THE NATURAL HISTORY OF BREAST CANCER AND THE LINK BETWEEN LOCAL RECURRENCE AND DISTANT METASTA- SES: IMPLICATIONS FOR THERAPY

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1 THE NATURAL HISTORY OF BREAST CANCER AND THE LINK BETWEEN LOCAL RECURRENCE AND DISTANT METASTA- SES: IMPLICATIONS FOR THERAPY Maurice Tubiana 1, Serge Kscielny 2 1 M.D. Hnrary Directr f the Institute Gustave Russy, Villejuif Prfessr Emeritus f Medicine at Paris Sud University President f the French Natinal Academy f Medicine, 2 PhD Department f bistatistics and epidemilgy f the Institute Gustave Russy, Villejuif, France Received July 30 th, 2001; received in a revised frm Octber 15 th, 2001; accepted 24 th Octber 2001 SUMMARY This study had tw aims: 1) t assess the tumur size at metastatic disseminatin by analyzing the relatinship between tumr diameter and incidence f distant metastases during the 25 years after initial treatment, 2) t investigate the impact f a residual tumr n the prbability f distant disseminatin. An analysis f the data registered at the Institut Gustave Russy in Villejuif was undertaken n abut 4000 breast cancer patients treated prir t the use f adjuvant chemtherapy and fllwed-up fr ver 15 years. The data shw that the vlume at which disseminatin ccurs in 50% f patients can be estimated in each subset f patients as defined by the size f the tumur, histpathlgic grade and number f invlved axillary ndes. This V 50 varies widely but is inversely crrelated with the histlgic grade and the number f invlved axillary ndes. Mrever, a gradual increase in the grade f the tumurs was bserved during their grwth, cnfirming the usefulness f early treatment and breast screening. The analysis f the delay between the initial treatment and clinical emergence f the metastases shws that the excess f distant metastases in patients with lcal recurrence crrespnds t disseminatins which are initiated after initial treatment, and therefre riginated frm the residual tumr. This finding emphasizes the imprtance f lc-reginal treatment. Whereas during the first 2 years after treatment the incidence f distant metastases was lwer in the arm treated by chemtherapy (P=0.32, NS), frm the third year n, the reverse was bserved and the incidence f metastases was significantly lwer in the grup treated by pst-p RT + ply A ply U (P<10-4 ). At 15 years, the incidence was significantly lwer in the grup treated by pst-p RT + ply A ply U (42% metastasis-free survival in the RT grup and 29% in the CT grup p=0.03). This result seems t be due mstly t lwer incidence f lcal recurrence. But even in patients withut lcal recurrence, the incidence f distant metastasis is nt greater than that in patients treated by CMF, which might be due t the favurable effect f ply A ply U. The results f this trial are cnsistent with thse f ther recent clinical trials, and emphasize the favurable impact f pst-p RT and the paramunt imprtance f lcal cntrl n the lng-term utcme f the disease. INTRODUCTION It was shwn a few decades ag that pst-perative raditherapy (pst-p RT) markedly reduced the incidence f lcal recurrence bth after a mastectmy and as a cnservative surgery; subsequently several cntrlled clinical trials reprted a higher survival in patients having received pst-p RT. Nevertheless, the usefulness f pst-p RT in rutine clinical practice is still cntrversial. The first reasn is that the data are smewhat cnflicting. The discrepancies appear t be mstly related t the quality f radiatin therapy. In the first studies, the dse was ften nt sufficient t cntrl residual disease [1,2,3,4], r the treatment duratin was t lng [5]. In rder t prevent lcal recurrence, a sufficient dse f Gy in 4-5 weeks has t be delivered [3,4]. After lwer dses r lnger prtractin, the incidence f lcal recurrence is appreciable [3]. Mrever, the txicity Prceedings f the Cnference Advances in Radiatin Onclgy: Diagnsis-Treatment Planning-Clinical Outcme, Pznań, April 19 th 21 st, 2001.

2 f RT is far frm being negligible when the dses t the heart, the great vessels r the lungs are high [6]. Thus the signifycance f the first meta-analysis was limited because trials with pr r satisfactry radiatin techniques and dses were pled tgether [7]. Since it is difficult retrspectively t discard trials with unsatisfactry techniques (such as rthvltages) nly recent trials shuld be cnsidered. Secndly, the methdlgy f the statistical studies was ften debatable. A five year fllw-up is much t shrt t allw any cnclusins t be drawn as we will shw belw. Mrever, statistical studies, in which nly the first site f recurrence is mnitred, are misleading: in patients submitted t pst-p RT lcal recurrences are suppressed r delayed, cnsequently, the frequency f distant metastases, as the first site f recurrence, is artefactually increased [8]. Similarly, in patients wh did nt receive RT, the high incidence f lcreginal recurrence cnceals the actual frequency f distant metastases. Thirdly, the interpretatin f the data must take int accunt the natural histry f breast cancer. Fr example, the grwth rate f breast cancer is slwer in lder patients [9] (Table 1), therefre the delay between treatment and recurrence is lnger, which may explain the difference between pre and pstmenpausal patients. Similarly, the grwth rate f histpathlgic grade 1 tumrs is slwer, and the delay TM (time interval between initial treatment and detectin f metastases) between treatment and recurrence, as well as the verall metastatic grwth duratin are lnger (Table 1). In general, in patients with gd prgnstic indicatrs, such as the absence f ndal invlvement, the delay is lnger and therefre a lnger fllw-up is required t evidence the beneficial effect f pst-p RT. Table 1. The median grwth duratin (GD) is the time interval between the first prliferatin f the first metastatic cell and the clinical detectin f the metastasis. It was calculated in each subset f patients with the methd previusly described (8). GD is equal t the sum f IT (the part f the metastatic grwth that has ccurred befre the treatment f the tumr) and TM (the time interval between initial treatment and detectin f the metastases). IT is calculated and TM measured. TM values are given in parentheses after the GD value. GD is apprximately equal t 20 dubling times (DT) (12). Therefre the mean DT appears t be abut 3 mnths. The values indicated in parenthesis are the theretical cumulated prprtins f patients with distant metastases after a very lng delay since treatment (23). The grwth duratins were cmputed assuming in (A) that metastases in excess were initiated befre initial treatment and in (B) that they riginated frm residual tumr after initial treatment. As discussed in this paper, A values are nt cnsistent with ur knwledge f tumr cell kinetics, therefre in the table the values given are thse calculated with the latter hypthesis. Median metastatic grwth duratin Prprtin f pts with met at 20 y in mnths Grups f patients in pts withut LR in pts with LR pts withut LR pts with LR Overall ppulatin Age Tumr diameter cm cm > 6 cm Ndal invlvement ( 0.75) > Histl. Grade A B I ( 0.85) II III Based n data frm reference 8.

3 This paper has tw aims: the first ne is t review ur knwledge n the natural histry f breast cancer and the link between lcal recurrence and distant disseminatin, and the secnd ne is t interpret the clinical results in the light f this knwledge. Natural histry f human breast cancer: Until recently, the descriptin f the natural histry f human cancers had remained purely qualitative. Hwever, with the intrductin f cmputerized cancer registries, we are nw able t extract reliable quantitative infrmatin that therwise culd nt have been btained frm the huge amunt f data fund in patient files [10,11,12,13,14,15,16]. The main event during the grwth f a human tumur is metastatic disseminatin [17]. Prir t its ccurrence, the breast cancer is a lcreginal disease which is easily cured by lcal treatment. The tumr size at metastatic disseminatin varies widely [10,15]. Disseminatin has already ccurred in sme breast cancers f less than 5 mm in diameter, whereas it has nt ccurred in sme bulky tumrs f mre than 8 cm in diameter cured by lcal treatment alne. A majr gal f the study f the natural histry f breast cancer is the analysis f the relatinship between tumr size and the prbability f metastatic disseminatin as well as the influence n this relatinship f the varius tumr characteristics, such as the histlgic grade and the number f invlved axillary ndes [15]. In 1975, we undertk a study which was based n the analysis f the data registered at the Institut Gustave-Russy in Villejuif n ver 3000 breast cancer patients treated prir t the use f adjuvant chemtherapy, their fllw-up ranging frm 15 t 32 years [10]. The data shwed that the prprtin f distant metastases appearing mre than 25 years after treatment is negligible. In patients withut lcal recurrence, the cumulative prprtin f patients with distant metastases after 25 years f fllw-up can therefre be assumed t be equal t the prbability f distant disseminatin befre initial treatment. We subdivided the ppulatin f patients int eight classes accrding t tumr vlume and the tumur diameter at surgery, and pltted fr each class the actuarial cumulated prprtin f patients with metastases as a functin f time after treatment up t 25 years. The patients with distant metastasis at initial wrk-up were included in this cumulated prprtin. The relatinship between the vlume at the time f diagnsis and the cumulative prprtin f patients with distant metastases is sigmid. The distributin f tumr size at initiatin is lg nrmal. Fr tumrs larger than 1 cm in diameter, a small decrease in the size f the tumr at initial treatment results in a marked reductin in the prprtin f patients with ccult metastases. This is the ratinale behind screening prcedures [10]. Mrever, it was fund that the average threshld vlume at which disseminatin ccurs is inversely crrelated with the number f invlved lymph ndes [13] and the histlgic grade f the tumr [15]. In rder t quantify the influence f histlgic grade n the prbability f metastatic disseminatin fr tumrs f all sizes, the patients were subdivided int three grups accrding t the histlgic grade. In each subgrup, there was a significant crrelatin between tumr size and the prbability f distant spread, but the median tumr size at disseminatin was markedly larger fr grade 1 tumrs [15] (Table 2). An interesting bservatin made during the study was that the prprtin f grade 1 tumrs was higher in small tumrs than in large nes, while the reverse was bserved fr grade 3 tumrs; these data suggest that, during their grwth, tumrs prgress twards higher grades [15]. Table 5 shws that fr a diameter f 0.35 cm half f the tumrs have already a grade higher than 1. This prgnsis f the grade was later cnfirmed by the Tabar et al. data [18]. The gradual increase in a tumr s malignant ptential cncurs with the cncept f tumr prgressin, which pstulates that tumrs evlve frm bad t wrse [19]. Anther finding was that the prprtin f patients withut lymph nde invlvement diminishes rapidly as a functin f tumr size, while the prprtin f patients with fur r mre invlved ndes increases markedly. These bservatins

4 are cnsistent with a mdel assuming the existence f a threshld vlume fr ndal invasin and gradual axillary nde invlvement during tumr grwth [13]. The data supprt a mdel in which there is an rderly pattern f ndal invlvement frm n lymph nde invlvement t invlvement f ne lymph nde and subsequently f tw lymph ndes and s n. The data strngly suggest that tumrs with early first nde invlvement are als thse which invade the secnd and the third nde early. Each tumr prgresses at its wn pace. The prpensity fr lymph nde invlvement varies frm tumr t tumr. Hwever, the data crrespnd t a unimdal distributin f the tumrs, frm thse with a high prpensity and the earliest ndal invlvement t thse with the lwest and the latest invlvement. These data are in clear cntradictin t the mdel f Slack et al. [20], which assumed the existence f tw subgrups f breast tumrs, thse with high and thse with lw prpensity. It is pssible t estimate the tumr diameter fr which 50% f tumrs have initiated distant metastases in patients with varius histlgical grades and numbers f invlved axillary lymph ndes (Table 3). Table 2. Median tumr diameter (cm) at the time f the invlvement f the first axillary nde and at initiatin f distant metastases, and median delay TM (mnths) between treatment and emergence f the first metastasis. (frm ref. 10, 12, 13). Grade Lymph nde invlvement Distant metastases Delay TM treatment - - emergence f the first met mnths mnths mnths Table 3. Tumr diameter (cm) fr which 50 % f tumrs have initiated distant metastases as a functin f the histlgic tumr grade, and number f invlved ndes (frm ref. 10). Number f invlved axillary ndes > 10 Grade Grade 2 r Once the size f the tumr at initiatin f distant metastasis and at invasin f the first lymph nde had been estimated it was pssible t shw that there was a strng and highly significant crrelatin between these tw sizes in the varius subsets f patients, and therefre t calculate fr a tumr f a given size the prbability f distant disseminatin as a functin f histlgic grade and number f invlved axillary lymph ndes (Table 4). Table 4. Prprtin f patients with distant metastases as a functin f diameter f the tumr, the histpatlgic grade (Gr), and the number (N) f invlved axillary ndes. (frm ref. 15). Tumr Diameter 1 cm 2 cm 4 cm N Gr Gr Gr The data als shw that, during tumr prgressin, the capacity fr lymphatic spread is n average acquired much earlier than the capacity fr hematgenus spread [15] (Table 5). Thus, the assumptin that all patients with invlved axillary ndes are at high risk f distant metastasis is verly pessimistic. Knwing the tumr diameter, the grade and the number f invlved axillary ndes f a patient, it becmes pssible t estimate the prbability f distant spread (Table 4). Tumr vlumes at the invasin f the first axillary nde are apprximately 1.5 times larger in patients with a tumr lcated in the inner quadrants than in thse with tumrs lcated in the uter quadrants and patients with uter quadrant tumrs have earlier axillary nde invasin (Table 6). Nevertheless, fr tumrs lcated in the inner r the uter quadrants, the median size at first metastatic disseminatin is nt statistically different in the tw subgrups, and, if anything, is slightly smaller fr the inner quadrant tumrs [13]. This discrepancy shws that the crrelatin between nde invlvement and distant spread is nt causal. Distant dissemi-

5 natin is nt a tw-step prcess. Axillary invlvement is a gd index f the prpensity f tumr cells t acquire the capacity fr hematgenus spread, but it is nt the cause f this spread. Table 5. Tumr size and prgnstic factrs. Tumr diameter 1. Grade 1 Grade > cm 2. Grade < 3 Grade 3 7 cm 3. Axillary lymph nde 1.3 cm Internal mammary chain 3.9 cm 0 1 (inner quadrants) 5. Distant metastases (pts withut lcal recurrence) 3.8 cm 7 M O M A The mean diameter f the tumr fr which in 50 % f patients: 1. the histlgical grade becmes greater than 1 2. the histlgical grade becmes equal t 3 3. the first axillary lymph nde is invlved 4. the first internal mammary chain lymph nde is invlved fr patients with breast tumr lcated in the inner quadrant 5. distant disseminatin ccurred. (cmpiled frm ref. 8, 13, 15) Table 6. Median tumr diameter (cm) at the time f first and secnd axillary nde invlvement and at metastatic disseminatin in inner and uter quadrant tumrs. (frm ref. 8 and 13). All pts Inner Quadrants Outer Quadrants Invlvement f first axillary nde Invlvement f secnd axillary nde Metastatic disseminatin Lcreginal recurrence rates are much higher in patients with ndal invlvement and are crrelated with the number f invaded ndes [4]. Lymphatic spread is therefre als a pinter f lcal tumr cell migratin and invasin f the surrunding tissues. Hence the studies f the cell kinetics f breast cancer and thse f its natural histry lead t several practical cnclusins: 1 The delay TM between the initial treatment and the clinical emergence f ccult metastases depends n (a) The grwth rates (i.e. their dubling time) f the metastases and f the primary tumr, (b) The size f the primary tumr at which distant disseminatin ccurred. (This critical size is smaller in tumrs f high grade and/r with ndal invlvement) and, (c) There is a strng crrelatin between the grwth rate f distant metastases and the time interval between detectin f metastases and death [9,15,21,22]. The grwth rate f the primary tumr r its DNA labelling index are very strng independent prgnstic factrs, a high prliferatie rate being assciated with a high prbability f early distant disseminatin [15,21]. 2 Early invlvement f axillary lymph ndes is strngly crrelated with early distant spread and with rapid grwth rate f the tumr and its metastasis. Hwever, despite this crrelatin, grwth rate and early lymph nde invlvement have an independent and highly significant prgnstic value [15]. 3 The grwth rate f breast cancer is relatively slw, the mean tumr dubling time is abut 9 mnths. The mean dubling time f metastases is much shrter, abut 4 mnths. Bth vary markedly and metastatic grwth duratin (GD) are shrter in patients under 40 and slightly lnger in patients ver 60 years (Table 1). They are als much shrter in patients with high grade tumrs r ndal invlvement. The grwth rate f tumr metastasis can be estimated in the varius subsets f patients by analyzing the delay TM between initial treatment and clinical emergence f the metastasis [8]. The median metastasis grwth duratin (GD) is equal t IT (time interval between the initiatin f metastases and treatment f the primary tumr) plus TM. TM can be measured and IT is evaluated in each subset f patients if the mean size f the primary tumr at the time f initial treatment and the primary tumr grwth rate are knwn. The size at metastatic

6 initiatin can be assessed if the histlgic grade and the number f invlved lymph ndes are knwn. The accuracy f the evaluatin f the grwth duratin f the metastases can be imprved by searching the best fit with the metastasis appearance curve [8]. GD is abut equal t 20 dubling times. The value evaluated fr GD crrespnds t a mean dubling time f a few mnths (3 t 4 mnths), which is cnsistent with the dubling time measured n sequential chest X-rays f patients with lung metastases [23,24]. The results f these evaluatins cnfirm the influence f the grade, the ndal invlvement, and the age n the metastatic grwth rate (Table 1). They als shw that the metastases detected after treatment f large tumrs have a mre rapid grwth rate [8], which is cnsistent with the cncept f tumr prgressin [19], illustrated by the prgressin frm hrmne dependence t independence [25] and the prgressin f histlgic grade [15,18]. The link between lcal recurrence and distant disseminatin Numerus data shw that there is als a strng crrelatin between the existence f residual disease after initial treatment and distant disseminatin [26,27,28,29,30, 31,32,33,34,35,36]. Tw pssible explanatins have been prpsed fr the increased incidence f distant metastases bserved in patients with lcreginal recurrences (LR). Either LR is the signature f tumr aggressiveness, and then aviding recurrences (i.e., by raditherapy) is f little value. The alternative is that LR is a nidus fr metastatic disseminatin. In rder t investigate this prblem, fur thusand patients cnescutively treated in the same institutin frm 1954 t 1975 were studied [8]. Nne f them had received adjuvant chemtherapy. Tumr characteristics, lcal recurrence, and first detectin f distant metastases had been prspectively registered fr each patient and mean values were calculated in the varius subsets f patients. The prprtin f metastasis-free patients was lwer by abut 80% in all subsets f patients with LR (Fig. 1) After 20 years fllw-up At diagnsis Fig. 1. Relatinship between clinical tumr vlume (lg-scale) and prprtins f metastases at lng-term (prbit scale). Each symbl crrespnds t a grup f patients: circles t grups f LR- patients, and squares t LR+. Grups are defined at 1 cm step in diameter. Patients with metastases are nt excluded. The lwer curve displays the relatinship between tumr vlume and prprtin f patients with synchrnus metastases. The slpes f the curve crrespnding t metastases detected during the fllw-up f LR- patients and f the lwer curve are equal. In LR+ patients, there is n significant crrelatin between tumr size and prprtin f patients with metastases, and the curve is nt parallel t the curve crrespnding t prpptins f patient with synchrnus metastases. The regressin lines were calculated after pling data cncerning LR+ and LR- patients. (frm ref. 8). In patients withut LR, the mnthly rate f distant metastases incidence decreases cntinuusly with time after initial treatment. Cnversely, in patients with lcal recurrence, this rate increases during the first year after initial treatment, and the metastases in excess appear slightly later than in patients withut lcal recurrence. Using a mathematical mdel, it can be shwn that, in patients with lcal recurrence, nearly all f the metastases in excess had been initiated after initial treatment [8]. The assumptin that even in patients with lcal recurrence the metastases in excess were initiated frm the primary tumr is nt plausible because if this were the case the grwth f the metastases wuld have t be much slwer than that f the metastases initiated frm the tumrs f patients withut lcal recurrence. On the ther hand it is knwn that the mst malignant tumrs have

7 a mre rapid grwth rate [17,21,22,23]. Mrever, if the metastases had a slwer grwth rate, the time interval between emergence f the metastases and death wuld be lnger [23], which is nt what was bserved [8]. Hence ur results are at variance with the hypthesis that a greater tumr aggressiveness in patients with LR explains the excess f metastases. Therefre, it can be cncluded that mst f the metastases in excess bserved in patients with lcal recurrence riginated after initial surgery frm the residual tumr [8]. Metastatic grwth duratin was estimated in each subset f patients (Table 1). Patients with lcal recurrence have shrter grwth duratin. This is in keeping with the well knwn clinical bservatin: lcal recurrence ccurs preferentially in patients with the mst malignant tumrs. Furthermre, the lack f any relatinship between tumr size and cumulative prprtin f metastases in patients with lcal recurrence is cnsistent with the hypthesis that residual tumr is the nidus fr distant spread [8]. As shwn in Table 2, amng patients with LR the lng-term prprtin f patients with metastases is ften equal t 80% - 90%. Even in the mst favurable subset f patients it is superir t 75%. This is in cntrast with grade 1 patients withut lcal recurrence in whm the cumulated prprtin plateaus arund 25% after a fllw-up f 20 years. These data emphasize that the prgnsis f tumrs becmes dramatically wrse when a lcreginal recurrence ccurs. Hwever, the delays between initial treatment and clinical detectin f metastases can be very lng in patients with lcal recurrence. Amng patients with favurable prgnstic factrs: the superir limit f the 95% cnfidence interval can be as lng as 30 years in grade 1 tumrs. These data underline the need fr a very lng fllw-up in patients with lcal recurrences and shw als the fallacy f cnclusins based n a fllw-up f less than 10 years, in particular fr patients with breast cancers f gd prgnsis. RT can prevent distant metastasis nly by cntrlling the residual tumr which culd be a nidus fr distant spread. RT, therefre, can be beneficial nly in patients withut ccult distant metastases at the time f initial treatment, and with a residual tumr after surgery [26]. Thus, accurate estimatin f the likelihd f distant spread in each subset f patients is a prerequisite fr identifying the subset f patients fr whm mre effective lcal treatment culd imprve the utcme. In patients with pr prgnstic factrs, the prprtin f patients withut ccult metastases is small. Cnversely, in patients with gd prgnstic factrs, the prprtin f patients with a residual tumr after surgery is small. Thus the beneficial effect f RT is likely t be small and, therefre, difficult t evidence [26]. Pst-p RT can cntrl residual tumrs, but it has n impact n the grwth rate f metastases. On the ther hand, adjuvant chemtherapy reduces the number f viable cells in metastasis at each administratin, and therefre, slws dwn their grwth rate during the treatment perid. It can be expected that it increases the time interval between initial treatment and clinical detectin f the metastasis and reduces the rate f emergence f distant metastases during the first few years after treatment. DISCUSSION OF THE CLINICAL DATA This knwledge f breast tumr natural histry and f the impact f treatment n the grwth rate f ccult metastases facilitates the interpretatin f clinical data. In the first cntrlled trial cmparing cnservative treatment and mastectmy by Atkins [1], the incidence f distant metastases was higher in stage II patients treated by cnservative surgery + raditherapy than in thse treated by mastectmy. This appears t be the cnsequence f a t lw radiatin dse which was unable t cntrl residual tumr. Later it was shwn in several cntrlled trials that when a dse f 50 Gy was delivered after cnservative surgery with a prper fractinatin and prtractin there was n difference in verall survival between cnservative treatment and radical mastectmy [37,38,39,40]. Several cntrlled trials have cmpared patients with r withut pst-p RT after

8 surgery [29,41]. Meta-analyses f these trials have been carried ut [7,42,43]. In the 1995 verview f 35 randmized trials f surgery and RT (including 28,465 wmen fr whm data n mrtality was available) there was n survival advantage f the irradiated ver the nn-irradiated grup after mastectmy r breast cnserving surgery [42]. RT reduced death frm breast cancer but was assciated with an increased risk f death frm ther causes. Hwever, as discussed in the intrductin, n analysis was made in this study f the radiatin dse and the technique f RT, whereas bth these factrs are likely t have a strng impact n the therapeutic results. In the subsequent meta-analysis published in 2000 by the Oxfrd Grup [43], there is a small benefit: the mrtality caused by the cancer is reduced; hwever this advantage is partly ffset by an increase in cardivascular mrtality. The better results f pst-p RT in the recent meta-analysis are prbably due t the inclusin f mre recent trials, in which the radiatin technique was better. It is als due t a lnger fllw-up since, as discussed abve, the favurable cnsequences f the cntrl f residual tumr are bserved after relatively lng fllw-ups (ver 7 r 8 years). This is why the excess f distant metastases attributable t the residual tumr is easily verlked at a fllw-up f nly five years. Indeed ur data shw that nly abut half f the distant disseminatin in excess in patients with lcal recurrence are detected during the first five years f fllw-up [8]. This prprtin is smaller in patients with gd prgnstic factrs (histlgic grade I r absence f ndal invlvement). Hwever, it shuld be recgnized that there is a wide discrepancy between the spectacular reductin in the incidence f lcal-reginal recurrence and the small decrease in cancer mrtality. In 1986, we already discussed this pint and shwed that, as discussed abve, pst-p RT can avid distant disseminatin nly in patients withut ccult metastases at initial treatment and with residual tumr, which will cause lcal recurrence when pst-p RT is nt perfrmed [26]. In 1986, we estimated that nly 15% t 20% f the patients belnged t this categry. This prprtin is prbably nt much greater tday, which is why the ptential gain is limited. Hwever, even if nt very large, this gain cmpares favurably with that assciated with adjuvant chemtherapy and des nt cmpete with it. RESULTS OF A RECENT CLINICAL TRIAL COMPARING CHEMOTHERAPY AND POST-OP RT It is relevant, in this cntext, t discuss the results f a French Federatin f Cancer Centers (FFCC) cntrlled trial recently updated at the Institut Gustave Russy [44] and which, in 500 patients with stage II and III breast cancer with invlved axillary ndes treated by mastectmy, cmpared tw adjuvant treatments: chemtherapy with CMF versus pst-p RT assciated with immuntherapy by ply A-ply U. The incidence f lcal recurrence was identical in the tw arms during the first tw years. Thereafter there were nly few recurrences in the RT-AU arm. At 15 years fllw-up, the cumulative incidence f lcal recurrence was 18% (CI ) in the pst-p AU arm and 45% (CI 38-53) in the CMF arm. This 40% reductin is highly significant (p<10-6 ). Thus despite the reductin in lcal recurrence induced by chemtherapy [45], the reductin in pst-p RT appears much greater despite the fact that in this multicenter trial the RT technique was prbably nt ptimal, as shwn by the relatively high incidence f lcal recurrence in the RT arm. Amng perable patients with tumrs f the inner quadrants and with invlved internal mammary chain, the mdel predicts that ver ne third f them have n distant metastases. This result as we have emphasized [26,28,41] is cnsistent with the effecttiveness f the treatment f the internal mammary chain. The annual incidence f distant metastases was lwer in the CMF arm during the first tw years, and the difference was statistically significant (lg rank). Hwever, frm the third year till the fifteenth, (Fig. 2) it became lwer in the RTAU arm, and the difference is highly significant. At 15 years fllw-up, the cumu-

9 lative incidence is 43% (CI ) in the RTAU arm and 29% (CI 36-23) in the CMF arm (p=0.04) (Fig. 5). The verall survival (OS) was nearly identical in the tw arms till the seventh year f the fllw-up. Frm the ninth year, it became slightly higher in the RTAU arm, but the difference is nt statistically significant. At the ten - year fllw-up the OS is 55% (CI 48-61) in the RTAU arm and 48% (CI 40-54) in the CMF arm and at 15 years fllw-up they are respectively 43% (CI 36-50) and 36% (CI 30-42). The relative risk f death in the RT ply AU arm, as cmpared with the CMF arm, is RR=0.87. There was n difference in the time interval between the clinical emergence f distant metastases and death between the tw arms f the trial, which shws that amng patients with distant metastases the grwth rate and aggressiveness f the disease were cmparable in the tw arms [8,23]. A cmparisn f the metastases-free survival arm as a functin f its histlgical grade [46], is f interest. In patients with grade 1 tumrs, there is n difference in the prprtin f metastases at 5 years whereas at 15 years fllw-up there is a clear difference (Fig. 3). In patients with grade 3 tumrs, the tw curves diverge after the secnd year, and are parallel frm the fifth till the fifteenth year f the fllw-up (Fig. 4). The data cncerning grade 2 tumrs are intermediary. These curves are cnsistent with what is knwn regarding the slw grwth rate f grade 1 tumrs, and the rapid grwth f grade 3 tumrs [8,9]. The FFCC trial was stpped prematurely because the incidence f lcal recurrence was identical in the tw arms during the first tw years; mrever the preliminary data suggested that CMF might give a lwer incidence f distant metastases. In fact, after a lnger fllw-up there is a reductin in the incidence f distant metastases by nearly ne third, which is greater than the gain bserved in the trials where pst-p (RT) is added t systemic therapy. Unfrtunately, the number f patients included in the trial cmparing CMF versus pst-p RT + ply AU was nt sufficient t make detailed cmparisns. Nevertheless, it allws several remarks: [1] The lng-term incidence f distant metastases is significantly lwer in pa-tients treated by RT+AU than in patients treated by CMF. In this pragmatic trial it is difficult t distinguish the rle f pst-p RT and that f immuntherapy. Nevertheless, we have attempted t estimate the respective impact f the tw treatment mdalities. The first methd that we used was t censr patients with lcal recurrence at the time f the detectin f the first distant metastases (Fig. 5). With this methd, the metastases that culd have been initiated in the residual tumr are ignred, and the metastases which are taken int accunt are mstly thse which riginated frm the primary tumr. In this case the metastases-free survival rates are similar, which suggests that the effectiveness f CMF and ply AU is analgus [2] Anther methd is t intrduce a crrectin factr (Fig. 6). Our previus study enabled us t evaluate the excess incidence f distant metastases which are assciated with lcal recurrence. If we intrduce these data in a simulatin mdel the benefit arising frm a lwer incidence f lcal recurrence can be excluded and it becmes pssible t assess the independent rle f immuntherapy. Indeed the curves f metastases-free survival, when crrected fr the metastases assciated with lcal recurrences, als suggest that the efficacy f CMF is nt greater than that f ply A ply U. This cnclusin is cnsistent with the results f the previus cntrlled trial cmparing patients with breast cancer receiving ply A ply U as an adjuvant immuntherapy t with thse nt receiving it [47,48]. If this cnclusin is crrect the difference between the tw grups in the incidence f distant metastases can be attributed t pst-p RT. This result is in accrdance with the results f recent trials assessing the impact f pst-p RT in patients receiving adjuvant chemtherapy t be discussed belw. Anther study, the secnd Stckhlm trial [29,49], cmpared, CMF versus pstp RT in 1020 patients with breast cancer. The incidence f lcal recurrence was markedly reduced in patients receiving pst-p RT, and the analysis f cumulated recurrence demnstrated a strng crrelatin between the lc-

10 1.0 Prprtin metastases free 1.0 Prprtin metastases free Histlgical Histlgical grade grade (SBR)=1 (SBR)=1 P 0.8 r P rp p 0.6 r r ti t 0.4 in 0.2 n Treatment Ply-AU+RT + RT CMF CMF Years since initial treatment Lg Rank test value: 3.47 p= 0.06 LgRanktestvalue:3.47 p=0.06 Fig. 2. Prprtin f metastasis-free patients studied by Kaplan Meier. During the first tw years, the incidence f metastatic disseminatin is lwer in the chemtherapy arm. Hwever, frm the third t the fifteenth, the incidence becmes lwer in the raditherapy + ply AU arm. At 15y, the cumulative incidence is 43% (CI 50-37) in RTAU arm and 29% (CI 36-23) in the CMF arm. P r 0.8 P p rp 0.6 r rti t 0.4 i n n 0.2 Treatment Ply-AU+RT + RT CMF CMF Years since initial treatment Lg Rank test value: 4.73 p= 0.03 Lg Rank test value: 4.73 p=0.03 Fig. 3. Prprtin f metastasis-free patients in the grup with histlgical grade P 0.8 r P rp p 0.6 rti r 0.4 t i n 0.2 n 0.0 Prprtin metastases free Histlgical grade (SBR)=3 Histlgical grade (SBR)=1 Treatment Ply-AU+RT + RT CMF CMF Years since initial treatment Lg Rank test value: 1.76 p= 0.18 LgRanktestvalue:1.76 p=0.18 Fig. 4. Prprtin f metastasis-free patients. Althugh after the third year the incidence f distant metastasis is lwer in the RT + ply AU arm, the difference is smaller and statistically nt significant. 1.0 Prprtin metastases free P r 0.8 P p rp 0.6 r rti t 0.4 i n n 0.2 Treatment Ply-AU+RT + RT CMF CMF Years since initial treatment Lg Rank test value: 0.6 p= 0.44 Lg Rank test value: 0.6 p=0.44 Fig. 5. In rder t eliminate the impact f lcal recurrence n the incidence f distant disseminatin, patients are censred at the time f lcal recurrence. The difference between the tw arms after the third year disappears.

11 Simulated (metastases attribuable t LR eliminated) 1.0 Treatment Ply-AU+RT+ RT CMF CMF 0.8 Prprt i n wi thut me tas tases Prprtin withut metastases Years since initial treatment Fig. 6. In this simulated curve, a crrective factr is intrduced. This factr is based n a previus study (ref. 8) which enabled the evaluatin f the excess incidence f distant metastases assciated with lcal recurrence. With this crrective factr, the difference between the tw metastasisfree survival curves als becmes very small. reginal cntrl and subsequent distant metastases. Thus the data are cnsistent with the abve results f the FFCC trial. Unfrtunately, in the Stckhlm trial, nly the first site f recurrence was mnitred, therefre a detailed cmparisn with the FFCC trial is difficult. RT acts by cntrlling the residual tissue, and thereby suppressing the nidus fr further disseminatin. The aim f adjuvant chemtherapy is t destry distant micr metastases. An analysis with a simulatin mathematical mdel f the metastasis appearance curve in treated and in cntrl patients has shwn that the maximum number f cells in the ccult metastases cntrlled by the chemtherapy is apprximately 10 6 [50]. Assuming that the prprtin f clngenic cells is 10-3, it fllws that the prprtin f surviving tumr cells after cmpletin f 6 cycles f CMF is 10-3 [50]. This crrespnds t a radiatin dse equal t 10D 50 (apprximately 25 Gy) delivered t the whle bdy in six sessins. Thus adjuvant chemtherapy and pstperative RT d nt cmpete but are cmplementary. Indeed, the mst recent trials have cmpared in patients treated by surgery and adjuvant systemic therapy (chemtherapy r tamxifen) thse with r withut pst-p RT [51,52]. The metaanalysis which has been carried ut in the eighteen trials identified (invlving 6367 patients), has shwn a strng reductin in lcal recurrence, imprved relapse-free survival and verall survival, cnfirming the results f these three trials [53]. Sme authrs have hypthesized that this favurable effect is bserved because adjuvant systemic therapy allwed lcreginal radiatin t manifest its effect [53]. Rather the abve discussin suggests that the beneficial effect has becme significant because 1) the trials are mre recent and, therefre, the irradiatin technique f adequate quality and, 2) the fllw-up is lnger. In these studies, adding pst-p RT t classical systemic therapy did nt raise any ethical prblems and is readily accepted, whereas it was clear in the FFCC trial that many nclgists were reluctant t withhld systemic adjuvant therapy in patients wh culd benefit frm it. Mrever, the statistical study f Frtin et al. [54] cncurs with urs [8] in demnstrating the causal respnsibility f lcal failure in the death f a significant prprtin f patients. The rle f immunlgical factrs in breast cancer is anther tpic which remains cntrversial. In the 1970s, sme authrs [55] described the depressin f immunlgical defenses caused by raditherapy and the alleged increase f distant spread in sme patients treated by raditherapy. Later, dubts have arisen regarding the efficacy f immuntherapy despite it s psitive effect bserved in ur previus trial [47,48]. The FFCC study brings new data t this debate [44], and justifies the pprtunity t carry ut new cntrlled clinical trials t assess the respective benefit f pst-p RT and immuntherapy. Mst trials assessing the benefits f pst-perative raditherapy have included nde psitive patients; it wuld be f interest t undertake studies n nde negative patients. In this cntext, the prblem discussed in the current literature is whether pst-p RT is merited in patients with gd prgnstic factrs and high prbability f cure withut pst-p RT [45,56,57,58]. Our data shw that althugh lcal recurrences are mre frequent in patients with pr prgnstic factrs, the in-

12 cidence remains relatively high even in the best subset f patients. A. Wallgren [57] has recently argued that in patients with small tumrs nly 6% f them will experience lcal relapse after a 5 - year fllw-up. Our data lead us t expect that this prprtin will increase up t 10 t 12% at a 10 - year fllw-up, and that 70% f patients with lcal recurrence will experience distant metastases. The delay between initial treatment, emergence f distant metastases and death, might be lng (ten t twenty-five years) but nevertheless this sequence f events is likely t be bserved [8]. Thus the benefit f pst-p RT shuld be f abut 7% t 8%, a gain which shuld nt be verlked since it crrespnds t abut a quarter f the verall mrtality in this type f breast cancer. Hwever, this ptential gain might be ffset by the lngterm txicity f radiatin if the irradiatin technique is nt ptimal. The ratinale behind pst-perative RT after mastectmy r tumrectmy is currently well dcumented [26,29,31,33,43, 54,58,59,60]. Here again the main questin is, therefre, the cst f the ptential gain in terms f radiatin txicity n lung, heart and the great vessels, and t what extent this txicity can be reduced r avided by advances in radiatin techniques. The analysis f cardiac txicity has shwn that the txicity is much greater in patients with large vlumes f the heart irradiated with relatively high dses (in particular in patients with tumrs lcated in the left breast) [6,61]. As recently discussed in several papers [6,62,63], we can reasnably expect that with electrns, multileaf cllimatrs and cnfrmal RT r intensity mdulated RT, the dse t the heart and the great vessels can be dramatically diminished, thereby minimizing vascular and cardiac mrbidity. This wuld eliminate the main reasn fr denying the benefit f pst-p RT t lw risk patients. The last questin is whether RT r systemic treatment shuld cme first. In principle, it wuld be lgical t start with RT, and this was the cnclusin f a retrspective study [64]. This cnclusin was challenged by a cntrlled trial carried ut n 244 patients [65]. Hwever, ur data shw that the fllw-up was much t shrt t draw any cnclusins. Anther pssibility culd be interdigitated treatment, which may decrease the txic risk, but this is a cmplex technique. In cnclusin, the analysis f the available data shws that there is a causal relatinship between the lack f lcal cntrl f the primary tumr and the increase in the incidence f distant metastases in patients with lcal failure. Pst-perative radiatin therapy is therefre justified, but the dse shuld be sufficient and the raditherapy technique shuld aim at minimizing the dse t the heart and the great vessels, which is nw pssible thanks t the mdern methds f raditherapy. REFERENCES 1. Atkins H, Hayward JL, Klugman DJ, Wayte AB. Treatment f early breast cancer: a reprt after ten years f a clinical trial. BMJ 1972;2: Fletcher GH, Mntague ED. Des adequate irradiatin f the internal mammary chain and supraclavicular ndes imprve survival rates. Int J Rad Oncl Bil Phys 1978; 4: Arriagada R, Muriesse H, Sarrazin D. Raditherapy alne in breast cancer. I. Analysis f tumr parameters, tumr dse and lcal cntrl: the experience f the Gustave-Russy Institute and the Margaret Hspital. Int J Radiat Oncl Bil Phys 1986;11: Tubiana M, Sarrazin D. The rle f pstperative raditherapy in breast cancer. In Ariel JM, Cleary JB. Breast Cancer Diagnsis and Treatment. New Yrk, McGraw Hill 1987; Clarke DH, Le MG, Sarrazin D, Lacmbe MJ, Fntaine F, Travagli JP, et al. Analysis f lcreginal relapses in patients with early breast cancers treated by excisin and raditherapy: experience f the Institut Gustave-Russy. Int J Radiat Oncl Bil Phys 1985;11: Kunkler I. Adjuvant irradiatin fr breast cancer: Mdern raditherapy techniques shuld reduce cardivascular mrtality. Brit Med J 2000;320: Cuzick J, Stewart H, Pet R, Baum M, Fisher B, Hst H, et al. Overview f randmized trials f pst-perative adjuvant raditherapy. Cancer treat rep 1987;71:15-30.

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14 30. Hayward J, Caleffi M. The significance f lcal cntrl in the primary treatment f breast cancer. Arch Surg 1987;122: Hellman S. Stpping metastases at their surce. N Engl J Med 1997;337: Kemperman H, Brger J, Hart A, Peterse H, Bartelink H, van Dngen J. Prgnstic factrs fr survival after breast cnserving therapy fr lcal I and II breast cancer. The rle f lcal recurrence. Eur J Cancer 1995;31A: Kurtz JM, Amalric R, Brandne H, Ayme Y, Spitalier JM. Hw imprtant is adequate raditherapy fr the lng term results f breast-cnserving treatment. Radither Oncl 1991;20: Levitt SH, Aeppli DM, Nierengarten ME. The impact f radiatin n early breast carcinma survival. A Bayesian analysis. Cancer 1996;78: Sttter A, Atkinsn EN, Fairstn BA, McNeese M, Oswald MJ, Balch CM. Survival fllwing lcreginal recurrence after breast cnservatin therapy fr cancer. Ann Surg 1990;212: Elkhuizen PH, van de Vijver MJ, Hermans J, Zanderland HM, van de Velde CJ, Leer JW. Lcal recurrence after breast cnserving therapy fr invasive breast cancer: high incidence in yung patients and assciatin with pr survival. Int J Radiat Oncl Bil Phys 1998;40: Clark RM, Whelan T, Levine M, Rberts R, Willian A, McCullch P, et al. Randmized clinical trial f breast irradiatin fllwing lumpectmy and axillary dissectin fr nde -negative breast cancer: an update. J Natl Cancer Inst 1996;88: Fisher B, Bauer M, Marglese R, Pissn R, Pilch Y, Redmnd C, et al. Five-ear results f a randmized clinical trial cmparing ttal mastectmy and segmental mastectmy with r withut radiatin in the treatment f breast cancer. N Engl J Med 1985;312: Fisher B, Redmnd C, Fisher ER, Bauer M, Wlmark N, Wickerham DL, et al. Ten-year results f a randmized clinical trial cmparing radical mastectmy and ttal mastectmy with r withut radiatin. N Engl J Med 1985;312: Sarrazin D, Dewar JA, Arriagada R, Benhamu S, Benhamu E, Lasser P, et al. Cnservative management f breast cancer. Brit J Surg 1986;73: Auquier A, Rutqvist LE, Hst H, Rtstein S, Arriagada R. Pst-mastectmy megavltage raditherapy: the Osl and Stckhlm trials. Eur J Cancer 1992;28: Early Breast Cancer Trialists Cllabrative Grup. Effects f raditherapy and surgery in early breast cancer. An verview f the randmized trials. N Engl J Med 1995; 333: Early Breast Cancer Trialists Cllabrative Grup: favurable and unfavurable effects n lng-term survival f raditherapy fr early breast cancer: an verview f the randmized trials. Lancet 2000;355: Laplanche A, Alzieu L, Delzier T, Berlie J, Veyret C, Farget P, et al. Plyadenylic- Plyuridylic acid plus reginal raditherapy versus chemtherapy with CMF in perable breast cancer: a 14 year fllw-up analysis f a randmized trial f the Fédératin Natinale des Centres de Lutte Cntre le Cancer (FNCLCC). Breast Cancer Research and Treat 2000;64: Sauer R. Adjuvant raditherapy after breast cnserving surgery fr breast cancer. Eur J Cancer 2000;36: Lacur J, Lacur F, Spira A, Michelsn M, Petit JY, Delage G, et al. Adjuvant treatment with plyadenylic-plyuridylic acid (ply A ply U) in perable breast cancer. Lancet 1980;2: Lacur J, Lacur F, Duct B, Spira A, Michelsn M, Petit JY, et al. Plyadenylicplyuridylic acid as an adjuvant in the treatment f perable breast cancer: recent results. Eur J Surg Oncl 1988;14: Dalberg K, Jhanssn U, Jhanssn H, Rutqvist LE. fr the Stckhlm Breast Cancer Study Grup. A randmized trial f lng term adjuvant tamxifen plus pstperative radiatin therapy versus radiatin therapy alne fr patients with early stage breast carcinma treated with breast-cnserving surgery. Cancer 1998;82: Rutqvist LE, Cenark B, Glas U, Jhanssn H, Rtskin S, Skg L, et al. Raditherapy, chemtherapy, Tamxifen as adjuncts t surgery in early breast cancer: a summary f three cntrlled trials. Int J Rad Oncl Bil Phys 1989;16:

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