High dose therapy of breast cancer: current status

Critical Reviews in Oncology/Hematology 30 (1999) 35–43

High dose therapy of breast cancer: current status

Lesley K. Dawson, Robert C.F. Leonard *

Department of Clinical Oncology, Western General Hospital NHS Trust, Crewe Road, Edinburgh, EH4 2XU, UK

Accepted 31 July 1998

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35

2. Drug resistance and dose intensification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35

3. Haematopoietic salvage techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38

4. High-dose chemotherapy in the adjuvant setting. . . . . . . . . . . . . . . . . . . . . . . . . . . 38

5. Metastatic cancer and high-dose treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39

6. Cost implications and health economics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41

7. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41

Reviewer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42

Refercnces . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42

Biographies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43

1. Introduction

Cancer is the second leading cause of death in theworld. In the UK cancer has overtaken heart disease asthe leading cause of death. Breast cancer is the mostcommon female cancer. In the UK one in 12 women or27 000 cases of breast cancer present annually. Two-thirds of these women are under the age of 70. Mostpatients have no evidence of metastatic disease at thetime of presentation, but many subsequently relapseand the current mortality rate is around 50% [1].

In early disease chemotherapy as adjuvant treatmentto surgery gives a 19–30% improvement in relapse-freeand a 10–26% improvement in overall survival at 10years [2].

Although breast cancer is one of the hormone sensi-tive cancers, one third of women are oestrogen receptornegative at presentation. They tend to be younger andpre-menopausal. All women who have metastatic dis-ease that is initially oestrogen sensitive ultimately de-velop hormone resistance. Chemotherapy will giveresponse rates of 45–80% with complete response ratesof 5–25%. However these responses are short-lived witha median duration of 5–13 months. Subsequent treat-ments have a poorer result with shorter and fewercomplete responses being achieved [3].

2. Drug resistance and dose intensification

Failure of chemotherapy to cure cancers has beenascribed to drug resistance. Resistance to cytotoxictherapy is due to a variety of mechanisms. Many

* Corresponding author. Tel.: +44-131-5372196; fax: +44-131-5371029.

1040-8428/99/$ - see front matter © 1999 Elsevier Science Ireland Ltd. All rights reserved.PII: S 1 0 4 0 -8428 (98 )00038 -9

L.K. Dawson, R.C.F. Leonard / Critical Re6iews in Oncology/Hematology 30 (1999) 35–4336

biochemical factors have been implicated but inade-quate dosing is also considered to be an important issue[4]. Drug resistance in tumours can be the result ofpharmacokinetic problems; insufficient uptake of cyto-toxic medication across the cell membrane; alterationsof the intracellular function of the cell reducingchemosensitivity or rapid inactivation and efflux of thedrug. For example, resistance to alkylating agents ismultifactorial and involves decreased membrane-baseddrug transport, increased intracellular glutathione andglutathione-S-transferase concentrations and enhance-ment of DNA repair. However in breast cancer modelsin vitro it appears relatively difficult to induce morethan a 2–10-fold resistance to alkylating agents.

Observation of the growth of L1210 leukaemia inanimals by Skipper [5] led to the formulation of anexponential model to describe tumour growth. Treat-ment with cytotoxic drugs increased the host’s survivaltime by their effect on the tumour cell population.Using mice as the host he calculated the number oftumour cells which had been killed to result in theobserved prolongation of life. With multiple treatmentsit was shown that the tumour growth delay was afunction of the level of clonogenic cell survival and therate of regrowth of the tumour cells. In this model cellkill was shown to be exponential and generated theconcept of log-kill kinetics, i.e. that the cell kill isproportional regardless of tumour burden. Failure ofchemotherapy to eradicate the tumour is therefore theresult of a tumour burden so large that total cell killcannot be achieved.

Human tumours however do not appear to followexponential patterns of growth. A Gompertzian typemodel can be used to describe their growth and regres-sion. In Gompertzian cell kinetics the doubling time ofa tumour increases with increasing tumour size. This isprobably as a result of a proportional decrease in theamount of cells in the tumour able to differentiate. Apatient with advanced cancer can be considered to havea large tumour mass with a low fraction of activelygrowing cells which are susceptible to the effects ofcytotoxic treatment. It can also be postulated thatmicro-metastatic disease will grow faster than the clini-cally apparent tumour because of its much smaller sizeand being composed of a proportionally greater num-ber of proliferating cells.

Single dose intensification treatments are best forcancers with a high growth rate and short cycling timeand appear to increase the response rate. Initial studiesof very high dose chemotherapy were in the context ofassessing the response obtained in a variety of non-haematological malignancies. Frei and Peters investi-gated the use of autologous bone marrowtransplantation in patients given escalating doses ofalkylating agents and detected a moderate responsive-ness in breast cancer [6,7]. Peters treated 22 patients

who had had no prior chemotherapy for metastaticbreast cancer with a single high-dose regimen of Cy-clophosphamide 5265 mg/m2, Cisplatin 165 mg/m2 andCarmustine 600 mg/m2. A total of 17 patients wereevaluable as there were five toxic deaths. A total of 12patients went into complete remission at a median of 18days and the median duration of response was 9months. Three patients remained in complete remissionafter 16 months follow-up.

With regards to the dose of chemotherapy requiredto achieve cell kill it is possible to generate dose re-sponse curves for a cytotoxic agents in vitro. The curvesgenerated in these cancer models are usually sigmoidalin shape with a threshold, a lag phase, a linear phaseand a plateau phase. Studies of breast tumour modelshave shown that there are steep dose response curvesfor some cytotoxic agents and that small increases indose have a significant effect on outcome. These incre-ments in dose can overcome treatment failures associ-ated with their use of the drug at conventional doses.

Reductions in dose in the linear phase of the doseresponse curve are associated with incomplete eradica-tion of all the tumour cells. This results in relapse afterapparent complete response of the tumour totreatment.

The shoulders and plateaus observed in these curvesmay indicate that increasing a cytotoxic dose abovethat of the shoulder will not result in an improvementin response.

Alkylating agents seem to exhibit such properties andhave little cross-resistance. For cyclophosphamide theslope of the curve varies considerably with tumour typeand size. Mitoxantrone has the greatest in vitro re-sponse per increment dose for breast cancer but has asignificant disadvantage in clinical practice due to dose-limiting cardiotoxicity [8,9]. Frei [6] proposed a numberof factors which should be considered in the construc-tion of a high-dose chemotherapy regimen including theuse of at least three agents which are known to haveindividual activity in metastatic disease and to combinedrugs which have been shown to be minimally ornon-cross resistant and which have clinical or experi-mental synergism. The agents chosen also have to besafe to give at 5-fold increased dose levels with haema-topoietic salvage.

Dose rate or total dose intensification may be ofmore significance in improving survival and cure ratesthan the actual dose administered on one occasion.Hryniuk [10] attempted to correlate treatment outcomewith relative dose intensity in retrospective analyses andfound significant correlations in the response rates andoverall survival although a number of important as-sumptions were made. For example, no account wastaken of different characteristics of the various drugs incombination regimens as well as variations in patientcharacteristics and supportive care. The only clear con-

L.K. Dawson, R.C.F. Leonard / Critical Re6iews in Oncology/Hematology 30 (1999) 35–43 37

clusion which can be drawn from this study is thatunderdosing is definitely deleterious. The increments indose achieved in the regimens studied were smallenough to be considered as falling in the range ofstandard therapy doses and therefore were unlikely tohave an impact on survival.

Wood [11] explored the principle of dose intensity inthe adjuvant setting in the treatment of 1572 patientsreceiving Cyclophosphamide, Doxorubicin and 5-Flu-ourouracil (5FU) for stage II node positive breastcancer. The patients were split into three groups. Thefirst group received Cyclophosphamide 400 mg/m 2 onday 1, Doxorubicin 40 mg/m2 on day 1 and 5-FU 400mg/m2 on days 1 and 8 of a 28 day cycle for a total of6 cycles. The second group received Cyclophosphamide600 mg/m2, Doxorubicin 60 mg/m2 and 5-FU 600mg/m2 given as above for a total of four cycles whilethe third group also received four cycles of treatmentgiven at half of the doses administered to the secondgroup. There was a statistically significant difference forboth disease-free survival (PB0.001) and overall sur-vival (PB0.004) between the first two groups and thethird low dose treatment group. No significant differ-ence was seen between the moderately high and higherdose treatment group. This study can be criticised fortreating one group of patients with sub-optimal dosesof chemotherapy. Hryniuk’s analysis was similarly criti-cised for under-dosing of patients’ treatments.

Tannock [12] studied this issue in the context ofmetastatic disease. The chemotherapy regimen con-sisted of Cyclophosphamide, Methotrexate and 5-FU at2 different doses in 133 patients. The first group re-ceived Cyclophosphamide 600 mg/m2, Methotrexate 40mg/m2 and 5-FU 600 mg/m2 given on day 1 of a 21 daycycle while the second group was treated with half thedose of these drugs on the same schedule. The patientshad not had previous chemotherapy for metastaticbreast cancer and had between 1 and 30 cycles oftreatment. If a response was not obtained the secondgroup could be switched to the higher dose. Of the 38patients with measurable disease who switched to thehigher dose regimen only one patient achieved a partialresponse. The response rate in the higher dose arm was30% compared to 11% in the lower dose arm and wasshown to be statistically significant (P=0.03). A sur-vival benefit was demonstrated for the higher dose armof 15.6 months compared to 12.8 months (P=0.026). Itwas therefore concluded that better palliation ofmetastatic disease was achieved with full dosechemotherapy. It was proposed that giving inadequate,sublethal doses of cytotoxic agents may promote thedevelopment of drug resistance by permitting the muta-tion of tumour cells or amplification of genes involvedin resistance.

These studies support the hypothesis that a thresholdon dose response curves can be identified and that

exceeding this dose level has a significant impact onsurvival outcomes.

Lalislang [13] tried an alternative approach to doseintensity and showed that with the use of G-CSF forhaematopoietic support it was possible to delivergreater overall doses of drugs by decreasing the inter-vals between treatments. The 49 patients with advancedbreast cancer in this study were treated with Epirubicinand Cyclophosphamide. In the first arm of the studypatients were initially treated with Epirubicin 140 mg/m2 and Cyclophosphamide 800 mg/m2 with the inten-tion of further increasing the doses but they wereactually reduced after treating six patients due to toxic-ity. The remaining patients in this arm of the studyreceived Epirubicin 120 mg/m2 and Cyclophosphamide700 mg/m2 with G-CSF support. The 36 patients in thesecond arm of the study were treated with Epirubicin75 mg/m2 and Cyclophospamide 500 mg/m2 with G-CSF cover at decreasing intervals between treatmentsof 14 to 8 days. Seven of the eight patients treated atintervals of 8 days developed significant dose limitingtoxicity and it was concluded that intervals of 10–14days were best tolerated. From comparison of theresponse rates it was concluded that giving a fixed doseof chemotherapy at more frequent intervals was shownto be superior to maintaining a fixed interval betweentreatments and increasing the dose on each occasion.This correlates with experimental models which pro-pose that shortening the intervals between treatmentskills more tumour cells as cells which had been dormantduring one treatment are subsequently recruited intothe cell cycle and susceptible to the cytotoxic effect ofthe next treatment.

More recently Savarese [14] advised caution in theevaluation of dose intensity. It is subject to manyconfounding variables including potential drug-tumourinteractions; duration, schedule and route of drug ad-ministration; dose received as opposed to that whichwas intended; total cumulative dose and patient charac-teristics which bias the outcome of treatments. It wasalso noted that many problems exist in the definition ofwhat is considered to be high and low dose therapy.

Toxicity of escalated dose limits dose intensity andcreates the requirement for methods of haematopoieticsalvage such as those offered by bone marrow orperipheral blood progenitor cell rescue. Concern hasbeen raised that a single high-dose treatment will nothave a uniform effect on the heterogeneous populationof cells within a cancer. Despite a marked reduction intumour volume after high-dose chemotherapy up to108–109 resistant tumour cells may remain [15]. Thissupports the hypothesis that there is a threshold ondose response curves and that exceeding this dose levelis important for survival outcomes. This has led to theuse of sequential high-dose therapy which has a basis inthe plateaus in response seen in dose response curvemodelling.


The advantages of high-dose regimens that requirehaematopoietic salvage include the assumption thattoxic effects of chemotherapy on bone marrow stem cellswill be similarly suffered by tumour stem cells. Theselection of drugs which are potentially non-cross resis-tant for use in very high dose therapy is limited to thoseagents whose main toxicity is haematological. The aimof combination therapy is to select agents with different‘second organ’ dose limiting toxicities resulting in subad-ditive overall toxicity [16].

While high-dose treatment appears to lead to a higherrate of tumour response, Eddy [17] cautioned in 1992that neither response rate or time to progression can beassumed to reflect overall patient benefit. More relevantmeasures of treatment benefit are the duration andquality of survival which are gained at the expense oftoxicity and short term reductions in quality of life.

3. Haematopoietic salvage techniques

Initial studies of chemotherapy at myeloablative dosesdepended on autologous bone marrow transplantationfor haematopoietic rescue and were associated withmortality rates of about 21% [6,7]. The morbidity andmortality of high-dose procedures have been reduced byincreasing experience of supportive care of patients andthe use of peripheral blood progenitor cells rather thanautologous bone marrow harvesting as haematopoieticrescue which reduces the duration of neutropenia andincreases the rate of platelet recovery [18]. Despitechanges in the choice in salvage therapy difficulties inmanagement of these patients still exist. Central venousaccess devices and mucositis contribute significantly tothe problems associated with the use of high-dose treat-ments [19].

A total of 55% of patients with a positive bone scanor plain films have bone marrow involvement which hasgenerated concern about the use of autologous bonemarrow as haematopoietic rescue. Re-infusion of bonemarrow may expose a patient to the risk of tumour cellcontamination and subsequent tumour dissemination.Even with peripheral blood stem cell rescue a retrospec-tive analysis of 27 patients found that of ten patientswho had progressed, all had bony metastases at theoutset and seven had bony progression suggesting thateven peripheral blood progenitor cell collections may becontaminated with tumour cells capable of regrowth. Sixof these patients also developed new sites of metastaticdisease [20]. This concern was also investigated byBrugger [21] who observed that release of tumour cellsfrom the bone marrow varied with the time of collectionfollowing chemotherapy.

Cytokeratin expression is the most frequently usedtarget for distinguishing epithelial cells in a haematopoi-etic milieu. Detection of infiltrated marrow can be

achieved by the use of flow cytometry or the reversetranscriptase polymerase chain reaction e.g. to detect theK19 cytokeratin message. It has been shown that theamount of K19 message increases with advancing stageand is associated with a poorer prognosis in those withstage IV disease [22].

The fact that contamination of autologous bone mar-row harvests and peripheral blood progenitor cell collec-tions can be contaminated by breast cancer cells isclearly significant. Clonogenic tumour cells isolatedfrom bone marrow or peripheral blood stem cell collec-tions can be grown in vitro [23]. It has been demon-strated that breast cancer cells re-infused with salvagebone marrow or stem cells after high-dose chemother-apy can return to the sinusoidal spaces within themarrow [24]. These chemo-resistant cells survive induc-tion chemotherapy to be harvested and are sparedhigh-dose cytotoxic treatment. They appear to grow soquickly by Gompertzian kinetics that the possible remis-sion achieved is shortened despite the eradication ofalmost all tumour cells [15].

The means of purging collections contaminated withtumour cells are still under investigation. Studies havetried agents such as amifostine and 4-hydroperoxycy-clophosphamide [25]. Interest is ongoing into ex vivoexpansion of progenitor cells and positive selection ofCD34+ progenitor cells. CD34+ cells can be purifiedby means of immunoadsorption using a biotinylatedanti-CD34 antibody 12.8 and passing the cells througha column of avidin-coated beads. Antibody-labelled cellsadhere to the beads and can be removed by mechanicalagitation. It has been shown that CD34+ selectiontechniques can reduce the time to marrow engraftmentto 21 days from over 30 days. The addition of G-CSFto this method has been shown to result in a faster timeto marrow engraftment of about 11 days [26].

4. High-dose chemotherapy in the adjuvant setting

It is generally perceived that adjuvant chemotherapymerely delays the inevitable relapse of breast cancer. Asa result the toxicity of treatment must be acceptable ifthe lifetime risk of dying from breast cancer albeit witha potentially longer survival free of cancer is unaltered.This is an important issue in the use of high-dosechemotherapy where the toxicity of the treatment inthose who have no demonstrable tumour activity maylead to morbidity and mortality replacing the complica-tions of progressive cancer. However studies have shownthat patients are willing to tolerate treatment that maysignificantly reduce their quality of life in return for asmall survival gain [27,28]. This is especially relevant forthose with five or more axillary lymph nodes involved atthe time of primary surgery whose survival rates are lessthan 50% at 5 years [29].


Table 1Trials comparing standard against intensive treatmenta

Eligibility Regimen high dose Regimen conventional Planned accrualCollaborators

800Stage IIA,IIB, IIIA Cyclo, Adr, 5FU Cyclo,Cancer and Acute Cyclo, Adr, 5FU. HDT+ABMT/PBSC: Cyclo,Carbo, BCNULeukaemia Group B Cis, BCNU

Adr. HDT+PBSC: Cyclo, Thio Adr, Cyclo, MTX,5FUAnglo–Celtic High risk disease 450Stage II or III

5FU, Epi, Cyclo 8005FU, Epi, Cyclo. HDT+ABMT Cyclo: ThioAdjuvantDutch1000Intensive sequentialSWOG Primary HDT+ABMT/PBSC: Cyclo, Cis, BCNU Cyclo,

Adr, Tax, CycloCarbo, Thio\1505FU, Epi, CycloPEGASE EBMT \8 positive nodes 5FU, Epi, Cyclo. HDT+ABMT: Cyclo, MTX,

L-PAM5FU, Epi, Cyclo 200High risk adjuvant 5FU, Epi, Cyclo. HDT+ABMT: Cyclo, Thio,Stockholm Breast

Cancer Study CarboGroup

a Adr, adriamycin; Cyclo, cyclophosphamide; 5FU, 5Fluorouracil; Epi, Epirubicin; Carbo, Carboplatin; MTX, Methotrexate; Cis, Cisplatin;Thio, Thiotepa; Tax, Paclitaxel; L-PAM, Melphalan; HDT, high dose therapy; ABMT, autologous bone marrow transplant; PBSC, peripheralblood progenitor cells.

The rationale for high-dose chemotherapy in theadjuvant setting is based on experimental models whichsuggest that increasing the dose of drugs will increasethe amount of cell kill. Laboratory based models haveproposed that there is an invariable and inverse rela-tionship between the size of the tumour and its curabil-ity with cytotoxic agents. This is most important insubclinical micrometastases which are proliferatingfaster than clinically obvious disease. It has been shownthat with careful and intensive pre-treatment evaluationup to 25% have occult metastatic disease [30]. Patientsreceiving adjuvant chemotherapy for presumed micro-metastatic disease should conform to these hypothesesby having a chemosensitive, low tumour burden.

Other benefits of administering more dose intensetreatments at this point include the fact that thesepatients tend to be younger and fitter than those withclinically apparent metastatic tumour and should there-fore be better able to tolerate more demanding treat-ments. This would contribute to a reduction intreatment associated morbidity and mortality. Aschemotherapy naı̈ve subjects the issue of drug resistanceshould also be less of an issue.

Only Phase II studies exist to support the use ofhigh-dose chemotherapy in the high risk adjuvant set-ting [31,32] but they do suggest a significant disease-freesurvival when compared with historical controls. Peterstreated 85 patients with high-dose Cyclophosphamide,Carmustine and Cisplatin with autologous bone mar-row rescue after four cycles of standard Cyclophos-phamide, Doxorubicin and 5-Fluorouracil. At 2.5 yearssurvival was 79% (95% confidence interval 0.64–0.88)and event free survival was 72% (95% confidence inter-val 0.56–0.82).

There are several trials ongoing comparing standardagainst intensive treatment (Table 1)

It is hoped that some preliminary results will beavailable in 12–18 months time from some of thesestudies. A subsequent meta-analysis may include datafrom 2500 to 3000 patients. However it may not bepossible to fully answer questions about quality of lifeand financial implications from these studies.

Sequential high-dose treatments have been tried us-ing combined salvage with bone marrow and stem cells.The aim of one study [33] was to use a well toleratedregimen avoiding the use of anthracyclines. Cyclophos-phamide, Methotrexate, Vincristine, Carboplatin andMelphalan were used in combination. Cyclophos-phamide was used as cytoreductive agent and the ad-ministration of Methotrexate was scheduled tomaximise its theoretical activity on the S-phase of thecell cycle of the tumour.

The long-term side-effects of high-dose chemother-apy are still not fully elucidated but from other diseasesites we know that the issues of second organ toxicity,second cancers, infertility and lymphocyte function dis-orders are issues of significant concern especially giventhat patients likely to benefit are young and likely tolive long enough for these problems to becomeapparent.

5. Metastatic cancer and high-dose treatments

The majority of experience with high-dose treatmentsfor breast cancer is in the management of metastaticdisease. The first description of the use of high-dosechemotherapy was by Tobias in 1977 [34]. Uncontrolledstudies were performed in the 1980’s and showed re-sponse rates of 60–80%. They were associated withsignificant morbidity and mortality relating to the useof bone marrow transplantation as haematopoietic sal-vage. Peters’ study had a mortality of 22% but with


improvements in supportive care and the use of progen-itor cell rescue, this has been reduced to 1–3% [7,35].

It was subsequently recognised that the use of induc-tion therapy would select responders likely to benefitfrom treatment intensification while sparing othersfrom potentially toxic treatment. Induction treatmentwould also reduce the tumour burden by eradicatingsmall volume or micrometastatic disease. This wouldresult in a better outcome with a significant proportionof those achieving a partial response to induction ther-apy going on to attain a complete response after high-dose treatment. Some have raised concerns thatinduction chemotherapy can result in multi-drug resis-tance and the growth of partially resistant clones whileothers argue that drug resistance is only relative to thedose used.

In a study by Ayash [36] the best responses were seenin those who had an interval of at least 24 months fromthe initial diagnosis of breast cancer to the onset ofmetastatic disease. Other predictive factors of a goodresponse were metastatic disease in a single site and acomplete response to induction chemotherapy. Eder[37] similarly showed that complete responses to treat-ment were more likely if no prior chemotherapy hadbeen given for metastatic disease and high-dose treat-ment was commenced within 3 months of the firstrecurrence. It was also observed that relapses occurredpredominantly in sites of bulk disease and appeared amedian of 6 months after the procedure. This wassupported by Dunphy [38] who identified 3 factorsassociated with improved progression-free survival viz.absence of liver or soft tissue involvement and less thantwo sites of disease.

Although partial responses to induction treatmentscan be converted to complete responses, the duration ofremission is not maintained. Of those who achieve acomplete response only 15–20% remain in remission at2 years [39].

Bezwoda [40] has performed a randomised controlledtrial which has been very influential in supporting theuse of high-dose chemotherapy. High-dose chemother-apy with either autologous bone marrow or stem cellrescue was used as primary treatment for 90 patientswith metastatic breast cancer. The patients were ran-domised to receive either 2 courses of Cyclophos-phamide 2400 mg/m2, Mitoxantrone 35–45 mg/m2 andEtoposide 2500 mg/m2 or six courses of Cyclophos-phamide 600 mg/m2, Mitoxantrone 12 mg/m2 and Vin-cristine 1.4 mg/m2. About half of the patients had hadadjuvant chemotherapy. There was a clearly significantimprovement in both response rates (overall responserates 96 cf 53% (PB0.01) and complete response rate51 cf 47% (PB0.01)) and in survival (median survival90 cf 45 weeks and duration of remission 80 cf 34weeks) in favour of the high dose regimen.

This study has been criticised for the possible con-founding use of Tamoxifen in all responding patients ofwhom there were more in the high-dose arm; the addi-tional dose of Cyclophosphamide in the high dose armused to mobilise stem cells and the use of differentdrugs rather than the same drugs at different doses. Theinvestigators also reported that the outcome for theconventional dose arm was poorer than that seen in aprevious trial establishing its use and worse than that ofother trials of conventional therapy.

Previous studies of high-dose chemotherapy havebeen criticised for their selectivity and this has beenunderlined by Greenberg [41] who reviewed the survivaldata for patients who had achieved disease remissionfollowing conventional dose chemotherapy formetastatic breast cancer. It was found that the pre-req-uisite for a durable response was attainment of a com-plete response to chemotherapy. This was achieved by16.6% of the patients reviewed. A total of 3.1% of thepopulation group remained disease-free for at least 5years having received Doxorubicin and alkylating agentbased regimens. These patients were more likely to havea low tumour burden, good performance status andsoft tissue metastases. They were also younger andpre-menopausal. The apparent survival benefit seenwith high-dose chemotherapy may be due to selectionbias choosing a group who have better responses toconventional treatment.

This was emphasised in Rahman’s report [42]. Itsuggested that the eligibility criteria for inclusion inhigh dose chemotherapy trials actually selects patientsfor intensive treatment who show a clearly superiorsurvival when treated with conventional dosechemotherapy.

The use of multiple transplants gives benefits ofincreased dose intensity. Theoretically the tumourshould also be more chemo-sensitive due to reductionthe bulk of disease during the first cycle (especially asinduction chemotherapy has only a modest effect onreducing tumour bulk) and improved tumour vascular-ity and oxygenation allowing better drug delivery. Cellswhich had not been actively cycling during the firstcourse of treatment could also be induced into the cellcycle and present new targets for cytotoxic action. Eachcycle of chemotherapy should result in increased cellkill. This hypothesis was tested in a Phase I/II study byBroun [43]. A total of 28 patients who were treated witha variety of induction chemotherapy regimens includingCMF (Cyclophosphamide, Methotrexate and5Fluorouracil) went on to a least 1 cycle of high-dosechemotherapy with Cyclophosphamide 6 g/m2, Carbo-platin 2 g/m2 and Etoposide 625 mg/m2. At the end oftheir induction treatment seven patients had a completeresponse and 19 patients had a partial response and twopatients had stable disease. Four patients had only onecycle of high-dose therapy due to treatment toxicity and


one patient died. At the end of the first cycle ofhigh-dose treatment 11 patients achieved a completeresponse and 11 patients obtained a partial responsegiving an overall response rate of 78.6%. Only twopatients were converted into complete response by asecond cycle of therapy and both subsequently re-lapsed. They commented that use of a different non-cross resistant regimen as the second high-dose regimenmay improve outcome and this is currently underassessment in newer randomised studies.

Technically these procedures are possible to performwith dose intensity being maintained although delaysoccur related to the supportive aspects of treatmentrather than delays in haematopoietic recovery and inparticular to leukapheresis catheter complications [44].Other non-haematological toxicities include veno-occlu-sive disease, congestive cardiac failure, pulmonaryfibrosis, renal failure and hepatitis.

It has been shown that it is possible to use repeatedcycles of high-dose chemotherapy which do not requirehaematopoietic salvage mainly due to improvements insupportive care and the advent of growth factors. Suchstudies [45] have been felt by some to merely demon-strate the important role of growth factors in limitingthe duration of significant cytopenia rather than anincrease in dose intensification.

The optimal strategy for the timing of high-dosechemotherapy still requires further investigation. Peters[46] has shown that immediate treatment has shownbetter disease-free survival than treatment on relapse.However deferring treatment until the time of relapsehas been correlated with better overall survival.

At the end of a successful course of treatment withhigh-dose the subsequent course of action is unclearwith some investigators using Tamoxifen for onlyoestrogen receptor positive tumours and others notonly irradiating the chest wall but sites of bulk disease.Concerns have been voiced about cardiotoxicity withchest wall irradiation following myeloablativechemotherapy and discussion about this is ongoing.

6. Cost implications and health economics

In the USA there has been a 6-fold increase in theuse of high-dose chemotherapy between 1989 and 1995.A total of 1500 patients per annum undergo high-dosetreatment at a cost of $1 billion. These patients whosemedian age is 44 years have many axillary nodes in-volved by tumour and do not reflect the breast cancerpopulation as a whole. Only 11% of those with stage IIand III tumours and less than 1% of those with stageIV disease have been entered into randomised con-trolled studies. With the explosion in the use of high-dose chemotherapy regimens especially for locallyadvanced disease the need to have clear data to support

its ongoing role becomes even more pressing [47]. Atotal of 7% of eligible and interested patients in oneAmerican study were unable to participate to the con-straints of insurance cover and individual financial ca-pability [32]. It may be hoped that with improvementsin supportive care and experience financial costs will bereduced by accommodating some patients close to thehospital and managing them primarily as out-patients.

Peters [48] attempted to give some assessment of thecost benefit of high dose chemotherapy with stem cellsupport and calculated that in 1991 the cost per year oflife extended by high dose was $73 300 compared to$31 500 for conventional chemotherapy. It has beenconcluded that peripheral blood stem cell rescue ischeaper than autologous bone marrow transplantationmainly due to the faster haematological recovery andresulting decreased in-patient stay and associated costsof laboratory and radiological investigations, medica-tion and blood products.

Hillner [49] used a decision analysis model to attemptto quantify the costs of high-dose chemotherapy andautologous bone marrow transplantation for hypotheti-cal American patients with metastatic breast cancer.The data from published studies was fed into thismodel and costs were based on local charges andMedicare data. It was concluded that autologous bonemarrow transplantation gave a 6 month survival benefitat 5 years at a cost of $115 800 per year of life saved.This costing is altered by considering the recurrencerisk to be constant or reducing with time.

The costs of a bone marrow transplant were alsoreported for the procedure to be carried out at theauthors’ hospital and were based on those of six pa-tients who had had an uncomplicated procedure withan average in-patient stay of 40 days. In 1990 theaverage charge was $87 980 with costs accounting for$66 200.

These costings make no allowance for the long-termtoxicities of high-dose cytotoxic therapy which are ob-viously more important in the adjuvant treatment ofbreast cancer.

7. Conclusions

Breast cancer is now the most common solid malig-nancy to be treated with high-dose chemotherapy [47]despite the lack of level I and II evidence to support itswidespread use. While it is not the solution for allpatients, it may offer the prospect of improvement insituations where clinicians know that the outcome fromconventional chemotherapy is inadequate.

High-dose chemotherapy is not the complete answerto dealing with those who are considered to be at highrisk of relapse. HER2/neu oncogene protein expressioncorrelates with the proliferative rate of breast car-


cinoma. Over-expression of this protein can be found in15–30% of primary breast cancers. One study [50]showed that all of those with this over-expression re-lapsed after high-dose chemotherapy. Another group ofpatients who need alternative treatment strategies arethose who are progesterone receptor negative or whohave high grade inflammatory breast cancer [51].

The requirement for randomised controlled studies isunderlined by the fact that variables such as the patho-logical type of the cancer, the patient’s menopausalstatus, the number and sites of metastatic disease, theprior use of chemotherapy, the time from initial recur-rence to treatment and the oestrogen receptor status allcan be more important in affecting prognosis than thetreatment actually delivered.

There are still many outstanding questions regardingthe use of high-dose chemotherapy in terms of patientselection; the timing of its use; the choice of drugregimen; whether the stem-cell harvest should bemodified in vitro; how to suppress the negative regula-tors of haematopoiesis which may be over-expressedafter bone marrow injury caused by high-dosechemotherapy [52]; the best methods of supportive careand what to do with residual disease. For adjuvanttherapy another important issue is improving curerather than merely improving disease-free survival whilein the metastatic setting the use of multiple high-dosetreatments needs investigation.

It is still not clear which is the best drug combinationto be used in high-dose regimens and the developmentof new drugs such as the taxanes and Vinorelbine havegenerated considerable interest and many Phase I andII trials are underway to assess their possible role.

The need to answer these questions and firmly definethe role of high-dose chemotherapy in the treatment ofbreast cancer must be emphasised to encourage partici-pation in future trials.

Reviewer

This paper was reviewed by Dr Janine L. Mansi, MDFRCP, Consultant Medical Oncologist, St. GeorgesHospital, Blackshaw Road, London SW17 0QT, UK.

References

[1] Leonard RCF, Rodger A, Dixon JM. Management of metastaticbreast cancer. Br Med J 1994;309:1501–4.

[2] Early Breast Cancer Trialists’ Collaborative Group. Systemictreatment of early breast cancer by hormonal, cytotoxic orimmune therapy. Lancet 1992;339:1–5:71–85.

[3] Harris JR, Morrow M, Bonnadonna G. Cancer of the breast. In:DeVita VT, Hellman S, Rosenberg SA, editors. Cancer Princi-ples and Practice of Oncology, 4th edition. Philadelphia: Lippin-cott, 1993:1264–332.

[4] Greenberg PAC, Hortobagyi GN, Smith TL, et al. Long-termfollow up of patients with complete remission following combi-nation chemotherapy for metastatic breast cancer. J Clin Oncol1996;14:2197–205.

[5] Skipper HE, Schabel FM, Wilcox WS. Experimental evaluationof potential anti-cancer agents. XII On the criteria and kineticsassociated with curability of experimental leukemia. CancerChemother Rep 1964;35:1–111.

[6] Frei E, Antmann K, Teicher B, et al. Bone marrow autotrans-plantation for solid tumours -prospects. J Clin Oncol1989;7:515–26.

[7] Peters WP, Shpall EJ, Jones RB, et al. High dose combinationalkylating agents with bone marrow support as initial treatmentfor metastatic breast cancer. J Clin Oncol 1988;6:1368–76.

[8] Bowers C, Adkins D, Dunphy F, et al. Dose escalation ofmitoxantrone with thiotepa and autologous bone marrow trans-plantation for metastatic cancer of the breast. Bone MarrowTransplant 1993;15:525–30.

[9] von Hoff D, Clark G, Geoffrey S, et al. Use of in vitrodose-response effects to select antineoplastics for high-dose orregional administration regimens. J Clin Oncol 1986;4:1827–34.

[10] Hryniuk W, Bush H. The importance of dose-intensity in thechemotherapy of metastatic breast cancer. J Clin Oncol1984;2:1281–8.

[11] Wood WC, Budman DR, Korzun AH, et al. Dose and doseintensity of adjuvant chemotherapy for stage II, node positivebreast cancer. New Engl J Med 1994;330:1253–9.

[12] Tannock IF, Boyd NF, DeBoer G, et al. A randomised trial of2 dose levels of Cyclophosphamide, Methotrexate and5Fluorouracil for patients with metastatic breast cancer. J ClinOncol 1988;6:1377–87.

[13] Lalislang RI, Wils JA, Nortier HW, et al. Comparative study ofdose escalation versus interval reduction to obtain dose-intensifi-cation of Epirubicin and Cyclophosphamide with granulocytecolony-stimulating factor in advanced breast cancer. J ClinOncol 1997;15:1367–76.

[14] Savarese DMF, Hsieh C, Stewart FM. Clinical impact ofchemotherapy dose intensity in patients with haematologicalmalignancies and solid tumours. J Clin Oncol 1997;15:2981–95.

[15] Norton L. A Gompertzian model of human breast cancergrowth. Cancer Res 1988;48:7067–71.

[16] Livingstone RB. Dose intensity and high dose therapy. CancerSuppl 1994;74(3):1177–83.

[17] Eddy DM. High dose chemotherapy with autologous bone mar-row transplantation for the treatmennt of metastatic breastcancer. J Clin Oncol 1992;10:657–70.

[18] Sheridan WP, Begley CG, Juttner CA. Effect of peripheral bloodprogenitor cells mobilised by filgrastim (G-CSF) on plateletrecovery after high dose chemotherapy. Lancet 1992;339:640–4.

[19] van der Wall E, Nooijen WJ, Baars JW. High dose carboplatin,thiotepa and cyclophosphamide (CTC) with peripheral bloodstem cell support in the adjuvant treatment of high-risk breastcancer: a practical approach. Br J Cancer 1995;71:857–62.

[20] Myers SE, Mick R, Williams SF. High dose chemotherapy withautologous stem cell rescue in women with metastatic breastcancer with involved bone marrow: a role for peripheral bloodprogenitor transplant. Bone Marrow Transplant 1994;13:449–54.

[21] Brugger W, Bross KJ, Glatt M, et al. Mobilisation of tumourcells and haematopoietic progenitor cells into the peripheralblood of patients with solid tumours. Blood 1994;83:636–40.

[22] Fields KK, Elfenbein GJ, Trudeau WL, et al. Clinical signifi-cance of bone marrow metastases as detected using the poly-merase chain reaction in patients with breast cancer undergoinghigh-dose chemotherapy and autologous bone marrow trans-plantation. J Clin Oncol 1996;14:1868–76.


[23] Ross AA, Cooper BW, Lazarus HM, et al. Detection and viabilityof tumour cells in peripheral blood stem cell collections frombreast cancer patients using immunocytochemical and clonogenicassay techniques. Blood 1993;82:2605–10.

[24] Brenner MK, Rill DR, Moen RC, et al. Genetic marking to traceorigin of relapse after autologous bone-marrow transplantation.Lancet 1993;341:85–6.

[25] Shpall EJ, Jones RB, Bast RC, et al. 4-hydroperoxycyclophos-phamide purging of breast cancer from the mononuclear fractionof bone marrow in patients receiving high-dose chemotherapy andautologous marrow support: a phase 1 trial. J Clin Oncol1991;9:85–93.

[26] Shpall EJ, Stemmer SM, Bearman SI, et al. New strategies inmarrow purging for breast cancer patients receiving high-dosechemotherapy with autologous bone marrow transplantation.Breast Cancer Res Treat 1993;26:19–23.

[27] Slevin ML, Stubbs L, Plant HJ, et al. Attitudes to chemotherapy:Comparing view of patients with those of doctors, nurses and thegeneral public. Br Med J 1990;300:1458–60.

[28] Coates AS, Simes RJ. Patient assessment of adjuvant treatmentin operable breast cancer. In: Williams CJ, editor. IntroducingNew Treatments for Cancer: Practical, Ethical and Legal Prob-lems. New York: Wiley, 1992:447–58.

[29] Carter CL, Allan C, Henson DE. Relation of tumour size, lymphnode status and survival in 24 470 breast cancer cases. Cancer1989;63:181–7.

[30] Crump M, Goss PE, Prince M, Girouard C. Outcome of extensiveevaluation before adjuvant treatment in women with breast cancerand 10 or more positive axillary lymph nodes. J Clin Oncol1996;14:66–9.

[31] Gianni AM, Bregni M, Siena S, et al. G-CSF reduces haematolog-ical toxicity and widens clinical applicability of high dose cy-clophosphamide treatment in breast cancer and non Hodgkin’slymphoma. Proc Am Soc Clin Oncol 1992;11:68.

[32] Peters WP, Ross M, Vredenburgh JJ, et al. High dose chemother-apy and autologous bone marrow support after standard-doseadjuvant chemotherapy for high-risk primary breast cancer. J ClinOncol 1993;11:1132–43.

[33] Gianni AM, Siena S, Bregni M, et al. Efficacy, tolerability andapplicability of high-dose sequential chemotherapy as adjuvanttreatment in operable breast cancer with 10 or more involvedaxillary lymph nodes: five-year results. J Clin Oncol1997;15:2312–21.

[34] Tobias JS, Weiner RS, Griffiths CT, et al. Cryopreserved au-tologous marrow infusion following high dose cancer chemother-apy. Eur J Cancer 1977;13:269–77.

[35] Vincent MD, Trevor J, Powles R, et al. Late intensification withhigh-dose melphalan and autologous bone marrow support inbreast cancer patients responding to conventional chemotherapy.Cancer Chemother Pharmacol 1988;21:255–60.

[36] Ayash LJ, Wheeler C, Fairclough D, et al. Prognostic factors forprolonged progression-free survival with high-dose chemotherapywith autologous stem-cell support for advanced breast cancer. JClin Oncol 1995;13:2043–9.

[37] Eder JP, Antman K, Peters W. High-dose combination alkylatingchemotherapy with autologous bone marrow support formetastatic breast cancer. J Clin Oncol 1986;4:1592–7.

[38] Dunphy FR, Spitzer G, Buzdar AU, et al. Treatment of oestrogenreceptor-negative or hormonally refractory cancer of the breastwith double high-dose chemotherapy intensification and bonemarrow support. J Clin Oncol 1990;8:1207–16.

[39] Antman K, Ayash L, Elias A, et al. A phase II study of high-dosecyclophosphamide, thiotepa and carboplatin with autologousmarrow support in women with measurable advanced breastcancer responding to standard-dose therapy. J Clin Oncol1992;10:102–10.

[40] Bezwoda WR, Seymour L, Dansey RD. High-dose chemotherapywith haematopoietic rescue as primary treatment for metastatic

breast cancer: a randomised trial. J Clin Oncol 1995;13:2483–9.

[41] Greenberg PAC, Hortobagyi GN, Smith TL, et al. Long-termfollow-up of patients with complete remission following combina-tion chemotherapy for metastatic breast cancer. J Clin Oncol1996;14:2197–205.

[42] Rahman Z, Frye D, Buzdar A, Hortobagyi G. A retrospectiveanalysis to evaluate the impact of selection processes for high-dosechemotherapy on the outcome of patients with metastatic breastcancer. Proc. Am. Soc. Clin. Oncol. 1995;14:95 (abst. 78).

[43] Broun ER, Sridhara R, Sledge GW, et al. Tandem autotransplan-tation for the treatment of metastatic breast cancer. J Clin Oncol1995;13:2050–5.

[44] Crown J, Kritz A, Vahdat L. Rapid administration of multiplecycles of high dose myelosuppressive chemotherapy in patientswith metastatic breast cancer. J Clin Oncol 1993;11:1144–9.

[45] Neidhart JA, Kohler W, Stidley C, et al. Phase I study of repeatedcycles of high-dose cyclophosphamide, etoposide, and cisplatinadministered without bone marrow transplantation. J Clin Oncol1990;8:1728–38.

[46] Peters WP, Jones RB, Vredenburgh J, et al. A large prospectiverandomised trial of high-dose combination alkylating agents(CPB) with autologous cellular support (ABMS) as consolidationfor patients with metastatic breast cancer achieving completeremission after intensive doxorubicin-based induction treatment(AFM).Proc. Am. Soc. Oncol. 1996.

[47] Antman KH, Rowlings PA, Vaughan WP, et al. High-dosechemotherapy with autologous haematopoietic stem-cell supportfor breast cancer in North America. J Clin Oncol 1997;15:1870–9.

[48] Peters WP, Rosner G. A bottom-line analysis of the financialimpact of haematopoietic colony-stimulating factors and G-CSFprimed peripheral blood progenitor cells. Blood 1991;78:8a.

[49] Hillner BE, Smith TJ, Desch CE. Efficacy and cost-effectivenessof autologous bone marrow transplantation in metastatic breastcancer. J Am Med Assoc 1992;267:2055–61.

[50] Britan JD, Samuels B, Trujillo Y, et al. Her2/neu overexpressionis associated with treatment failure in women with high-risk stageII and stage IIIA breast cancer (\10 involved lymph nodes)treated with high-dose chemotherapy and autologous haemato-poietic progenitor support following standard-dose adjuvantchemotherapy. Clin Cancer Res 1996;2:1509–13.

[51] Somlo G, Doroshow JH, Forman SJ, et al. High-dose chemother-apy and stem-cell rescue in the treatment of high-risk breastcancer: Prognostic indicators of progression-free and overallsurvival. J Clin Oncol 1997;15:2882–93.

[52] Rabinowitz J, Petros WP, Stuart A, et al. Effect of endogenousserum tumour necrosis factor-a (TNF) on myelopoiesis inducedby recombinant, human granulocyte colony-stimulating factor(rHuG-CSF). Blood 1991;78(Suppl 1):259a.

Biographies

Dr Robert C.F. Leonard, MBBS, MD, FRCPE,FRCP is a Consultant Physician and Part-time SeniorLecturer in Medical Oncology. He is an author of fourbooks and 230 papers in peer-reviewed journals. He isa member of EORTC Breast Group, British BreastGroup, Chair of Anglo-Celtic Group (InternationalHigh-dose Trial), UKCCCR and Scotish Breast Cancercommittees. His main interests are immunotherapy andintensive chemotherapy.

Dr Lesley K. Dawson, MBChB, MRCP, is a SpecialistRegistrar in Medical Oncology. Her main interests arebreast and gastrointestinal malignancies.

Documents

High dose therapy of breast cancer: current status