Evolving Concepts in the Systemic Adjuvant …...SYSTEMIC ADJUVANT TREATMENT OF BREAST CANCER CMFx6...

[CANCER RESEARCH 52, 2127-2137, April 15, 1992]

Perspectives in Cancer Research

Evolving Concepts in the Systemic Adjuvant Treatment of Breast CancerGianni Bonadonna1

Division of Medical Oncology, Â¡stilatoNazionale Tumori, Via Venetian, I, Milan, Italy

At the turn of this century, breast cancer ranks as the singlemost common female malignancy in many geographical areasof the world. Its growing incidence frightens women, puzzlesscientists, challenges doctors, and keeps the media busy. Technological advances, namely early detection by mammography,a variety of breast-conserving procedures, and systemic adjuvanttreatments, created survival probabilities and therapeutic implications. However, for resectable breast cancer the controversies among academic physician scientists, as publicly displayedin countless meetings, professional journals, and nonmedicaiarticles, have generated little concrete guidance that has somewhat blurred the true clinical progress achieved in about twodecades of trials and errors. Doctors and patients have becomeobsessed with treatment options; often they appear unable todecide.

This paper will review the evolution of scientific conceptsunderlying major clinical trials undertaken since the early 1970swith systemic adjuvant and neoadjuvant treatments for resectable breast cancer. To protect the readers from the deluge ofreports that have appeared in the medical literature on thesubject in question, this review will purposely avoid dissectingindividual studies. Rather, on the basis of important treatmentfindings, it will attempt to provide a guide as how the strategicapproach has been progressively changing in the effort to improve the control of high risk breast cancer.

Biological Hypotheses and Clinical Strategy

The golden age of adjuvant chemotherapy began in the early1970s. At that time, a few clinical and laboratory findingshelped to formulate new treatment strategies for several malignancies, in particular breast cancer (Table 1). First of all, theevaluation of two surgical trials (1,2) challenged the principlesof Halstedian hypothesis and lent clinical support to pioneeringlaboratory investigations (3) on the mode of spread of breastcancer. The high recurrence rate, especially during the first 3years from Halsted, and enlarged radical mastectomies couldhave only one reasonable explanation, i.e. the presence ofdistant micrometastases at the time of surgery. The clinicalchallenge of the anatomic and mechanistic dogma opened thepathway to biological hypotheses and paved the road to bothconservative surgery and systemic adjuvant treatment. Anotherimportant information was derived from the seminal studiescarried out in experimental animal systems (4, 5). In micebearing mammary tumors, surgery followed by chemotherapyyielded survival results superior to either modality alone. Theabove mentioned studies also stressed the importance of drugdose and tumor cell burden and suggested that micrometastaticfoci could be more vulnerable to the effects of cell cycle-specificagents (6). A third information, which emerged from laboratoryand clinical investigations, indicated that in some malignancies,namely acute leukemia, Hodgkin's disease, and a variety of

Received 11/25/91; accepted 2/10/92.1To whom requests for reprints should be addressed.

pediatrie tumors, multiple drug regimens had the potential forcure (7, 8).

The early biological hypothesis concerning micrometastaticdisease and potential benefit from adjuvant chemotherapy wasfirst tested through randomized clinical trials by the NSABP2

(9) and the Milan Cancer Institute (10). The first NSABP studyutilized single agent chemotherapy (L-phenylalanine mustardor melphalan) while the Milan trial elected to use a multipledrug regimen known as CMF. Eventually, the multidisciplinarystrategy with combination chemotherapy prevailed and becamethe standard approach for given patient subsets (11). Manyclinicians were perplexed before the early results of the newtreatment strategy (9, 10), and only a few were gifted withintuition to foresee that early findings could largely predict forlong-term results (12). Fortunately, in spite of numerous difficulties to cross medical compartments, many research physicians accepted the message of the multidisciplinary approachand began to set up further prospective trials.

Chemotherapy Results in Node-positive Tumors

The comparative data of the first CMF trial are now availablefor the 15-year analysis. The long-term results of the entire caseseries (total, 386 patients) confirmed once more that the scientific principles underlying clinical strategy were correct. Inmost patients with histologically positive axillary lymph nodesresectable breast cancer should be considered a systemic diseasethe micrometastatic foci of which can benefit from an intensiveadjuvant systemic treatment. Besides the therapeutic advantage,trial results provided evidence or confirmation of importantbiological and pharmacological concepts, namely prognosticimportance of tumor cell burden, dose-response effect, andclinical drug resistance.

Fig. \A shows that the maximum recurrence rate occurredduring the first 3 years from radical mastectomy; from this timeon, the difference between control and CMF remained aboutthe same for the subsequent 12 years. This observation indicatedthat the early findings could predict with sufficient accuracy forthe late outcome and suggested that micrometastases includedvery aggressive cell lines mostly resistant to cytotoxic chemotherapy. Total survival difference (Fig. \B) was progressivelyincreasing after the seventh year from starting adjuvant therapy.As detailed in previous publications (11, 13, 14), the results ofthe CMF program confirmed the importance of nodal extent,for there was a consistent inverse relationship between numberof involved lymph nodes and treatment outcome. The 5- and10-year analysis provided the opportunity to review the effectof drug dose in a clinical adjuvant setting. In the first CMFprogram, the significant achievements in premenopausalwomen (Fig. 2) were not duplicated in postmenopausal patients.In this latter subset, as a consequence of trial design or protocoldeviations, chemotherapy included initial low doses and was

2The abbreviations used are: NSABP, National Surgical Adjuvant Breast and

Bowel Project; CMF, cyclophosphamide, methotrexate, and fluorouracil; ER,estrogen receptor.

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SYSTEMIC ADJUVANT TREATMENT OF BREAST CANCER

Table 1 Clinical observations, laboratory findings, and biological hypothesesinfluencing the beginning of modern adjuvant chemotherapy for high risk

operable breast cancer

By the time cancer becomes clinically detectable, is advanced (near 30 doublings),and has had ample opportunity to establish distant micrometastases.

Frequency of metastatic disease is directly related to tumor mass, and surgicalcure rates drop as tumor volume at surgery increases.

Tumor growth fraction is inversely related to population size.

Effective drug kill follows first order reaction kinetics.

Combination of drugs is superior to single agents and can eradicate 10-100 timesas many cells.

In transplantable tumors surgical adjuvant chemotherapy increases the long-termcure rates.

The optimal kinetic conditions to achieve cure exist when microscopic foci ofdisease are present after curative surgery and/or radiotherapy.

A100

pER

I-NT

LOG-RANK: P - 0.002

W1LCOXON: P - 0.0001

CMF

SURGERY ALONE

5 7 9 11 13 15

YEARS

B100

LOG-RANK; P - 0.08

WILCOXON: P - 0.08

CMF

5 7 9 11 13 15

YEARS

Fig. 1. First CMF program: 15-year results. A, comparative relapse-free survival; B, comparative total survival.

often arbitrarily reduced during most cycles (15). This important pharmacological aspect will be discussed later.

The results of the second CMF adjuvant program (12 versus6 cycles in a series of 459 node-positive patients) leave room tospeculate about drug resistance at clinical level. At 14 years,

both relapse-free (Fig. 3) and total survival rates between treat

ment groups remain nonsignificant. Most probably, full or nearfull doses of chemotherapy, as delivered in this trial, are sufficient to kill most (at times all) drug-sensitive tumor cells whileearly and late relapses are due to the overgrowth of primaryresistant neoplastic cells. Comparable findings with the sametheoretical and practical considerations were subsequently reported by Henderson et al. (16) and Fisher et al. (17) utilizingAdriamycin-containing regimens.

The CMF adjuvant results were largely confirmed worldwide(18) and this triple drug regimen, delivered for six monthlycycles, became the standard adjuvant regimen in clinicalpractice.

Tamoxifen Trials

The concept that at least a fraction of breast tumors is"hormone dependent" and therefore responsive to various en

docrine manipulations is an old one, supported by innumerablelaboratory and clinical observations. The discovery of hormonereceptors in the mid-1970s provided the rationale for a moreselective application of endocrine treatment. In advanced dis-

A100

pERCE 50NT

LOG-RANK; P - 0.002

WILCOXON: P - 0.0001

^

CMF

SURGERY ALONE

B 100

1 3 5 7 9 11 13 15

YEARS

LOG-RANK: P = 0.02

WILCOXON: P = 0.02

CMF

YEARSFig. 2. First CMF program: 15-year results in premenopausal women. A,

comparative relapse-free survival; B, comparative total survival.

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CMFx6

9 11 135 7

YEARS

Fig. 3. Second CMF program. Comparative relapse-free survival at 14 years.

ease endocrine ablative or additive therapies give a responserate of 30% in unselected patients, around 50% in ER-positive,and as high 80% when both ER and progesterone receptor arepositive. Only 5-10% of receptor-negative tumors will respondto hormonal manipulations. The response rates are proportional to the level of hormone receptors measured and thereceptor status in the primary tumor probably corresponds, atleast to a large extent, to that of any occult metastasis left aftersurgery.

Since the initial proposal of Schnitzinger in 1889 aboutadjuvant oophorectomy, there have been over 20 trials of various types of ovarian ablation (19). The earliest endocrine trialswere essentially affected by the same defects of many early trialswith adjuvant chemotherapy, i.e., historical nonmatched, non-randomized controls; insufficient information on nodal status.Interpretation of results was further hampered by the absenceof adequate statistical methodology for survival analysis. Anumber of subsequent trials with ovarian ablation, includingseveral prospective randomized studies, showed improvementin both recurrence-free and overall survival rates.

In 1977 the Nolvadex Adjuvant Trial Organization designedthe first modern adjuvant trial with the antiestrogen tamoxifenversus control. In a large case series (total, 1131 patients) withnode-positive and node-negative breast cancer the 5- and 10-year results provided evidence that total survival was moderately but significantly improved (20). Trials on adjuvant tamoxifen rapidly proliferated among major research centers. In particular, the results of large randomized studies, activated inEurope during the late 1970s, confirmed the benefit of adjuvanttamoxifen especially in women presenting with high receptor-positive tumors (21-23). Despite some inconsistency in published reports concerning menopausal, nodal, and steroid receptor status, over the past decade tamoxifen became widely usedin clinical practice, primarily in postmenopausal women presenting with 1-3 positive nodes and ER-positive tumors.

The largest randomized study on adjuvant tamoxifen (total,2644 patients) was mounted in 1980 by the NSABP group innode-negative and estrogen receptor positive tumors. The 5-year results showed a highly significant (P < 0.000005) reduction in both local-regional and distant mÃ©tastases.The benefit

was observed regardless of menopausal status. However, at 5years no significant survival advantage could be documented(24).

The International Overview

To assess the impact of various adjuvant systemic treatments(hormonal, cytotoxic, or immune therapy) on total survival, theEarly Breast Cancer Trialists' Collaborative Group has set up

in 1984 an International Overview with the cooperation ofmore than 100 individual investigators who have contributedtheir data. Utilizing proper statistical procedures (25), meta-analysis was conducted on a total of about 30,000 study patientsto evaluate the 5-year results (adjuvant treatment versus noadjuvant treatment). When all drug treatments (i.e., singleagents as well as various combinations) were considered, meta-analysis detected a significant overall reduction in the odds ofdeaths (14%, P < 0.001) in favor of the chemotherapy-treatedpatients. When only CMF-type regimens were considered, thereduction was superior for the total series (23%, P < 0.0001),with a 37% reduction in women younger than 50 years old anda 9% reduction for older women. Thus, polychemotherapy wassignificantly superior to single agents. A similar analysis wascarried out on women randomized to receive adjuvant tamoxifen or no tamoxifen. There was an overall reduction in the oddsof death of 16% during the first 5 years. Among women olderthan the age of 50 years, the reduction was 20%.

The updated meta-analysis was conducted on a total of75,000 women enrolled in 133 randomized trials involving31,000 (40%) recurrences and 24,000 (32%) deaths. All patientsreviewed included 30,000 women in tamoxifen trials, 11,000 inpolychemotherapy trials, 15,000 in other chemotherapy comparisons, 3,000 in ovarian ablation trials, and 6,000 in immu-notherapy trials (18). Briefly, the findings indicated the following: (a) the long-term (10-year) results essentially confirmedthe intermediate (5-year) results, and the cumulative differencein total survival was larger at 10 than at 5 years; (b) longerchemotherapy (e.g., 12 months) was no better than shorterchemotherapy (e.g., 6 months); (c) at the 10-year analysispolychemotherapy was documented to reduce tumor mortalityalso in 50-year-old women; (d) for the all-ages ER-"poor" (i.e.,<10 fmol/cytosol total protein) subset the 10-year mortalityreduction following adjuvant tamoxifen was 11% compared to21% for the ER-"rich" subset; (e) among the 1817 women aged

less than 50 years, ovarian ablation was associated with a highlysignificant improvement in overall survival (25%); (f) adjuvantimmunotherapy was unable to influence recurrence-free andoverall survival.

It is expected that also the updated results of the InternationalOverview will make a considerable impact on clinical practicefor they provide a solid confirmation of major individual trials,which already had substituted facts for opinions. The moderatebut clinically relevant reduction in tumor mortality could notalways achieve the sanctity of statistically significant differencein individual randomized studies. The main reason was essentially lack of statistical power even in major trials accruing 300-400 patients.

The overall validation of benefits from adjuvant systemictreatments reemphasized the importance of previously reportedclinical observations underscoring biological concepts. In fact,the highest recurrence rate documented within the first 3-4years implies a considerable fraction of primary resistant tumorcells, which cannot benefit from the prolonged administration

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of the same polychemotherapy. Also the observation that, following adjuvant tamoxifen, the risk reduction is higher inestrogen receptor-"rich" than in receptor-"poor" assays sug

gests that tumor heterogeneity plays a major role in treatmentoutcome. However, in spite of their considerable positive aspects, meta-analyses do not necessarily reflect the state of theart nor should they be expected to provide detailed informationto guide physicians in the choice of treatment outside thecontext of clinical trials, because overviews are not appropriateto answer all specific clinical questions. Besides the abovementioned words of caution, it should be stressed that the mostrecent trial results with full dose chemotherapy, sequential drugregimens, and role of anthracyclines could not be evaluated inthe 10-year overview.

In conclusion, the updated International Overview can provide an adequate average measure of what a practicing physiciancan expect from adjuvant tamoxifen for the majority of studypatients were managed with 20 mg/day for a minimum of 2years. As far as chemotherapy is concerned, the term "poly-chemotherapy" comprises a heterogeneous group of treatments

delivered through various drugs, doses, and intensity. Thisremark applies also to CMF, the most widely tested drugcombination, although this drug regimen was "the only one

with separately demonstrated survival advantage in the presentoverview" (18).

New Drug Combinations

During the past decade new randomized studies were designed for node-positive breast cancer by major research groupsin the attempt to improve the results achieved in the earliertrials. The studies concern the role of anthracyclines in anadjuvant setting and the therapeutic potential of combiningchemotherapy and hormones. After 20 years from the firstclinical observations (26), Adriamycin (doxorubicin) remainsthe single most effective drug in the treatment of advancedbreast cancer. Once it was clear that the optimal duration ofadjuvant chemotherapy could be limited to about 6 months(13), it became almost logical to test whether anthracycline-containing regimens could be more effective than conventionaldrug combinations also in an adjuvant setting. The biologicalproblem of primary resistant tumor cells in micrometastaticfoci was the underlying strategy for the Milan studies. In 486women with 1-3 involved nodes, i.e., the subset most benefitingfrom CMF, four cycles of Adriamycin at full dose (75 mg/m2

every 3 weeks) were delivered following eight courses of i.v.CMF in the attempt to eradicate CMF-resistant cell lines. At 5years, the similarity in treatment outcome between CMF andCMFâ€”Â»Adriamycinsuggested the possibility that prolongedadministration of full dose CMF actually resulted in the selection of cell-resistant sublines, which were all refractory toAdriamycin (27).

In patients presenting with more than three positive nodes, adifferent approach was attempted. Adriamycin was administered in both treatment arms either before CMF or alternatedwith two courses of CMF (28). The superiority of sequentialversus alternating regimen is displayed in Fig. 4 for the entirecase series (total, 403 cases). When the results were brokendown according to degree of nodal involvement, in patientswith 4-10 nodes the efficacy of sequential regimen was evidentthroughout the entire period of observation (Fig. 5). By contrast, in those presenting with more than 10 positive nodes thedifference favoring sequential chemotherapy emerged only after

the third year (Fig. 6). The findings suggest that in this nodalsubset there are patients with tumor cell burden which is sohigh that even the "best" available conventional regimen will

have little, if any, chance to exert effective tumor cell kill onresistant cells. The correct interpretation of reported data isdifficult on clinical grounds. A point to be considered is theasymmetrical delivery of drug treatments in the alternatingregimen. A clinical trial involves more complexity than anymathematical models may encompass and probably tolerate.Even Goldie and Goldman (29) in their model caution that notevery alternating program can be expected to show benefit. Ifthe assumption about lack of symmetry between Adriamycinand CMF is correct, then the advantage of using an optimalsequential schedule rather than an alternating schedule can besubstantial.

Other recent adjuvant findings on Adriamycin-containingregimens relate to the studies of NSABP including 1790 cases(30). The marginal advantage, if any, observed by the additionof Adriamycin to melphalan plus fluorouracil or to the samedrugs plus tamoxifen is probably due to the low dose (30 mg/m2) of Adriamycin utilized in this study.

Awo

so

LOG-RANK: P = 0.002

ADM -*CMF

CMF/ADM

YEARS

B100

SO

ADM * CMF

CMF/ADM

LOG-RANK: P = 0.002

YfcARS

Fig. 4. Adriamycin (/!DA/)-containing regimens: 6-year results in patients with>3 positive axillary lymph nodes. A, comparative relapse-free survival; B, comparative total survival.

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100

CMF/ADM

LOG-RANK: P = 0.009

3

YEARS

Fig. 5. Adriamycin (/4OA/)-containing regimens. Comparative relapse-freesurvival in patients with 4-10 positive axillary lymph nodes.

The addition of hormonal agents, usually tamoxifen, to adjuvant chemotherapy for resectable breast cancer has receivedmuch attention in recent years. The biological rationale forcombining these two treatment modalities lies primarily intumor cell heterogeneity, i.e., various populations of cells withdiffering sensitivities to chemotherapeutic and endocrineagents. Current adjuvant findings (31) remain inconsistent andcontroversial because there is not yet a clear evidence fromindividual trials that the addition of tamoxifen to effectivechemotherapy (CMF or CMF-like regimens) has considerablyimproved treatment outcome versus chemotherapy alone. Bycontrast, combined chemotherapy and tamoxifen yielded superior treatment outcome versus prolonged adjuvant tamoxifen(3-5 years) in postmenopausal ER-positive tumors (32, 33).

The pharmacological reasons remain essentially unproven. Invitro studies have illustrated that endocrine therapies may decrease the cytotoxic effect of chemotherapeutic drugs by alteringtheir cell kinetics (34). This can indeed occur when chemotherapy and hormonal treatments are delivered concurrently. Anattractive working hypothesis would be to test the sequentialrather than concurrent administration of the two modalities.Relatively short intensive chemotherapy should be given firstto kill rapidly proliferating tumor cells; after cytotoxic drugs,tamoxifen should be given for prolonged periods of time tofurther increase the long-term disease free status.

Chemotherapy for High Risk Node-negative Breast Cancer

For many decades, generations of surgeons believed thathistologically node-negative breast cancer represented an almost invariably curable disease. This was a logical consequenceof the Halstedian hypothesis of cancer management. About twodecades ago, the previously mentioned evaluation of large surgical series (1,2) began to clearly indicate that the overall 10-year relapse-free survival following radical mastectomy in thispatient subgroup was about 70-75%. As in women with node-positive tumors, regardless of tumor size and menopausal statusabout one-half of all new disease manifestations could be documented within the first 3 years from local-regional treatmentand particularly in distant anatomic sites.

In spite of these findings, for at least another two decadessurgeons retained the opinion that all node-negative tumors

were associated with good prognosis. More recent researchefforts, aimed at the identification of new prognostic variables,indicated or reemphasized that in given subsets the distantrecurrence rate could be as high as 50%. These clinical findingswere in agreement with the previously mentioned hypothesison the importance of early hematogenous dissemination ofcancer cells.

During the late 1980s the reports of a few randomized trialsin ER-negative tumors lent considerable support to the strategyadvocating a multidisciplinary approach in high risk subsets.The famous Clinical Alert released in May 1988 by the NationalCancer Institute, "a poor idea prematurely used" (35) because

of too much emphasis on positive treatment findings, served tostimulate physicians and to inform women about the need toreconsider the overall prognosis of node-negative breast cancerand to participate into clinical trials in the attempt to refinepatient subsets and treatment outcome.

Fig. 7 illustrates the updated relapse-free and total survivalrates of the Milan randomized trial activated in 1980 (11). Inspite of the limited number of available patients (total, 90)because of poor referral from surgeons, the advantage of intravenous CMF remains quite evident at 8 years regardless ofmenopausal status. Premenopausal women given CMFachieved 82% relapse-free survival, while the figure for postmenopausal patients was 76%. Nontreated pre- and postmenopausal controls recorded 8-year relapse-free rates of 40 and36%, respectively. Also the trend was in the direction of benefitfrom adjuvant chemotherapy in Grade 3 tumors and in thosewith high proliferative rate (36).

The magnitude of benefit between control and treated patients was less evident in subsequent large American series (37,38) although in untreated tumors >3 cm the 5-year relapse rateof the Intergroup trial was 40%. At 5 years or more thetreatment arm of the three studies, as summarized in Table 2,yielded comparable results. This finding indicates that combination chemotherapy can effectively reduce the annual odds ofrecurrence by at least 30% in node-negative breast cancer.

Should all node-negative patients undergo adjuvant systemictherapy? At least for the time being, the answer is no. Althoughlack of precise rank of available morphological and biologicalindicators of prognosis renders it somewhat difficult to clearlydistinguish between high risk and low risk tumors (39), it does

100

ADM-*-CMF

CMF/ADM

1 3 sYEARS

Fig. 6. Adriamycin (/l/WJ-containing regimens. Comparative relapse-freesurvival in patients with >10 positive axillary lymph nodes.

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A100

CMF

^ SURGERY ALONE

LOG-RANK: P = 0.0002

YEARS

B IDO

PER

IÂ«NT

CMF

SURGERY ALONE

LOG-RANK: P = 0.005

YEARS

Fig. 7. Adjuvant CMF in node-negative and estrogen receptor-negative breastcancer: 8-year results. A, comparative relapse-free survival; B, comparative totalsurvival.

not make it impossible. The low risk subsets, i.e., women withless than 15% chance of relapse, are usually those with tumors<2 cm in diameter, and/or Grade 1 malignancy, and/or positivesteroid receptors (particularly when both ER and progesteroneare highly positive), and/or a low proliferative rate. The vastmajority of these women can be spared chemotherapy. Theconverse is true in patients with a potentially high risk ofrecurrence (something more than 30%) having tumors >3 cmin largest diameter, and/or tumor Grade 3, and/or negativesteroid receptors, (particularly when both are negative), and/orhigh rate of proliferation. If at least two of these unfavorableprognostic factors are present (e.g., large tumor size and highS-phase), adjuvant chemotherapy should be strongly advised.Most probably, patient selection will further improve also bythe exhaustive morphological search for axillary lymph nodeinvolvement (40) as well as the addition of newer biologicalindicators.

Prognostic Indicators

Laboratory studies and clinical experience have demonstratedthat breast cancer is a highly multiform disease in its patholog

ical and clinical behavior. Thus, it is not surprising that theclinical course of this malignancy, namely risk of relapse andresponse to systemic therapy, is often variable. In general, themajor determinants of prognosis remain tumor cell burden anddrug resistance. During the 1970s the criteria to define highrisk patients were nodal status, number of histologically involved axillary nodes, tumor size, and grade. These firmlyestablished prognostic features were later followed by steroidreceptor values and tumor cell proliferative activity (thymidinelabeling index, DNA ploidy, and S-phase fraction). Since theabove mentioned indicators are not, however, absolute, clinicians need additional information that may reflect biologicaldifferences to better define tumors associated with poor prognosis. In recent years, biochemical and immunocytochemicalvariables became the subject of numerous studies. Excessiveliterature is available on the efficacy of these prognostic indicators, without enabling clinicians to compare the variableswith each other and to select the most useful ones among them.The sharpness of P values is not enough to provide completeinformation. Provisional data from many research groups isstill conflicting as to provision of definitive evidence of additional predictive potential compared to conventional prognosticfactors.

The constellation of newly proposed variables (e.g., oncogeneoverexpression, epidermal growth factor receptor, protease ca-thepsin D, stress-response proteins, studies utilizing monoclonal antibodies for detection of peritumoral lymphatic and bloodvessel invasion to high molecular weight mucin-like antigens)claimed to influence treatment outcome or to help in thetreatment decision making remains confusing, and probablydisappointing, for the average clinician. In particular, with thepossible exception of HER-2/neu protein overexpression innode-positive breast cancer (39), identification of oncogenes asprognostic indicators remains, as yet, of unproved clinical value.In the attempt to correlate laboratory findings with clinicaldata, a sufficiently large series of consecutive patients, stagedand managed according to uniform treatment programs andincluding information on established prognostic factors, is mandatory. Timing, methods for prolonged follow-up, and properstatistical analysis should further qualify the case series (14,41). The recent publications on timing of breast cancer surgeryduring menstrual cycle and its relation to survival of premeno-pausal women are a case in point. In a retrospective studyinvolving 41 premenopausal women, Hrushesky et al. (42)reported that mastectomy performed during the perimenstrualperiod was followed by a quadrupled relapse rate compared tothat of women operated on during the midcycle. This provocative report implying the influence of chronobiology on a numberof clinical events was followed by other similar retrospective

Table 2 Chemotherapy in node-negative breast cancer: results of modernadjuvant studies

SelectioncriteriaMenopausa!statusTumorsizeER

statusRegimenNo.

ofpatientsMedianfollow-up%

of relapse-freesurvivalControlgroupChemotherapyPMilanPre

andpostTl-T3aNegativeCMP

i.v.908yr39800.0002NSABP

(37)Pre

andpostAnyNegativeM-.F7375yr66780.0007Intergroup

(38)Pre

andpostAnyNegative:

allTPositive:T > 3cmCMFP425Syr6183<0.0001

2C, cyclophosphamide; M, methotrexate; F, fluorouracil; P, prednisone.

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evaluations (43-45). The results yielded inconsistent findingsalthough they concurred in showing that there was no differencein patient outcome between perimenopausal and midcycle mastectomy. The critical points are not the underlying biologicalprinciples (e.g., natural killer cell activities, other immunolog-ical or endocrine considerations) or prior laboratory evidence(46) but the risk of drawing treatment indications on the basisof limited retrospective series having inconsistent variables suchas stage, follow-up, and adjuvant treatment.

In conclusion, the search for new biological indicators ofprognosis, an ever expanding field of investigation, remainsimportant for curious and skeptical clinicians but the noveltissue markers should be handled with care in clinical decisionmaking.

Primary Chemotherapy

The idea of testing the efficacy of primary combinationchemotherapy dates back to 1973 (11) when the Milan CancerInstitute started the first prospective study with Adriamycinplus vincristine in locally advanced disease (Stage III). At thattime, the aim of chemotherapy was to achieve prompt tumorshrinkage and thus facilitate subsequent irradiation or radicalmastectomy. The 10-year results of those studies indicated thatthe major prognostic factors were tumor cell burden (primarytumor size, clinical nodal status) and adjuvant chemotherapyafter local regional treatment (47). These findings were confirmed by American and European research groups utilizing avariety of drug regimens within a similar strategic approach(11).

Two subsequent events have recently brought chemotherapyup front also in earlier disease stages: the similarity of treatmentoutcome between breast conserving procedures and radical mastectomy in small tumors (48, 49); and both the efficacy and thesafety of modern chemotherapy (11). The need to decrease thefrequency of mutilating surgery in tumors measuring >3 cm ledthe Milan Cancer Institute to conceive a prospective study withprimary (neoadjuvant) chemotherapy in conventionally operable breast cancer (50). The reverse approach, i.e., chemotherapyprior to surgery, could possibly improve long-term results overthe classical strategy, i.e., surgery followed by chemotherapy.In fact, in animal models, extensive prior experience has shownthat the response to drugs is superior in untreated versus recurrent tumors. The updated results of the Milan study on 227Ã©valuablepatients presenting with resectable breast cancer >3cm are summarized in Table 3. The degree of tumor responsewas inversely proportional to the initial tumor diameter andhistopathological complete remission was documented in 8 of220 cases subjected to surgery (4%). Conservative surgery(quadrantectomy plus full axillary dissection) was performed ina total of 201 of 220 (91%). Additional important informationsfrom this prospective study are the following: (a) tumor response was unrelated to the four drug combinations [CMF,FAC (fluorouracil, Adriamycin, cyclophosphamide), FEC (epi-rubicin substituting for Adriamycin), FNC (mitoxantrone substituting for anthracycline)] with no difference between threeand four cycles of either CMF and FAC; (b) three cycles ofAdriamycin alone (75 mg/m2 every 3 weeks) yielded comparable

objective tumor response (79%) as combination chemotherapy(78%); (c) age, menopausal status, labeling index, and DNAploidy failed to influence the degree of tumor reduction whilethe frequency of response was greater in receptor-negativetumors. With a median follow-up of 18 months, relapse-free

Table 3 Operable breast cancer candidate to mastectomy: clinical versus surgicaldiameters following 3-4 cycles of primary chemotherapy

Initial tumor(cm)3.0-4.0

4.1-5.0>5Patients

subjectedto surgery110

7337Tumor

at surgery(cm)<393%79%

62%011105pCRÂ°53Conservative

surgery97%

92%73%

" pCR, pathological complete remission.

and total survival rates remain too early to fully evaluate.However, it is important to stress that only 2 local recurrenceswere detected in 201 patients subjected to conservative surgeryplus postoperative breast irradiation.

Drug Dose Intensity and Sequence

Few topics in cancer chemotherapy have received as muchattention in recent years as the interrelation of dose, doseintensity, and response. It is well known that the principle ofdose response is fundamental to pharmacology. In the medicaltreatment of cancer, the experimental support for steep dose-

response curves is derived from model systems in which a smallincrease in drug dose results in a disproportionately largeincrease in tumor cell kill (6, 51-53). In many experimentalanimal systems the log kill will be greater for the higher doseintensity regimen because that log kill is the difference betweencell death and tumor regrowth. The interplay between tumorand drug(s) is actually very complex. Dose response in fact is aproperty of tumor size, type, proliferative rate, and geneticresistance as well as the differential sensitivity of the normaland tumor cells to the effect of drug(s).

Aside from the initial studies with polydrug regimens foracute leukemia (54) and Hodgkin's disease (8), only during the

past decade did clinicians begin to realize that treatment failurecould be the consequence of insufficient dose intensity of oneor more of the agents in the combination (55, 56). As far as theadjuvant therapy of breast cancer was concerned, the MilanCMF program was the first to provide evidence that outcomeat 5 and 10 years was related to full dose treatment ( 13, 15). Inspite of the limitations intrinsic to retrospective evaluations,the findings generated progressive widespread interest on thesubject of dose intensity. Dose intensity is actually a conceptdeveloped a few years later by Hryniuk (57) and coworkers whoemphasized received dose rate rather than total dose received.The concept is complex because it is not just the total amountof drug received, nor is it just the amount of drug received perunit time (e.g., mg/m2/week). It is a mathematical combination

of both.Hryniuk et al. (58, 59) have recently evaluated the relation

ship between relapse-free survival and dose intensity of CMFadjuvant chemotherapy in node-positive breast cancer. Theseanalyses showed a highly significant relationship between projected dose intensity and 3-year relapse-free survival for studiescontaining all four subsets of patients (positive nodes 1-3 and>3; pre- and postmenopausal women). Henderson et al. (56)summarized in a review paper the results of retrospective analyses of chemotherapy dose and treatment outcome in adjuvantchemotherapy trials. Although conclusions from data-derivedresults may be biased, it appears rather clear that the findingsof trials refuting the dose-response hypothesis included most ofthe case series given single agent or low dose combinationchemotherapy. Recent prospective randomized trials carried

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out in advanced breast cancer showed that the higher dose ofCMF regimens proved to be superior to low dose regimens (60,61).

Dose-intensive chemotherapy is currently on study within anadjuvant setting when >10 axillary nodes are involved. Adopting the concepts of weekly chemotherapy, sequential administration of antimetabolites, and continuous infusion of fluorour-acil, Abeloff et al. (62) devised a five-drug regimen to minimizedose reduction and treatment delay. At a median follow-up of17 months, 8 patients of 53 relapsed. The encouraging therapeutic results (which, however, deserve a longer follow-up observation), manageable side effects, and the authors' ability to

deliver over 90% of the planned doses provide the rationale fora Phase III comparison of this new dose-intensive regimenversus standard chemotherapy.

During the 1980s, the use of high-dose chemotherapy andautologous bone marrow transplantation has been shown toproduce rapid and complete responses in patients with advancedbreast cancer (63). With the exception of a few women presenting with "small" tumor burdens, sustained complete remissions

were limited in number. The main reason for this partial successmay be attributed to a high percentage of drug-resistant tumorcells. More recently, the strategy of autologous bone marrowtransplantation was focused on the adjuvant setting for womenpresenting with >10 positive axillary nodes. It is expected thatin the absence of absolute drug resistance, increasing the doseintensity will increase the log kill and thus improve the clinicalresults. Table 4 presents the ongoing treatment program of theMilan Cancer Institute. Drug therapy consists of sequentialadministration of cyclophosphamide, vincristine, and metho-trexate plus folinic acid, cisplatin, and melphalan. It is important to point out that because of the hematopoietic stem cell-spearing properties of cyclophosphamide, patients enjoyed benefit from the use of recombinant human granulocyte-macro-phage colony-stimulating factor as a means of harvesting byleukaphereses very large quantities of peripheral blood precursors capable of accelerating hematopoietic recovery after subsequent myeloablative chemotherapy (64). Although clinicaldata are still premature inasmuch as only 48 patients weretreated, with a median follow-up period of 21 months the 2-year relapse-free survival is 93%. Present findings appear superior to those achieved with the "best" available adjuvant

therapy, i.e., Adriamycinâ€”Â»CMFthe 2-year relapse-free survivalof which in the subset with >10 nodes is 60% (28).

During the past two decades, academic research physicianswere influenced in their design of treatment schedules by twostrategic models. The Skipper-Schabel hypothesis, derived fromexperimental animal systems, indicated that for most drugs thelog kill increased with increasing dose (5, 6, 51). The Goldie-Coldman mathematical model expanded the horizon by suggesting a new strategy for combining non-cross-resistant drugsin alternating treatment schedules (29, 65, 66). More recently,two distinct conceptual approaches to drug dosing and scheduling were proposed, namely Day's "worst drug rule" and the"Norton-Simon hypothesis" (67). Both can be considered late

intensification strategies, although by completely different linesof mathematical reasoning.

The worst drug rule involves the optimal scheduling of twononequivalently active drugs (or drug combinations). Accordingto Day, "if drug B is more effective than drug A in the sense of

having a larger log kill, then the critical task will be to eliminatethe cells that are resistant to B. Since only drug A can dothis..., every effort must be made to utilize A to the utmost"

Table 4 Milan high dose chemotherapy regimen for the adjurant treatment ofpatients having more than 10 positive axillary nodes

RegimenSurgeryCyclophosphamiderhGM-CSF"

(^g/kg/day)Leukaphereses

(CPCharvest)BonemarrowharvestVincristineMethotrexate

+rescueCisplatinMelphalanMarrow

plus CPCautoinfusionRadiotherapy(45 Gy)i.v.

dose(mg/m2)700051.4800060200Approximatescheduledday-30

to-4501

to14-1613-1617181823

and30404160

Â°rhGM-CSF, recombinant human granulocyte-macrophage colony-stimulat

ing factor; CPC, circulating progenitor cells.

(67). In other words, in a clinical setting, e.g., adjuvant systemictherapy for breast cancer, research physicians should start withdrug (or treatment) A and then switch to the more powerfuldrug (or treatment B). Does this strategic approach fit well withavailable clinical findings? Probably yes, only if we supposethat Adriamycin alone is not as active as the combination CMF.However, in some circumstances, as for instance in our trialwhere four cycles of Adriamycin were followed by CMF (28),the optimum schedule could be represented by starting with thestronger drug and switching very early (68). The explanationoffered by Day is that "the scheduling, not the patient group,is responsible for the difference." The next logical step would

be to test the use of single agent Adriamycin. In fact, the recentMilan data on primary chemotherapy for breast cancer presenting with tumor >3 cm (14) clearly indicate that the responserate between CMF and Adriamycin is very similar (73% versus79%).

Conceptual Modification, Revision, and Evolution

The primary therapy of resectable breast cancer was initiatedabout a century ago on the principle of centrifugal diseasespread along anatomic pathways. Studying the biology of thedisease has resulted in the abandonment of the belief thatmammary carcinoma always spreads sequentially from the primary site to the nearest draining lymph nodes and then system-ically. The adoption of the concept that some cancers mayinvade the blood stream early to form micrometastases becamevery helpful in developing several forms of mull Â¡disciplinarystrategies. The new biological model was followed by successeswhen correctly applied through prospective randomized trialswhich, in turn, were capable of generating newer biologicalconcepts, pharmacological strategies, and clinical approaches.

The multidisciplinary strategy has contributed to emphasizethe complexity of breast cancer, namely the biological heterogeneity of the primary tumor (69). Tumor heterogeneity has infact become the major prognostic determinant of treatmentselection and outcome and remains the major stumbling blockto the cure of a large fraction of patients, even when optimaldrug dose intensity is delivered. Our understanding of theinteractions between clinical and biological factors and how toconstruct probabilities for prognosis from these interactionsremains incomplete. What we have learned is that the management of the local-regional disease, if done properly by any of anumber of methods, does not influence total survival; rather,survival depends primarily on the presence or absence of micro-mÃ©tastasesand on the ability of systemic treatment, besidesnormal defenses of the body, to control their growth.

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In the control of distant micrometastases and downstaginglarge primary tumors to allow easy and safe breast conservation,the contribution of cancer medicine has been substantial (11,14, 31, 50, 70-73). Available clinical results are far from beingoptimal, and medical oncologists still must face many failures.However, mortality reductions such as those now demonstratedthrough meta-analysis at 5 and 10 years can well prevent orsignificantly delay hundreds of thousands of deaths. Thus, thenatural history of resectable breast cancer has been perturbedas a result of the administration of adjuvant systemic therapiesand in particular of modern full dose chemotherapy.

Current results should encourage revision of "standard" drug

treatments. Improvement in clinical outcome may now beachieved by the delivery of drug dose intensity and the sequential administration of given non-cross-resistant agents. Our ownpromising and provocative treatment results with Adriamycinfollowed by CMF should start a revision of prior concepts aboutoptimum delivery of single drugs or combinations of drugs andmerit a number of genuine tests in randomized clinical trials.Furthermore, chemotherapy and endocrine therapy are notmutually exclusive. Rather than competing for given patientsubsets, they should now become effective partners. Considering steroid receptor heterogeneity, the combined treatment withhormone manipulations and cytotoxic drugs seems rational,because combining both therapies has already shown someadditive effect in a few adjuvant studies (32, 33, 74). In fact,given the mixed receptor-"rich" and receptor-"poor" tumor cell

populations, improvement in treatment outcome may occur bydelivering the two modalities sequentially rather than concurrently. The concomitant administration of both modalities mayresult in an antagonistic effect due to their specific mode ofaction (34). One reasonable basis for this antagonism is thatantiestrogens probably are cytostatic for cancer cells, whereascertain chemotherapy agents are cell cycle active and thusrequire DNA synthesis to exert their maximum effect. Therefore, adjuvant treatment should start with chemotherapy, whichwould affect fast growing receptor-poor cells, and be followedby prolonged administration of endocrine therapy, such astamoxifen, to keep in check the comparatively slower growingreceptor-rich cells.

As far as new drugs and treatments are concerned, probablyonly taxol (75, 76) holds promises to become a new effectivecytotoxic drug in the treatment of breast cancer. This prototypeof a novel class of antimicrotubule agents that induces excessivepolymerization of tubulin has demonstrated significant activityin advanced refractory ovarian epithelial neoplasms and objective responses in various malignancies including breast cancer.Taxol is currently undergoing broad investigation at the PhaseII level, but it will take a few years before this novel compoundcould be taken into consideration for primary or adjuvanttreatment in high risk breast cancer. The area of investigationreferred to as "biochemical modulation" is the development of

strategies that favorably alter the interaction of conventionaltherapeutic agents with their target end points in both malignant and nonmalignant cells. Therapeutic trials using fluorour-acil/leucovorin in refractory and, subsequently, as initial therapy in untreated advanced breast cancer showed encouragingresults in the past few years. More recent Phase II trials fromVanderbilt and Baylor Universities (77,78) using a combinationof mitoxantrone with leucovorin-modulated fluorouracil in previously treated metastatic breast carcinoma hold promise foran effective second line chemotherapy. Therefore, comparisonwith other standard combinations either as first or second line

treatment for breast cancer is indicated. Finally, high dosechemotherapy with autologous bone marrow transplantation inan adjuvant setting should be further pursued and refined butwithin the context of clinical trials. In contrast, current resultson biological response modifiers (e.g. Â«-interferon, lymphokine-activated killer cells, recombinant human tumor necrosis factor)have yielded thus far disappointing or controversial results inthe treatment of advanced breast cancer as well as in an adjuvantsituation (18). Last but not least, prevention strategies, particularly with tamoxifen, may represent a new treatment approachin healthy women at increased risk for developing breast cancer.European and American investigators concur with the idea thatwomen who are cancer free but who have a clearly definedincreased lifetime risk for breast cancer will be eligible for arandomized trial. However, several concerns remain regardingthe conduct of such a trial (79).

Changes in biological concepts and treatment results shouldalso favor the most important evolution in clinical practice, i.e.,the true multidisciplinary approach to cancer patients. As correctly outlined by Durant (80), proper multidisciplinary teamsand environments could provide a cohesive information onmanagement for any given stage of disease. An objective methodfor decision making would be to discuss with the patient theprimary treatment options, whether single or multimodal;whether breast preservation is possible; who should follow thepatient; and what the appropriate procedures are. Under broadminded clinical leadership, this team approach would ameliorate the age-old medical practice ("my patient," "our patients")

and limit the obsession of seeking for second opinions which,too often, yield only conflicting advices.

In conclusion, treatment findings cumulated during the pasttwo decades indicate that modern systemic adjuvant therapiesare not a fugitive venture. They are here to stay and to befurther improved. Both laboratory and clinical results providedbiological and therapeutic models that became very helpful indeveloping contemporary multidisciplinary strategy and moreeffective polydrug regimens. The real improvement of prognosisin high risk breast cancer was obtained only by means of clinicaltrials which were able to validate ideas and theoretical deliberations. The interplay between laboratory research and clinicalinvestigation also confirmed that breast cancer is a highlyheterogeneous disease and even single micrometastatic foci canprovide a healthy supply of drug-resistant phenotypes. In thefuture, more efforts should be devoted to selecting or tailoringthe "ideal" therapy for each individual case and to properly

inform the patients about reasonable treatment alternatives.

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