, which became the standard surgical treatment of breast cancer for nearly 100 years. Later in this period, theories suggesting that breast cancer was a systemic disease at inception were championed by Bernard Fisher. This alternative hypothesis of biological predeterminism was based upon results of randomized clinical trials comparing breast conserving therapy with mastectomy, which showed similar overall survival outcomes. Nonetheless, data from metaanalyses suggest that inadequate local therapy can increase risk of local recurrence, which can subsequently increase mortality. In this review, the authors provide an historical account of how local therapy of breast cancer has evolved in the face of improved adjuvant therapies and better understanding of disease biology. Prior to the 20th century there was no unified approach among surgeons for the resection of breast tumors. Guided mainly by anecdotal evidence and personal experience, surgeons employed a cornucopia of procedures that generally yielded suboptimal results. However, progression towards more enlightened surgery, which was underpinned by both theory and clinical outcomes, can be identified among the writings of several notable surgeons throughout the 18th and 19th centuries. These developments were based on the premise that more extensive local excision of a tumor would yield the greatest chance of survival and minimize local recurrence. This concept was ultimately embraced and surgically articulated by William Halsted.
KEYWORDS
• breast cancer • breast
conserving surgery • historical • local therapy • radical mastectomy • surgery
Pre-Halstedian era ●●17th & 18th centuries
The concept of breast cancer as a localized tumor that spreads in a sequential manner to local lymph nodes with a propensity to recur was detailed by Henri Francois Le Dran (1685–1773) who challenged the existing humoral theory of Galen [1] . He described a surgical approach that was dependent upon presentation, “Suppose the schirrous tumor in the breast … moveable within the adipose substance and not adherent to the pectoral muscle we may be well assured that there is no other diseased gland in the neighboring fat … in such a case we are only to extirpate the single gland that is schirrous without any injury to the other part of the breast. When the obstruction extends throughout the breast the whole [breast] must be taken off … After having extirpated this fat we sometimes find an obstructed gland situated near the axillary vessels which we must be careful not to leave behind as it might give rise to a fresh cancer” [1] . The observation by Le Dran that a localized neoplasm will eventually involve the lymphatics and axillary nodes with worsening of prognosis as nodal infiltration increased alludes to a temporal Division of Surgical Oncology, University of Texas Health Science Center, San Antonio, TX, USA Cambridge Breast Unit, Addenbrooke’s Hospital, Cambridge University NHS Foundation Trust, Cambridge, UK *Author for correspondence: [email protected] 1 2
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Review Halsted, Jatoi & Benson factor in treatment [2] . For a small mobile mass that does not clinically involve the lymphatics or skin, Le Dran advocated a more limited surgical excision rather akin to a contemporary lumpectomy. Furthermore, he was one of the first surgeons to recommend removal of axillary lymph nodes as part of the primary surgical treatment of breast cancer. An early form of local resection for breast cancer was performed by the Parisian surgeon Jean Louis Petit (1674–1750), who modeled his technique in accordance with principles espoused by Le Dran [3] . Thus, Petit removed the breast, any palpable axillary lymph nodes together with the pectoral fascia while preserving much of the breast skin. If pectoralis major involvement was evident, then this structure would be sacrificed. Except for skin preservation, this procedure was remarkably similar to a radical mastectomy. Petit’s operation – which was considered very bold at the time – saw merit in resection of too much rather than too little tissue. Hence ‘more was better’ in contrast to the contemporary adage of breast surgery, which states “less is more” [4] . This line of reasoning was adopted by the Scottish surgeon Benjamin Bell (1749–1806) who “advised that the whole breast be removed even if the lump was small” [5] . Bell supported the practice of leaving overlying skin intact and routinely made a separate incision for resection of axillary lymph nodes. ●●19th century
There was little further progress in surgical techniques for breast cancer until the latter half of the 19th century. Joseph Pancoast (1805–1882) was an American surgeon working in Philadelphia (USA), who, in 1852, documented the importance of excising the entire breast along with clinically positive axillary nodes in continuity [6] . Indeed, he was the first surgeon to recommend en bloc removal of the breast [7] . In 1867, Charles Moore (1821–1879), an English surgeon from the Middlesex Hospital in London (UK), observed how breast cancer surgery was frequently inadequate in terms of local disease control and recurrence rates [8] . This led him to issue some guidance on how the procedure should be undertaken to achieve optimal outcomes. These were summarized by Brooks and Daniel in 1940 [9] : ●● Recurrence of cancer of the breast is due to a
local condition not belonging to structures out of continuity with the first tumor;
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●● Centrifugal dispersion determines the recur-
rence of cancer; ●● Cancer of the breast requires the careful extir-
pation of the entire organ; ●● Besides the breast, unsound adjoining struc-
tures, especially the skin, should be removed in the same mass with the principal disease. Moore asserted that breast cancer and implantation of secondary deposits emanated from a single index tumor within the breast and was not a manifestation of systemic disease [9] . Furthermore, piecemeal extirpation of the tumor was purported to cause local recurrence by spreading tumor cells within the surgical site; Moore maintained that the tumor itself should not be exposed during surgery, but instead be cocooned and contained by surrounding normal tissue during surgical excision [8] . Other surgeons, most notably those of German extraction, continued this development and formalization of breast surgery with description of procedures, which would eventually define the essence of the radical mastectomy. Richard von Volkmann (1830–1889) advocated complete breast excision including its integument with removal of pectoralis major and minor muscles in severe cases [10] . This latter intervention was justified when pectoralis fascia was found to contain cancer cells even when the muscle did not appear to be involved macroscopically [11] . Ernst Kuster (1874–1953) was the first to recommend clearance of axillary nodes regardless of their clinical status [12] . At about the same time in 1889, Lothar Heidenhain (1860–1940) identified cancer cells within the pectoralis muscle [10] . He made the assertion that cancer cells could potentially cross the pectoralis fascia and continue their spread via blood vessels and lymphatics. He championed removal of a portion of superficial muscle only if the tumor was freely mobile and complete extirpation of the pectoralis major only when the tumor was clinically fixed to the chest wall [7] . Rudolph Virchow (1821–1902) is commonly referred to as the ‘father of modern pathology’ and proposed a cogent and influential model for metastastic spread of cancer. These ideas were gleaned from dissecting and studying postmortem specimens of breast cancer patients [13] . The following excerpt from his text entitled ‘Cellular Pathology’ compares two contrasting
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A historical account of breast cancer surgery cancers that spread at different rates but invariably traverse the lymphatics: “Cancroid remains for a very long time local, so that the nearest lymphatic glands often do not become affected until after the lapse of years, and then again the process is for a long time confined to the disease of the lymphatic glands, so that a general outbreak of the disease in all parts of the body does not take place until late … in cancer proper the local progress is often very rapid and the disease early becomes general” [13] . According to Virchow, lymph nodes serve as a buffer between the cancerous source (primary tumor) and the remainder of the body until saturation with malignant, inflammatory material occurs and this can no longer be contained by the lymph nodes. Systemic dissemination thereafter ensues. In terms of the initial insult, Virchow believed that breast tumors arose from epithelial cells within the breast parenchyma and was ultimately a local disease that became systemic in a temporally dependent manner. This viewpoint served to be the cornerstone upon which the radical mastectomy was based.
Figure 1. William Stewart Halsted (1852–1922). Reproduced with permission from the Alan Mason Chesney Archives of the Johns Hopkins Medical Institutions.
Halstedian era Spurred on by advances in anesthesia and antisepsis, William Stewart Halsted (1852–1922; Figure 1) built upon and consolidated techniques conceived by his predecessor Volkmann and refined en bloc resection of the breast tissue along with overlying skin, pectoralis muscles, lymphatic channels and ipsilateral axillary lymph nodes [7] . He described a meticulous dissection lasting between 3 and 4 h, which was “literally an almost bloodless one” [12] . By systematically excising the pectoralis muscles together with contiguous tissues as a single specimen, Halsted believed that local recurrence rates would be much reduced; he expressed reservations about Volkmann’s procedure that involved “frequent division of tissues which are cancerous, and does not give the disease a sufficiently wide birth” [12] . Halsted reasoned that division of lymphatic vessels and cancerous tissue within the surgical site could release individual cancer cells that could ultimately be responsible for local recurrence of cancer. Halsted was also critical of Volkmann for not consistently recommending excision of the pectoral muscles. It was his belief that these muscles were responsible for ‘sweeping’ cancer cells from the breast towards the axilla along lymphatic vessels thus allowing cancer cells “at any moment be carried with startling rapidity
from one end of the muscle to the other” [12] . While Halsted acknowledged that the pectoralis muscles were infrequently directly invaded by tumor, he nonetheless advocated removal of these structures in all cases. Halsted’s operation, therefore, removed the breast, pectoral muscles and ipsilateral axillary nodes. Results of his first 50 cases published in 1894 demonstrate dramatic improvement in local recurrence rates, which were reported to be a mere 6% at 3 years in contrast to his European counterparts whose local recurrence rates ranged from 50 to 80% [7,12] . It is important to note that among surgeons of the mid-late 19th century, the definition of local and regional recurrence varied considerably. Theodor Billroth (1829–1894) considered a local recurrence as a return of the cancer at the surgical site within 18 months, and all subsequent events were viewed as independent and de novo growth [12] . Halsted considered his patients safely outside the window for local recurrence at 3 years. There were also difficulties in identifying whether recurrences were local versus regional with the former representing failure of surgery. When comparing his results to those of other surgeons, Halsted exclaimed that he wished “it had been practicable to separate the true local from the regionary recurrences … but the descriptions of the recurrences are sometimes
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Review Halsted, Jatoi & Benson so vague that I have not done so” [12] . He commented that “the efficiency of a breast cancer operation is measured truer in terms of local recurrence than of ultimate cure…” [14] . There is something of a mythos associated with Halsted’s procedure, which is reinforced by a perfectionist attitude and reproducibility of the procedure by other surgeons. It was noted by Brooks and Daniel that the radical mastectomy “is founded on a principle which makes it obligatory to assume that even a small difference in the technique would frequently produce a total difference in the result obtained” [9] . They noted that the operation of radical mastectomy performed by Halsted and those who trained with him was likely to differ significantly from those performed by surgeons who were reliant for information solely on published accounts of the operation. Indeed, Halsted’s own accounts of his procedure were inconsistent to some extent and in a state of flux, “all of those who were fortunate enough to be associated with Dr Halsted while he was performing operations for the cure of carcinoma of the breast have an indelible picture of a Halstedian operation, others, because of the continuously changing technique and even conflicting statements in the published accounts, would probably obtain quite different ideas of the Halsted operation” [9] . Brooks contended that some of the criticisms of Halsted’s operation were unfair because earlier and less refined versions were being erroneously used as d efinitive examples of the procedure. It is well recognized that the radical mastectomy was a procedure associated with considerable morbidity postoperatively and distinct drawbacks. Although Halsted attempted to mitigate disability from the operation by asserting an ‘inappreciable’ loss in arm function and citing women’s main complaint as being inability to ‘dress their back hair’, many adverse side effects were noted [14] . Routine axillary dissection (to level III) often led to chronic lymphoedematous swelling of the ipsilateral arm, while pectoral muscle excision was associated with disability well beyond that of brushing one’s hair. Of equal importance were the psychological sequelae of the disfigurement consequent to this extensive surgical procedure with complete loss of the breast and impact upon a female’s body image and sexuality [15] . The nature of the radical mastectomy must be viewed in the context of the typical clinical presentation in Halsted’s time. In an age of limited public awareness and screening for breast cancer,
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women presented at a much later point in the natural course of breast cancer. On reviewing the initial presenting features of 50 cases undertaken by Halsted between 1889 and 1894, 56% had nipple retraction, 72% had clinically palpable axillary nodes, 56% had skin involvement and/or ulceration and 68% had painful breasts [12] . Excluding two outliers, the average length of time from detection of a palpable breast mass until presentation was 17.5 months, with a median time of 11 months. Approximately 10% of patients (n = 6) presented with tumors that were fixed to the pectoralis major muscle. A powerful insight into Halsted’s judgement on the relative size of tumors can be ascertained from a hospital report in which he refers to a patient with an 8 cm tumor as having a ‘small’ lesion [16] . In the light of more advanced stage at presentation and belief that cancer spread through lymphatic pathways and along fascial planes, the rationale for performing more extensive surgical resection as in Halsted’s radical mastectomy is upheld. After widespread adoption of Halsted’s procedure, improvements in pathological node examination provided new insights into patterns of nodal involvement in breast cancer. In 1949, the British surgeon Richard Handley (Middlesex Hospital, London, UK) performed internal mammary node biopsy on patients scheduled for radical mastectomy and found a third (34%) to have malignant infiltration [17] . An intuitive conclusion, in accordance with the Halsted doctrine of contiguous spread, was that a radical mastectomy was not radical enough. In 1951, the New York surgeon, Jerome Urban (1914–1991) devised what he called the extended radical mastectomy, which incorporated en bloc resection of the chest wall and internal mammary nodes with standard radical mastectomy [18] . Even more surgically ambitious was the super-radical mastectomy that combined cervical and mediastinal node exploration with a standard radical mastectomy and entailed a median sternotomy with its concomitant morbidity. Perhaps the most extreme form of these more aggressive resections was conducted by Antonio Prudente (1906–1965) in 1949; he undertook several radical mastectomies in conjunction with trans-scapulothoracic disarticulations with amputation of the upper extremity en bloc [19] . These procedures were associated with significant perioperative mortality but had no demonstrable benefit in terms of longer-term survival outcomes. They were promptly abandoned and excluded from routine surgical repertoires
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A historical account of breast cancer surgery well before the original radical mastectomy became outmoded. Within the first decades of the 20 century, criticisms of the radical mastectomy were starting to gain ground. Following detailed studies of the lymphatic anatomy of the chest wall, JH Gray (University College London, UK) declared in 1939 that the deep fascia overlying the pectoralis major fascia was relatively devoid of lymphatic channels [19] . The English surgeon David Patey (1899–1977) interpreted this to mean that the pectoralis major was unlikely to be involved in most cases of carcinomatous spread and conceived what is now referred to as the modified radical mastectomy [20] . Described later by the surgeon John Madden (1912–1999) as an operation “equally satisfactory” to the standard radical mastectomy, the modified radical mastectomy included total mastectomy with complete axillary dissection yet preserved the pectoralis major muscle, making it a less disfiguring procedure [21] . Patey monitored the progress of 118 women who were treated with either standard or modified radical mastectomy at the Middlesex Hospital in London from 1930 to 1943. It was found that both procedures had comparable rates of local recurrence and similar longerterm survival [20] . Although limited in sample size, this was one of the first studies attempting to compare different local therapies in terms of objective outcomes. A retrospective study by Ivor G Williams (1907–1989) in 1953 compared 10-year results for 1044 women treated with varying surgical approaches (simple excision, radical mastectomy, modified radical mastectomy and no surgery) with or without chest wall radiation at St Bartholomew’s Hospital (London, UK) from 1930 to 1939 [22] . A subgroup of 505 patients were given either radical (n = 338) or modified radical (n = 167) mastectomy with or without radiation. No differences in overall survival were noted between these two groups, although patients with radiation therapy had lower rates of recurrence. It should be noted that Patey’s modified radical mastectomy was almost identical to the procedure detailed by Moore over half a century earlier. It was more popular and gained wider acceptance within the surgical communities of Europe compared with the USA where the standard radical mastectomy continued to be practiced for many years subsequent to Patey’s modification. American surgeons were profoundly influenced by the ‘Halstedian paradigm’, which was reinforced by
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a surgical ‘battle-cry’ issued by William W Keen (1837–1932) at the Cleveland Medical Society in 1894 [23] :” There is no question at all in the present day that [breast cancer] is of local origin. In my earlier professional life, it was one of the disputed points constantly coming up in medical society as to whether it was local or from the first a constitutional disease, and whether the latter it was said that no good could come from operating on the breast. But this question of local origin is no longer confronting us. It is a settled thing, a point won, and women must be taught that this brings hope to them.” Biological paradigms The so-called ‘Halstedian paradigm’ is one of two dominant paradigms of breast cancer biology that have governed the management of breast cancer over the past century. This Halstedian paradigm was predicated on Virchow’s theory for centrifugal dissemination of breast cancer in which a tumor was considered to initially invade local tissues and to subsequently spread in a progressive, sequential and predictable manner upon ever more distant structures that lay in anatomical continuity [12,13] . The lymph nodes were thought to act as mechanical filters that formed a circumferential line of defence against such centrifugal dissemination and temporarily impeded the spread of cancer. However, once this filtration capacity was exhausted, cancer cells would then pass into the efferent lymphatics and thence to more distant sites. This model provided the rationale for Halsted’s radical mastectomy in which an en bloc resection of tumor and loco-regional tissues was performed. As a tumor was believed to spread in a sequential manner with successive involvement of structures in anatomical continuity, such en bloc resection was considered to offer the best chance of ‘cure’. Although the operation of radical mastectomy provided high rates of local disease control, there was no evidence for improved survival relative to lesser surgical procedures. This implied that some ‘event’ had occurred prior to mastectomy that predetermined survival and was unaffected by surgical intervention per se. Analysis of survival data for patients undergoing radical mastectomy revealed that fewer than a quarter of these patients shared a similar hazard ratio as an age-matched control population [24] . Therefore, radical mastectomy could not be hailed as a general curative procedure for breast cancer, and fostered some doubt in the underlying paradigm.
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Review Halsted, Jatoi & Benson It was perhaps ironic that this Halstedian paradigm replaced an existing concept of breast cancer as a systemic disease caused by an excess of black bile within the body, which dated back to the time of Galen [25] . Bernard Fisher’s alternative paradigm championed a resurgence of breast cancer as a systemic disease, which was firmly founded on scientific principles. This considered breast cancer to be largely a systemic disease at the outset as a consequence of cancer cells entering the bloodstream at an early stage in tumor development [26] . In particular, such hematogenous dissemination was not conditional upon lymph node involvement, and regional lymph nodes were not viewed as the instigators of distant metastases. Rather, they reflected a tumor–host relationship that favored dissemination and formation of micrometatastic foci of disease. Experimental models were employed to demonstrate transnodal passage of tumour cells together with destruction of tumor cells by lymph nodes [27] . These findings repudiated the concept of lymph nodes as passive filters, and showed that cancer cells could pass not only directly into efferent lymphatics, but also into the bloodstream via lymphatico–venous communications [28,29] . Furthermore, animal models had shown that dormant tumor cells could develop into overt metastases under appropriate conditions. These experimental observations formed the basis for an alternative paradigm of biological predeterminism in which cancer is viewed as a predominantly systemic disease at inception with clinical outcome predetermined by micrometastases present at the time of diagnosis. Prognosis is ultimately determined by the propensity for these micrometastases to develop into overt metastatic disease – through some process of being ‘kickstarted’ [30] . In terms of therapeutic sequelae, this paradigm of biological predeterminism would predict that the extent of primary surgery does not influence overall survival, as the latter is dependent upon micrometastases that are present in all patients irrespective of surgical procedure. Trials of breast conservation surgery have confirmed that lesser surgical resections do not compromise overall survival, though are associated with higher rates of local recurrence [31,32] . The six trials that identified breast conserving therapy as an equivalent alternative were the Milan-WHO, IGR-Paris, NSABP-06, EORTC 10801, Danish and US National Cancer institute trials [33] . A meta-analysis by the Early Breast Cancer Trialists Collaborative Group reinforced the link between local failure and survival and underlined how
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individual breast conservation therapy trials have insufficient power to detect any effect secondary to impaired local disease control on overall survival in the longer term [34] . A reanalysis of the EORTC trial with 20 years of follow-up has shown that despite significant differences in ipsilateral breast tumor recurrence the time to distant metastases and overall survival remain similar within the two arms of the trial [35,36] . These observations suggest that ipsilateral breast tumor recurrence is not an important source for distant metastatic disease but as this group of patients had larger more advanced stage (II) tumors, pre-existent micrometastases are more likely among patients randomized to either breast conservation therapy or mastectomy within these trials. These micrometastases are a competing source of overt metastatic disease and a driver of mortality. Therefore individual trials of breast conservation therapy have confirmed that overall survival rates are uninfluenced by the extent of primary surgery, and support the notion of predeterminism based on subclinical dissemination of micrometastases [37] . The second therapeutic sequela of this hypothesis is that initiation of systemic therapies, which can destroy these putative micrometastases, should improve prognosis. This aspect of treatment would, therefore, be complementary to loco-regional therapy (surgery ± radiotherapy) and should impact on the natural history of the disease. Clinical trials of both adjuvant and neoadjuvant (primary) therapies for breast cancer have provided corroborative evidence for this second prediction of this alternative paradigm [38,39] . Although this alternative paradigm of biological determinism has become pre-eminent in recent years, both are relevant to our current understanding of the natural history of breast cancer and indeed an intermediate paradigm may be most appropriate for guiding management in the present era. Thus, there appear to be a group of less aggressive tumors that behave in accordance with Halstedian postulates, while others have a more intrinsically aggressive signature and disseminate to distant sites at an early stage in the neoplastic continuum. The former are typically lower-grade, estrogen receptor-positive and HER2-negative tumors in postmenopausal women, while the latter are higher-grade, estrogen receptor-negative, HER2-positive (or triple-negative) tumors in premenopausal women. Molecular profiling of individual tumors provides some evidence for this dichotomy of behavior; a low recurrence score (31) with Fisherian tumors [40] .
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A historical account of breast cancer surgery Conclusion William Halsted laid the cornerstone for the modern surgical treatment of breast cancer. Indeed, following its introduction, the Halsted radical mastectomy remained the standard surgical treatment of breast cancer for nearly a century. Although its effect on mortality is poorly understood, the radical mastectomy achieved local control of disease, and thereby played an important role in improving the quality of life for countless of women afflicted with breast cancer. Halsted rejected the long-held belief that breast cancer was a systemic disease at inception, and asserted that it was a loco-regional problem. The local versus systemic nature of breast cancer has been a controversial topic even in recent years, and modern treatment is now based on an amalgamation of the two paradigms and recognition that optimum outcomes are based on multimodality treatments [41] . Future perspective Surgical excision of breast cancer reduces the risk of local recurrence, but adjuvant radiotherapy and adjuvant systemic therapies are also important. As more effective systemic therapies
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become available, local recurrence rates will likely decline even further. In the past, much emphasis was placed on achieving wide margins of microscopic clearance following local tumor excision. In consequence, many patients required a second operation after their initial lumpectomy to obtain surgically clear margins. It is now acknowledged that wider margins do not necessarily reduce rates of local recurrence in the context of multimodality treatment and ‘no tumor at ink’ may be acceptable as a minimum margin for invasive tumors [42] . Disclosure William Halsted is an ancestor of the author CP Halsted.
Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
EXECUTIVE SUMMARY Breast cancer was initially considered a systemic disease ●●
Galen’s theory of bile imbalance as a cause of cancer predominated throughout the 16–18th centuries.
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During the 18th and 19th centuries, European surgeons and scientists viewed breast cancer as a local disease that became systemic over time.
●●
In the late 19th century, Halsted modelled the radicality of his surgery on the premise that local recurrence is a failure of surgery and avoidance of local recurrence improves longer-term survival.
Radical mastectomy as the gold standard for almost a century ●●
Rates of local recurrence were drastically improved by the operation of radical mastectomy.
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The morbidity of the procedure was considered an acceptable price to pay for local control of disease.
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The radical mastectomy remained a popular choice of local therapy in the USA up until the 1970s.
Resurgence of the concept of breast cancer as a systemic disease ●●
Fisher proposed that breast cancer is a local manifestation of a systemic disease and championed less extensive surgery to the breast.
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Randomized controlled trials of the 1970s and 1980s supported Fisher’s hypothesis – variations in extent of local therapy yielded no significant difference in survival outcomes. Results from trials of breast conserving surgery coincided with emergence of effective systemic therapies.
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Meta-analyses such as the Early Breast Cancer Trialists Collaborative Group confirmed that long-term mortality is influenced by prevention of loco-regional recurrence by more extensive surgery.
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Modern treatment is now based on an intermediate paradigm which draws upon the concepts embodied in the paradigms of both Halsted and Fisher.
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Review Halsted, Jatoi & Benson References Papers of special note have been highlighted as: •• of considerable interest
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One of the six famous randomized controlled trials that demonstrated the viability of breast conserving therapy. Veronesi is a founder of breast-conserving surgery.
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Very famous study with considerable impact on shifting attitudes towards more conservative surgical therapy.
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Landmark meta-analysis of the breastconserving randomized controlled trials, with findings that suggest that local breast cancer recurrence has an effect on mortality in the long term.
35 Litiere S, Werutsky G, Fentiman IS.
Breast-conserving therapy versus mastectomy for stage I–II breast cancer: 20 year follow up of the EORTC 10801 Phase 3 randomised trial. Lancet 13(4), 412–419 (2012). 36 Benson JR. Long-term outcome of breast
conserving surgery. Lancet Oncol. 13(14), 331–333 (2012). 37 Benson JR, Teo K. Breast cancer local
therapy: what is its effect on mortality? World J. Surg. 1432–2323 (2012). 38 Early Breast Cancer Trialists’ Collaborative
Group. Tamoxifen for early breast cancer: an overview of the randomized trials. Lancet 351, 1451–1461 (1998).
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Group. Polychemotherapy for early breast cancer: an overview of the randomised trials. Lancet 352(9132), 930–942 (1998). 40 Paik S, Shak S, Tang G A multigene assay to
node-negative breast cancer. N. Engl. J. Med. 351(27), 2817–2826 (2004). 41 Jatoi I. Breast cancer: a systemic or local
disease? Am. J. Clin. Oncol. 20(5), 536–539 (1997).
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margins in lumpectomy for breast cancer – bigger is not better. N. Engl. J. Med. 367(1), 79–82 (2012).
predict recurrence of tamoxifen-treated,
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A historical account of breast cancer surgery: beware of local recurrence but be not radical Charles P Halsted1, John R Benson2 & Ismail Jatoi*,1
ABSTRACT: In the late 19th century, William Halsted proposed the radical mastectomy, which became the standard surgical treatment of breast cancer for nearly 100 years. Later in this period, theories suggesting that breast cancer was a systemic disease at inception were championed by Bernard Fisher. This alternative hypothesis of biological predeterminism was based upon results of randomized clinical trials comparing breast conserving therapy with mastectomy, which showed similar overall survival outcomes. Nonetheless, data from metaanalyses suggest that inadequate local therapy can increase risk of local recurrence, which can subsequently increase mortality. In this review, the authors provide an historical account of how local therapy of breast cancer has evolved in the face of improved adjuvant therapies and better understanding of disease biology. Prior to the 20th century there was no unified approach among surgeons for the resection of breast tumors. Guided mainly by anecdotal evidence and personal experience, surgeons employed a cornucopia of procedures that generally yielded suboptimal results. However, progression towards more enlightened surgery, which was underpinned by both theory and clinical outcomes, can be identified among the writings of several notable surgeons throughout the 18th and 19th centuries. These developments were based on the premise that more extensive local excision of a tumor would yield the greatest chance of survival and minimize local recurrence. This concept was ultimately embraced and surgically articulated by William Halsted.
KEYWORDS
• breast cancer • breast
conserving surgery • historical • local therapy • radical mastectomy • surgery
Pre-Halstedian era ●●17th & 18th centuries
The concept of breast cancer as a localized tumor that spreads in a sequential manner to local lymph nodes with a propensity to recur was detailed by Henri Francois Le Dran (1685–1773) who challenged the existing humoral theory of Galen [1] . He described a surgical approach that was dependent upon presentation, “Suppose the schirrous tumor in the breast … moveable within the adipose substance and not adherent to the pectoral muscle we may be well assured that there is no other diseased gland in the neighboring fat … in such a case we are only to extirpate the single gland that is schirrous without any injury to the other part of the breast. When the obstruction extends throughout the breast the whole [breast] must be taken off … After having extirpated this fat we sometimes find an obstructed gland situated near the axillary vessels which we must be careful not to leave behind as it might give rise to a fresh cancer” [1] . The observation by Le Dran that a localized neoplasm will eventually involve the lymphatics and axillary nodes with worsening of prognosis as nodal infiltration increased alludes to a temporal Division of Surgical Oncology, University of Texas Health Science Center, San Antonio, TX, USA Cambridge Breast Unit, Addenbrooke’s Hospital, Cambridge University NHS Foundation Trust, Cambridge, UK *Author for correspondence: [email protected] 1 2
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Review Halsted, Jatoi & Benson factor in treatment [2] . For a small mobile mass that does not clinically involve the lymphatics or skin, Le Dran advocated a more limited surgical excision rather akin to a contemporary lumpectomy. Furthermore, he was one of the first surgeons to recommend removal of axillary lymph nodes as part of the primary surgical treatment of breast cancer. An early form of local resection for breast cancer was performed by the Parisian surgeon Jean Louis Petit (1674–1750), who modeled his technique in accordance with principles espoused by Le Dran [3] . Thus, Petit removed the breast, any palpable axillary lymph nodes together with the pectoral fascia while preserving much of the breast skin. If pectoralis major involvement was evident, then this structure would be sacrificed. Except for skin preservation, this procedure was remarkably similar to a radical mastectomy. Petit’s operation – which was considered very bold at the time – saw merit in resection of too much rather than too little tissue. Hence ‘more was better’ in contrast to the contemporary adage of breast surgery, which states “less is more” [4] . This line of reasoning was adopted by the Scottish surgeon Benjamin Bell (1749–1806) who “advised that the whole breast be removed even if the lump was small” [5] . Bell supported the practice of leaving overlying skin intact and routinely made a separate incision for resection of axillary lymph nodes. ●●19th century
There was little further progress in surgical techniques for breast cancer until the latter half of the 19th century. Joseph Pancoast (1805–1882) was an American surgeon working in Philadelphia (USA), who, in 1852, documented the importance of excising the entire breast along with clinically positive axillary nodes in continuity [6] . Indeed, he was the first surgeon to recommend en bloc removal of the breast [7] . In 1867, Charles Moore (1821–1879), an English surgeon from the Middlesex Hospital in London (UK), observed how breast cancer surgery was frequently inadequate in terms of local disease control and recurrence rates [8] . This led him to issue some guidance on how the procedure should be undertaken to achieve optimal outcomes. These were summarized by Brooks and Daniel in 1940 [9] : ●● Recurrence of cancer of the breast is due to a
local condition not belonging to structures out of continuity with the first tumor;
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●● Centrifugal dispersion determines the recur-
rence of cancer; ●● Cancer of the breast requires the careful extir-
pation of the entire organ; ●● Besides the breast, unsound adjoining struc-
tures, especially the skin, should be removed in the same mass with the principal disease. Moore asserted that breast cancer and implantation of secondary deposits emanated from a single index tumor within the breast and was not a manifestation of systemic disease [9] . Furthermore, piecemeal extirpation of the tumor was purported to cause local recurrence by spreading tumor cells within the surgical site; Moore maintained that the tumor itself should not be exposed during surgery, but instead be cocooned and contained by surrounding normal tissue during surgical excision [8] . Other surgeons, most notably those of German extraction, continued this development and formalization of breast surgery with description of procedures, which would eventually define the essence of the radical mastectomy. Richard von Volkmann (1830–1889) advocated complete breast excision including its integument with removal of pectoralis major and minor muscles in severe cases [10] . This latter intervention was justified when pectoralis fascia was found to contain cancer cells even when the muscle did not appear to be involved macroscopically [11] . Ernst Kuster (1874–1953) was the first to recommend clearance of axillary nodes regardless of their clinical status [12] . At about the same time in 1889, Lothar Heidenhain (1860–1940) identified cancer cells within the pectoralis muscle [10] . He made the assertion that cancer cells could potentially cross the pectoralis fascia and continue their spread via blood vessels and lymphatics. He championed removal of a portion of superficial muscle only if the tumor was freely mobile and complete extirpation of the pectoralis major only when the tumor was clinically fixed to the chest wall [7] . Rudolph Virchow (1821–1902) is commonly referred to as the ‘father of modern pathology’ and proposed a cogent and influential model for metastastic spread of cancer. These ideas were gleaned from dissecting and studying postmortem specimens of breast cancer patients [13] . The following excerpt from his text entitled ‘Cellular Pathology’ compares two contrasting
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A historical account of breast cancer surgery cancers that spread at different rates but invariably traverse the lymphatics: “Cancroid remains for a very long time local, so that the nearest lymphatic glands often do not become affected until after the lapse of years, and then again the process is for a long time confined to the disease of the lymphatic glands, so that a general outbreak of the disease in all parts of the body does not take place until late … in cancer proper the local progress is often very rapid and the disease early becomes general” [13] . According to Virchow, lymph nodes serve as a buffer between the cancerous source (primary tumor) and the remainder of the body until saturation with malignant, inflammatory material occurs and this can no longer be contained by the lymph nodes. Systemic dissemination thereafter ensues. In terms of the initial insult, Virchow believed that breast tumors arose from epithelial cells within the breast parenchyma and was ultimately a local disease that became systemic in a temporally dependent manner. This viewpoint served to be the cornerstone upon which the radical mastectomy was based.
Figure 1. William Stewart Halsted (1852–1922). Reproduced with permission from the Alan Mason Chesney Archives of the Johns Hopkins Medical Institutions.
Halstedian era Spurred on by advances in anesthesia and antisepsis, William Stewart Halsted (1852–1922; Figure 1) built upon and consolidated techniques conceived by his predecessor Volkmann and refined en bloc resection of the breast tissue along with overlying skin, pectoralis muscles, lymphatic channels and ipsilateral axillary lymph nodes [7] . He described a meticulous dissection lasting between 3 and 4 h, which was “literally an almost bloodless one” [12] . By systematically excising the pectoralis muscles together with contiguous tissues as a single specimen, Halsted believed that local recurrence rates would be much reduced; he expressed reservations about Volkmann’s procedure that involved “frequent division of tissues which are cancerous, and does not give the disease a sufficiently wide birth” [12] . Halsted reasoned that division of lymphatic vessels and cancerous tissue within the surgical site could release individual cancer cells that could ultimately be responsible for local recurrence of cancer. Halsted was also critical of Volkmann for not consistently recommending excision of the pectoral muscles. It was his belief that these muscles were responsible for ‘sweeping’ cancer cells from the breast towards the axilla along lymphatic vessels thus allowing cancer cells “at any moment be carried with startling rapidity
from one end of the muscle to the other” [12] . While Halsted acknowledged that the pectoralis muscles were infrequently directly invaded by tumor, he nonetheless advocated removal of these structures in all cases. Halsted’s operation, therefore, removed the breast, pectoral muscles and ipsilateral axillary nodes. Results of his first 50 cases published in 1894 demonstrate dramatic improvement in local recurrence rates, which were reported to be a mere 6% at 3 years in contrast to his European counterparts whose local recurrence rates ranged from 50 to 80% [7,12] . It is important to note that among surgeons of the mid-late 19th century, the definition of local and regional recurrence varied considerably. Theodor Billroth (1829–1894) considered a local recurrence as a return of the cancer at the surgical site within 18 months, and all subsequent events were viewed as independent and de novo growth [12] . Halsted considered his patients safely outside the window for local recurrence at 3 years. There were also difficulties in identifying whether recurrences were local versus regional with the former representing failure of surgery. When comparing his results to those of other surgeons, Halsted exclaimed that he wished “it had been practicable to separate the true local from the regionary recurrences … but the descriptions of the recurrences are sometimes
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Review Halsted, Jatoi & Benson so vague that I have not done so” [12] . He commented that “the efficiency of a breast cancer operation is measured truer in terms of local recurrence than of ultimate cure…” [14] . There is something of a mythos associated with Halsted’s procedure, which is reinforced by a perfectionist attitude and reproducibility of the procedure by other surgeons. It was noted by Brooks and Daniel that the radical mastectomy “is founded on a principle which makes it obligatory to assume that even a small difference in the technique would frequently produce a total difference in the result obtained” [9] . They noted that the operation of radical mastectomy performed by Halsted and those who trained with him was likely to differ significantly from those performed by surgeons who were reliant for information solely on published accounts of the operation. Indeed, Halsted’s own accounts of his procedure were inconsistent to some extent and in a state of flux, “all of those who were fortunate enough to be associated with Dr Halsted while he was performing operations for the cure of carcinoma of the breast have an indelible picture of a Halstedian operation, others, because of the continuously changing technique and even conflicting statements in the published accounts, would probably obtain quite different ideas of the Halsted operation” [9] . Brooks contended that some of the criticisms of Halsted’s operation were unfair because earlier and less refined versions were being erroneously used as d efinitive examples of the procedure. It is well recognized that the radical mastectomy was a procedure associated with considerable morbidity postoperatively and distinct drawbacks. Although Halsted attempted to mitigate disability from the operation by asserting an ‘inappreciable’ loss in arm function and citing women’s main complaint as being inability to ‘dress their back hair’, many adverse side effects were noted [14] . Routine axillary dissection (to level III) often led to chronic lymphoedematous swelling of the ipsilateral arm, while pectoral muscle excision was associated with disability well beyond that of brushing one’s hair. Of equal importance were the psychological sequelae of the disfigurement consequent to this extensive surgical procedure with complete loss of the breast and impact upon a female’s body image and sexuality [15] . The nature of the radical mastectomy must be viewed in the context of the typical clinical presentation in Halsted’s time. In an age of limited public awareness and screening for breast cancer,
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women presented at a much later point in the natural course of breast cancer. On reviewing the initial presenting features of 50 cases undertaken by Halsted between 1889 and 1894, 56% had nipple retraction, 72% had clinically palpable axillary nodes, 56% had skin involvement and/or ulceration and 68% had painful breasts [12] . Excluding two outliers, the average length of time from detection of a palpable breast mass until presentation was 17.5 months, with a median time of 11 months. Approximately 10% of patients (n = 6) presented with tumors that were fixed to the pectoralis major muscle. A powerful insight into Halsted’s judgement on the relative size of tumors can be ascertained from a hospital report in which he refers to a patient with an 8 cm tumor as having a ‘small’ lesion [16] . In the light of more advanced stage at presentation and belief that cancer spread through lymphatic pathways and along fascial planes, the rationale for performing more extensive surgical resection as in Halsted’s radical mastectomy is upheld. After widespread adoption of Halsted’s procedure, improvements in pathological node examination provided new insights into patterns of nodal involvement in breast cancer. In 1949, the British surgeon Richard Handley (Middlesex Hospital, London, UK) performed internal mammary node biopsy on patients scheduled for radical mastectomy and found a third (34%) to have malignant infiltration [17] . An intuitive conclusion, in accordance with the Halsted doctrine of contiguous spread, was that a radical mastectomy was not radical enough. In 1951, the New York surgeon, Jerome Urban (1914–1991) devised what he called the extended radical mastectomy, which incorporated en bloc resection of the chest wall and internal mammary nodes with standard radical mastectomy [18] . Even more surgically ambitious was the super-radical mastectomy that combined cervical and mediastinal node exploration with a standard radical mastectomy and entailed a median sternotomy with its concomitant morbidity. Perhaps the most extreme form of these more aggressive resections was conducted by Antonio Prudente (1906–1965) in 1949; he undertook several radical mastectomies in conjunction with trans-scapulothoracic disarticulations with amputation of the upper extremity en bloc [19] . These procedures were associated with significant perioperative mortality but had no demonstrable benefit in terms of longer-term survival outcomes. They were promptly abandoned and excluded from routine surgical repertoires
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A historical account of breast cancer surgery well before the original radical mastectomy became outmoded. Within the first decades of the 20 century, criticisms of the radical mastectomy were starting to gain ground. Following detailed studies of the lymphatic anatomy of the chest wall, JH Gray (University College London, UK) declared in 1939 that the deep fascia overlying the pectoralis major fascia was relatively devoid of lymphatic channels [19] . The English surgeon David Patey (1899–1977) interpreted this to mean that the pectoralis major was unlikely to be involved in most cases of carcinomatous spread and conceived what is now referred to as the modified radical mastectomy [20] . Described later by the surgeon John Madden (1912–1999) as an operation “equally satisfactory” to the standard radical mastectomy, the modified radical mastectomy included total mastectomy with complete axillary dissection yet preserved the pectoralis major muscle, making it a less disfiguring procedure [21] . Patey monitored the progress of 118 women who were treated with either standard or modified radical mastectomy at the Middlesex Hospital in London from 1930 to 1943. It was found that both procedures had comparable rates of local recurrence and similar longerterm survival [20] . Although limited in sample size, this was one of the first studies attempting to compare different local therapies in terms of objective outcomes. A retrospective study by Ivor G Williams (1907–1989) in 1953 compared 10-year results for 1044 women treated with varying surgical approaches (simple excision, radical mastectomy, modified radical mastectomy and no surgery) with or without chest wall radiation at St Bartholomew’s Hospital (London, UK) from 1930 to 1939 [22] . A subgroup of 505 patients were given either radical (n = 338) or modified radical (n = 167) mastectomy with or without radiation. No differences in overall survival were noted between these two groups, although patients with radiation therapy had lower rates of recurrence. It should be noted that Patey’s modified radical mastectomy was almost identical to the procedure detailed by Moore over half a century earlier. It was more popular and gained wider acceptance within the surgical communities of Europe compared with the USA where the standard radical mastectomy continued to be practiced for many years subsequent to Patey’s modification. American surgeons were profoundly influenced by the ‘Halstedian paradigm’, which was reinforced by
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a surgical ‘battle-cry’ issued by William W Keen (1837–1932) at the Cleveland Medical Society in 1894 [23] :” There is no question at all in the present day that [breast cancer] is of local origin. In my earlier professional life, it was one of the disputed points constantly coming up in medical society as to whether it was local or from the first a constitutional disease, and whether the latter it was said that no good could come from operating on the breast. But this question of local origin is no longer confronting us. It is a settled thing, a point won, and women must be taught that this brings hope to them.” Biological paradigms The so-called ‘Halstedian paradigm’ is one of two dominant paradigms of breast cancer biology that have governed the management of breast cancer over the past century. This Halstedian paradigm was predicated on Virchow’s theory for centrifugal dissemination of breast cancer in which a tumor was considered to initially invade local tissues and to subsequently spread in a progressive, sequential and predictable manner upon ever more distant structures that lay in anatomical continuity [12,13] . The lymph nodes were thought to act as mechanical filters that formed a circumferential line of defence against such centrifugal dissemination and temporarily impeded the spread of cancer. However, once this filtration capacity was exhausted, cancer cells would then pass into the efferent lymphatics and thence to more distant sites. This model provided the rationale for Halsted’s radical mastectomy in which an en bloc resection of tumor and loco-regional tissues was performed. As a tumor was believed to spread in a sequential manner with successive involvement of structures in anatomical continuity, such en bloc resection was considered to offer the best chance of ‘cure’. Although the operation of radical mastectomy provided high rates of local disease control, there was no evidence for improved survival relative to lesser surgical procedures. This implied that some ‘event’ had occurred prior to mastectomy that predetermined survival and was unaffected by surgical intervention per se. Analysis of survival data for patients undergoing radical mastectomy revealed that fewer than a quarter of these patients shared a similar hazard ratio as an age-matched control population [24] . Therefore, radical mastectomy could not be hailed as a general curative procedure for breast cancer, and fostered some doubt in the underlying paradigm.
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Review Halsted, Jatoi & Benson It was perhaps ironic that this Halstedian paradigm replaced an existing concept of breast cancer as a systemic disease caused by an excess of black bile within the body, which dated back to the time of Galen [25] . Bernard Fisher’s alternative paradigm championed a resurgence of breast cancer as a systemic disease, which was firmly founded on scientific principles. This considered breast cancer to be largely a systemic disease at the outset as a consequence of cancer cells entering the bloodstream at an early stage in tumor development [26] . In particular, such hematogenous dissemination was not conditional upon lymph node involvement, and regional lymph nodes were not viewed as the instigators of distant metastases. Rather, they reflected a tumor–host relationship that favored dissemination and formation of micrometatastic foci of disease. Experimental models were employed to demonstrate transnodal passage of tumour cells together with destruction of tumor cells by lymph nodes [27] . These findings repudiated the concept of lymph nodes as passive filters, and showed that cancer cells could pass not only directly into efferent lymphatics, but also into the bloodstream via lymphatico–venous communications [28,29] . Furthermore, animal models had shown that dormant tumor cells could develop into overt metastases under appropriate conditions. These experimental observations formed the basis for an alternative paradigm of biological predeterminism in which cancer is viewed as a predominantly systemic disease at inception with clinical outcome predetermined by micrometastases present at the time of diagnosis. Prognosis is ultimately determined by the propensity for these micrometastases to develop into overt metastatic disease – through some process of being ‘kickstarted’ [30] . In terms of therapeutic sequelae, this paradigm of biological predeterminism would predict that the extent of primary surgery does not influence overall survival, as the latter is dependent upon micrometastases that are present in all patients irrespective of surgical procedure. Trials of breast conservation surgery have confirmed that lesser surgical resections do not compromise overall survival, though are associated with higher rates of local recurrence [31,32] . The six trials that identified breast conserving therapy as an equivalent alternative were the Milan-WHO, IGR-Paris, NSABP-06, EORTC 10801, Danish and US National Cancer institute trials [33] . A meta-analysis by the Early Breast Cancer Trialists Collaborative Group reinforced the link between local failure and survival and underlined how
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individual breast conservation therapy trials have insufficient power to detect any effect secondary to impaired local disease control on overall survival in the longer term [34] . A reanalysis of the EORTC trial with 20 years of follow-up has shown that despite significant differences in ipsilateral breast tumor recurrence the time to distant metastases and overall survival remain similar within the two arms of the trial [35,36] . These observations suggest that ipsilateral breast tumor recurrence is not an important source for distant metastatic disease but as this group of patients had larger more advanced stage (II) tumors, pre-existent micrometastases are more likely among patients randomized to either breast conservation therapy or mastectomy within these trials. These micrometastases are a competing source of overt metastatic disease and a driver of mortality. Therefore individual trials of breast conservation therapy have confirmed that overall survival rates are uninfluenced by the extent of primary surgery, and support the notion of predeterminism based on subclinical dissemination of micrometastases [37] . The second therapeutic sequela of this hypothesis is that initiation of systemic therapies, which can destroy these putative micrometastases, should improve prognosis. This aspect of treatment would, therefore, be complementary to loco-regional therapy (surgery ± radiotherapy) and should impact on the natural history of the disease. Clinical trials of both adjuvant and neoadjuvant (primary) therapies for breast cancer have provided corroborative evidence for this second prediction of this alternative paradigm [38,39] . Although this alternative paradigm of biological determinism has become pre-eminent in recent years, both are relevant to our current understanding of the natural history of breast cancer and indeed an intermediate paradigm may be most appropriate for guiding management in the present era. Thus, there appear to be a group of less aggressive tumors that behave in accordance with Halstedian postulates, while others have a more intrinsically aggressive signature and disseminate to distant sites at an early stage in the neoplastic continuum. The former are typically lower-grade, estrogen receptor-positive and HER2-negative tumors in postmenopausal women, while the latter are higher-grade, estrogen receptor-negative, HER2-positive (or triple-negative) tumors in premenopausal women. Molecular profiling of individual tumors provides some evidence for this dichotomy of behavior; a low recurrence score (31) with Fisherian tumors [40] .
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A historical account of breast cancer surgery Conclusion William Halsted laid the cornerstone for the modern surgical treatment of breast cancer. Indeed, following its introduction, the Halsted radical mastectomy remained the standard surgical treatment of breast cancer for nearly a century. Although its effect on mortality is poorly understood, the radical mastectomy achieved local control of disease, and thereby played an important role in improving the quality of life for countless of women afflicted with breast cancer. Halsted rejected the long-held belief that breast cancer was a systemic disease at inception, and asserted that it was a loco-regional problem. The local versus systemic nature of breast cancer has been a controversial topic even in recent years, and modern treatment is now based on an amalgamation of the two paradigms and recognition that optimum outcomes are based on multimodality treatments [41] . Future perspective Surgical excision of breast cancer reduces the risk of local recurrence, but adjuvant radiotherapy and adjuvant systemic therapies are also important. As more effective systemic therapies
Review
become available, local recurrence rates will likely decline even further. In the past, much emphasis was placed on achieving wide margins of microscopic clearance following local tumor excision. In consequence, many patients required a second operation after their initial lumpectomy to obtain surgically clear margins. It is now acknowledged that wider margins do not necessarily reduce rates of local recurrence in the context of multimodality treatment and ‘no tumor at ink’ may be acceptable as a minimum margin for invasive tumors [42] . Disclosure William Halsted is an ancestor of the author CP Halsted.
Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
EXECUTIVE SUMMARY Breast cancer was initially considered a systemic disease ●●
Galen’s theory of bile imbalance as a cause of cancer predominated throughout the 16–18th centuries.
●●
During the 18th and 19th centuries, European surgeons and scientists viewed breast cancer as a local disease that became systemic over time.
●●
In the late 19th century, Halsted modelled the radicality of his surgery on the premise that local recurrence is a failure of surgery and avoidance of local recurrence improves longer-term survival.
Radical mastectomy as the gold standard for almost a century ●●
Rates of local recurrence were drastically improved by the operation of radical mastectomy.
●●
The morbidity of the procedure was considered an acceptable price to pay for local control of disease.
●●
The radical mastectomy remained a popular choice of local therapy in the USA up until the 1970s.
Resurgence of the concept of breast cancer as a systemic disease ●●
Fisher proposed that breast cancer is a local manifestation of a systemic disease and championed less extensive surgery to the breast.
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Randomized controlled trials of the 1970s and 1980s supported Fisher’s hypothesis – variations in extent of local therapy yielded no significant difference in survival outcomes. Results from trials of breast conserving surgery coincided with emergence of effective systemic therapies.
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Meta-analyses such as the Early Breast Cancer Trialists Collaborative Group confirmed that long-term mortality is influenced by prevention of loco-regional recurrence by more extensive surgery.
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Modern treatment is now based on an intermediate paradigm which draws upon the concepts embodied in the paradigms of both Halsted and Fisher.
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Review Halsted, Jatoi & Benson References Papers of special note have been highlighted as: •• of considerable interest
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Future Oncol. (2014) 10(9)
One of the six famous randomized controlled trials that demonstrated the viability of breast conserving therapy. Veronesi is a founder of breast-conserving surgery.
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22 Williams IG, Murley RS, Curwen MP.
Very famous study with considerable impact on shifting attitudes towards more conservative surgical therapy.
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Landmark meta-analysis of the breastconserving randomized controlled trials, with findings that suggest that local breast cancer recurrence has an effect on mortality in the long term.
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predict recurrence of tamoxifen-treated,
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