New cytotoxic agents and schedules for advanced breast cancer

New

Cytotoxic

Agents and Schedules Breast Cancer

Harold Cytotoxic

chemotherapy

women

with

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breast

alone

or

and

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use

of chemotherapy,

effects

on

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cancer.

in

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of

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availcombi-

biological with

availability

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novel

growing

for

modifications Finally,

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Company.

YTOTOXIC AGENTS have an important role in the management of both early-stage and advanced breast cancer. For women with advanced disease, these drugs offer palliation of symptoms, disease control, and prolonged survival. The role of cytotoxic chemotherapy as adjuvant therapy is discussed elsewhere in this issue. In the past 5 to 10 years, a variety of new agents have entered investigational or approved use for treating women with breast cancer. Many offer improved efficacy and easier tolerability than prior chemotherapy regimens. This review will highlight these newer agents, emphasizing their side effects, dose and administration schedules, and use in the management of women with advanced breast cancer.

C

From the Department of Adult Oncology, Dana-Farber Cancer Institute, Department of Medicine, Brigham B Women’s Hospital, Harvard Medical School, Boston, MA. Supported in part by NIH Grant No. 5T32 CA09172-24. The authors have participated in studies supported by grants from the following pharmaceutical companies: Bristol-Myers Squibb, Eli Lilly, Genentech, Glaxo Wellcome, Liposome, Nouartis, Awntis, Sequus Address reprint requests to Eric P. Winer, MD, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115. Copyright 0 2001 by W.B. Saunders Company 0093.7754/01/2804~0005$35.00/0 doi:l0.1053/sonc.200J .26146 344

A. Bunnell,

and Eric P. Winer

PRINCIPLES FOR USE OF CYTOTOXIC CHEMOTHERAPY IN ADVANCED BREAST CANCER

activity advances

include

side with

of

as principles

Recent

chemotherapeutics.

therapies

with

breast reduce

clinical

as well

reviewed.

for to

treatment of agents

The

agents,

Craig

hormone-refrac-

A variety

role

chemotherapy

improve

of breast

cancer.

are

the

for or

in combination.

of many

chemotherapy studies

is important

hormone-insensitive

advanced

effective,

J. Burstein,

for Advanced

Cytotoxic chemotherapy is important for palliation of women with hormone-refractory or hormone-insensitive breast cancer. The therapeutic goals are control of disease progression, relief of symptoms, and prolongation of life. Objective response to chemotherapy can improve cancerrelated symptoms, particularly pain, shortness of breath, and mood disturbance.’ While a small fraction of women with metastatic breast cancer will be long-term survivors following treatment with chemotherapy, most patients are not being treated with curative intent. Under these circumstances, clinicians and patients must carefully weigh the expected benefits of therapy against the likely side effects. Certain principles of therapy have emerged through decades of experience using chemotherapy to control advanced breast cancer.233 These are helpful in planning care for patients. Adverse prognostic factors such as poor performance status, multiple and/or visceral sites of disease, short disease-free or response intervals, and failure of prior therapy predict reduced likelihood of success for any subsequent therapy. Patients treated with adjuvant chemotherapy may exhibit less response to chemotherapy for metastatic breast cancer.425 First-line therapy is associated with a higher response rate than second- or subsequent-line therapy, and so forth. Higher response rates tend to be seen in single-institution phase II studies than in multicenter phase III trials. Combination regimens and dose-intensive regimens are frequently associated with higher response rates and, in some instances, prolonged progression-free survival. However, these regimens have not convincingly been shown to improve overall survival.6,7 High-dose chemotherapy with autologous stem cell transplantation does not improve either disease-free or overall survival for women with advanced breast cancer who are Seminars in Oncology, Vol 28, No 4 (August),

200 I: pp 344-358

CYTOTOXIC

CHEMOTHERAPY

FOR ADVANCED

BREAST

CANCER

responding to standard chemotherapy regimens, and is associated with greater toxicity.819 It has not been possible to identify subgroups of patients with metastatic breast cancer who might selectively benefit from high-dose chemotherapy.iO,ii l Continuous therapy in responding patients is generally associated with prolonged progression free survival, but not overall survival, when compared to intermittent therapy offered at the time of disease recurrence/progression.i2 l Patients with objective responses to treatment have improved survival compared with patients who do not respond to treatment.13 l Patients with objective responses to chemotherapy are likely to have improvement in their cancer related symptoms, particularly pain, shortness of breath, and depression.1 l There are few compelling data that one regimen is markedly superior to another regimen, or promotes improved long-term survival.l4 A recently reported randomized study demonstrated that initial therapy with either singleagent or novel phase II drugs (generally ineffective) prior to standard combination chemotherapy did not adversely effect breast cancer survival.15 This is both a sobering measure of the relatively small differences between available treatment regimens, and a rationale for the ongoing exploration of novel drugs and regimens. l For women with HER-2-positive metastatic breast cancer, initial combination treatment with chemotherapy and trastuzumab (Herceptin; Genentech, South San Francisco, CA) appears to afford survival advantage over chemotherapy alone.16 Thus, women with HER2-positive metastatic breast cancer who are candidates for chemotherapy merit consideration of concurrent trastuzumab therapy. The available options for women with advanced breast cancer have expanded over the past 5 years. This article will review recent experience with some of the cytotoxic agents used in women with metastatic breast cancer, emphasizing newer drugs and treatment schedules. TAXANES

The taxanes, paclitaxel (Taxol; Bristol-Myers Squibb, Princeton, NJ) and docetaxel (Taxotere; Aventis, Collegeville, PA), are microtubule-stabi-

345

lizing compounds that inhibit cell division by preventing depolymerization of the tubules. The development of these drugs and analyses of their broad spectrum of antineoplastic activity have been reviewed elsewhere.i7-19 These drugs are among the most active agents against metastatic breast cancer.zQzi The preliminary results of a single, large randomized trial suggest that the addition of paclitaxel to adjuvant doxorubicin/cyclophosphamide chemotherapy may confer a survival advantage among women with node-positive, early-stage breast cancer.22 Similar trials using docetaxel are currently underway, and a variety of other adjuvant regimens that incorporate taxanes are under investigation. Thus, there is widespread interest in defining the optimal use of taxanes for women with breast cancer. Pa&&:

Dose and Schedule Considerations

Historically, paclitaxel has been administered as a bolus infusion every 3 weeks. Several large, randomized trials have examined the effect of dose and infusion schedules on paclitaxel efficacy in metastatic breast cancer. These studies are summarized in Table 1, Dose escalation and prolonged infusion schedules have been associated with greater toxicity, and in some instances increased response rates, but have not enhanced overall survival. For most patients, the standard regimen in the United States remains 175 mg/m’ as a 3-hour infusion every 3 weeks, although weekly therapy is frequently used based on data derived from phase II/III trials. Different infusion schedules may alter the clinical activity of paclitaxel. A phase II study at Memorial Sloan-Kettering Cancer Center examined the effectiveness of a 96-hour paclitaxel infusion in patients who had previously experienced tumor progression while receiving treatment with shorter duration infusions of taxanes.23 Despite the apparent refractoriness of these patients to paclitaxel, 27% had a clinical response to treatment with the prolonged infusion. This observation suggests that antitumor activity may be affected by the infusion schedule. However, randomized trials comparing the outcomes of treatment with paclitaxel given as either a 3-hour infusion or a 24- or 96-hour infusion have failed to demonstrate clinical advantages that would justify the logistical effort, expense, or patient inconvenience of longer infusions (Table 1).

346

BURSTEIN,

Paclitaxel Study Nabholtz

3

2120122

I75

3

5124129

I75

3

6115/21

210

3

5123128

250

3

I75

3

na/nal29

I75

24

na/nal32

250

3

nalnal40

250

24

nalnal50

et al,+*

(N = 521) B-2699

(N = 516) Anderson’ooJo’

(N =

175)

CR, complete

Abbreviations: survival;

RR, response

Docetuxel:

250

3

140

96

response;

PR, partial

T T P favors

250;

no OS advantage;

more

toxicity

No difference longer Higher

3120123 2127129 response;

No

OR,

overall

Dose and Schedule Considerations

Study

Metastatic

et al”‘2 et allo

in T T P or OS in either

infusion,

et allo et allo

Chevallier Chan

Adachi Salminen O’Brien

et al1o6

et allo7*

Nabholtz

higher

doses

RR, greater

differences

arm; more

neutropenia

with

less neuropathy toxicity

with

longer

infusion

in RR, OS

response;

na, not available;

TTP, time

to

progression;OS,~ved

95% confidence intervals, and the patient populations treated at 75 mg/m2 may be different from those offered therapy at 100 mg/m2. In practice, many patients with metastatic breast cancer require docetaxel dose reductions due to lower performance status, prior chemotherapy, toxicity, or liver function test abnormalities.24 Resistance to one taxane may not imply resistance to another. In one trial, patients with pacli-

for Disease

Treatment No. of Patients

Dose every

Prior

@g/m?

Anthracycline

2 I days)

Exposure

et allow et alto9 et aP4 et al””

Overall Response (%)

Rate (%)

0 0

37

100

49

54

35

75

I5

40

I6

100

0

37

75

63 57

52 68

100 Dieras

with

51 I 7122

No. of Prior

Fumoleau

175; no OS advantage

rate.

Regimens

Trudeau

WINER

Comment T T P favored

There are no randomized studies published to date that explore the importance of dose in the activity of docetaxel. A variety of phase II/III trials have been reported, and are summarized in Table 2. Among women with metastatic breast cancer, there appears to be a trend towards higher response rates with higher doses of 100 mg/m’. However, all of these studies have broad, overlapping

Hudis

AND

Rate

135

(N = 475)

M.D.

Response (CRIPRIOR)

9342q7

NSABP

of

Infusion

(N = 471)

Peres

Hours

(wlm*)

et al96

CALGB

Dose

BUNNELL,

0

39

75

53

52

0

35

100

29

68

O-I

161

100

0

47

O-I

203

100

100

30

o-2

72

60

32

44

o-3

31

100

100

48

o-3

377

75- IO0

91

46

Bokkel

Huinink

39

100

56

58

Ravdin

et aI”*

I -2

42

100

100

57

Valero

et al ’ I3

I-3

34

100

100

51

Archer

et al’ I4

22

22

75- IO0

100

24

* Docetaxel

et al”’

arm of randomized

trial.

CYTOTOXIC

CHEMOTHERAPY

FOR ADVANCED

BREAST

CANCER

347

taxel-resistant breast cancer were subsequently treated with docetaxeL25 A response rate of 25% was seen in these women who had failed to respond to paclitaxel infused over 3 hours on an every-3-week schedule. By contrast, there were no responses to docetaxel among women who had failed to respond to paclitaxel given as a 24-hour infusion.

Weekly Taxanes

Administered on an every-3-week basis, taxanes have predictable side effects. For paclitaxel, these include myelosuppression, alopecia, neuropathy, and myalgias/arthalgias. Hypersensitivity reactions can occur, most commonly with the first paclitaxel treatment.26 Premeditation with corticosteroids and antihistamines reduces the incidence of these reactions. Among patients not experiencing hy persensitivity reactions to the first paclitaxel dose, subsequent reactions are uncommon, and modified premeditation regimens that reduce or omit the corticosteroid dose may be adequate.zT-29 Docetaxel is also associated with myelosuppression and alopecia, and can be associated with skin lesions and mucositis. Fluid retention, characterized by pleural effusions, pedal edema, and weight gain, is a side effect of docetaxel related to cumulative dose. Corticosteroids may attenuate the risk of fluid retention,30 and prompt initiation of diuretics at the first sign of fluid retention may help ameliorate the condition. Both taxanes are metabolized by the liver, and require dose adjustment for patients with abnormal liver function tests.”

3. Phase

II Trials

Line of Therapy Study

for Metastatic

Paclitaxel Seidman et aIll Fornier et al’ I6

l-3 l-4

Perez et al”’ Breier

et al’ va

Disease

I -4 I >I

Taxanes in Combination Breast Cancer

Regimens for Metastatic

Taxanes have been incorporated into innumerable combination regimensfor treatment of met-

of Weekly

Weekly

Breast Cancer

Because the optimal dose-response relationship for taxanes in breast cancer is not established, weekly schedules of taxane therapy have been examined. Both paclitaxel and docetaxel are active when given on a weekly basis (Table 3). Weekly paclitaxel has also been shown to induce tumor responses in patients who had been previously treated with paclitaxel on an every-3-week schedule.32 The side effect profiles of these drugs are altered by the lower dose and more frequent administration. Myelosuppression becomes quite mild, and is not cumulative. Other acute toxicities, such as stomatitis or hypersensitivity reactions, are also modest. Alopecia develops after extended therapy. Extensive paclitaxel administration is limited by the development of peripheral neuropathy. With prolonged administration of docetaxel, fatigue and fluid retention become limiting factors. It is not known if weekly therapy is clinically superior to treatment every 3 weeks, but randomized studies are underway to address this question. For patients in whom prevention of certain toxicities is a major concern, or for patients receiving concurrent treatment with biologically based therapies, weekly taxanes may be a reasonable therapeutic option.

Taxanes: Side Effects

Table

for Metastatic

Taxanes

for

Metastatic

Breast

Cancer

Dose Schedule

(m&3

Response

80-I 00 90 80

Weekly Weekly Weekly

80 80

Weekly Weekly

40 35

Weekly

X 6, 2 weeks

50 30-4.5

Weekly Weekly Weekly

X 2, I week off X 6, 2 weeks off

35 35

Weekly Weekly

X 6, 2 weeks X 6, 2 weeks

Rate (%)

53% 44% (HER-2-negative 23%

(with Herceptin)

33% 39%

Docetaxel Burstein Climent

et al’19 et al120

l-2 >I

Pica-t et aP” Lijffler et al’21 Jackisch et all22

2

Stemmler

o-4

et al123

l-2 l-3

off

off off

41% 36% 34% 50% 29% 34%

subser)

348

BURSTEIN.

Doxorubicin

k dexrazoxane

Epirubicin Mitoxantrone S-FU i leucovorin lfosfamide Vinorelbine Cisplatin Carboplatin Topotecan lrinotecan Cyclosphosphamide

2 doxorubicin

Gemcitabine Edetrexate Trastuzumab

(Herceptin)

Doxil D-99 Multitargeted

antifolate

astatic breast cancer. A partial list of combination regimens is given in Table 4. Interest in combinations of taxanes and anthracyclines is most widespread, and several of these regimens are entering use in randomized, adjuvant chemotherapy trials. Such combinations may be appropriate for use in patients with metastatic cancer, although these regimens generally result in greater toxicity and there are no data that combination regimens confer a survival advantage over sequential, single+ agent treatment. NEW

ANTHRACYCLINE-LIKE

PRODUCTS

Doxorubicin (Adriamycin; Pharmacia, Kalamazoo, MI) remains a standard chemotherapy agent for treatment of early- and advanced-stage breast cancer, with response rates in the metastatic setting of 35% to 50% as a single agent. With repetitive treatment, cardiac toxicity becomes doselimiting. Patients receiving cumulative doses in excess of 450 to 500 mg/m2, or patients with pre-existing heart disease, are at greater risk for developing cardiac impairment from doxorubitin .33,34 More frequent administration of lower doses of doxorubicin, or administration by continuous infusion, may reduce the likelihood of cardiac side effects.35 The addition of a chemoprotectant, such as dexrazoxane (Zinecard; Pharmacia), has been shown to facilitate prolonged therapy with doxorubicin by delaying the onset of cardiac dys-

BUNNELL,

AND

WINER

function.36J’ There are concerns that cardioprotectant therapies may still leave patients vulnerable to cardiac damage and might impair the efficacy of doxorubicin. Epirubicin (Ellence; Pharmacia) is an anthracy cline product derived from doxorubicin, and is also effective in advanced breast cancer.38 Epirubicin is widely used in Europe in both the adjuvant and metastatic setting, and is now approved in the United States for adjuvant treatment. Epirubicin shares both efficacy and toxicity features with doxorubicin. A randomized trial in which either doxorubicin (60 mg/m’) or epirubicin (90 mg/m2) was administered every 3 weeks to women with metastatic breast cancer found similar response rates, survivals, and side effects, including cardiac toxicity.39 To avoid significant risk of heart damage, it is recommended that the maximum cumulative dose of epirubicin not exceed 900 mg/m2.40 The related anthracenedione chemotherapeutic agent, mitoxantrone, is also active in metastatic breast cancer both singly and as part of combination chemotherapy regimens.4l In comparison to doxorubicin, mitoxantrone appears to be somewhat less clinically active, but is associated with less alopecia and possibly less cardiac toxicity.42,43 The anthrapyrazoles have been developed in an attempt at preserving the antitumor efficacy of DNA intercalators but without the cardiac side effects.44 Loxoxantrone, one such product, has been shown to have a response rate of 63% among breast cancer patients without prior anthracycline exposure, but was associated with mild cardiac toxicity.45 LIPOSOMAL

ANTHRACYCLINES

Liposomal anthracyclines may alter the side effect profile of doxorubicin. These drugs involve the incorporation of doxorubicin into small liposomal vesicles, encapsulated by phospholipid membranes.46347 Different products can be derived based on the physical properties of the specific liposomes. TLC D-99 (Evacet; The Liposome Company, Princeton, NJ) one of the liposomal preparations, has been compared in randomized trials to doxorubicin. At equal doses, D-99 appears to have response rates equivalent to doxorubicin,48 with a lower incidence of either congestive heart failure or decline in ejection fraction.49 Further dose escalation of D-99 did not appear to increase response rates but greatly increased the observed

CYTOTOXIC

CHEMOTHERAPY

FOR ADVANCED

BREAST

CANCER

cardiac toxicity compared to standard doses of D-99.50 D-99 has also been substituted for the anthracycline component of such widely used regimens as cyclophosphamide, doxorubicin, and fluorouracil (CAF) and retains the same activity (response rate 73%) as would be expected with the traditional agent. 5i In randomized trials, D-99 has been used in combination with cyclophosphamide, and compared to either doxorubicin/cyclophosphamide (AC)s2 or epirubicin/cyclophosphamide (EC)5s standard combination regimens. Both of these trials showed at least equivalent efficacy for the D-99 combination when D-99 was substituted for the traditional anthracycline. Overall toxicity profiles were also quite similar, with the exception of a lowered incidence of cardiac complications in patients treated with the liposomal doxorubicin. Because of this activity and the possibility of improved safety, there is interest in bringing liposoma1 doxorubicin-containing regimens into the adjuvant setting. Doxil (Sequus Pharmaceuticals, Menlo Park, CA) is a formulation of doxorubicin encapsulated in small, sterically stabilized, liposomal vesicles. Doxil has a longer half-life than doxorubicin, and different tissue distribution, preferentially being concentrated in tumors as a result of its formulation.s+56 Liposomal encapsulation alters the toxicity profile for Doxil in comparison to doxorubitin. In clinical trials, Doxil has been associated with less cardiac toxicity, neutropenia, and alopecia compared to free doxorubicin (given as a short intravenous injection) .57,58 By contrast, Doxil has been associated with stomatitis and palmar-plantar erythrodysesthesia (hand-foot syndrome), which prove to be the dose-limiting toxicities upon repetitive treatments. 59 Doxil is active in breast cancer at doses in the range of 45 to 60 mg/m2 every 4 weeks.60 In a multicenter trial using Doxil as first- or second-line therapy for metastatic breast cancer, 3 1% of patients had objective responses.61 ORAL

FLOUROURACIL

ANALOGS

Fluorouracil (5FU) is a fluorinated pyrimidine analog with a long history of use in breast cancer, both as a single agent and within such classic combination regimens as cyclophosphamide, methotrexate, and 5-FU (CMF) and CAF. 5-FU works by binding to the enzyme thymidylate synthase, thereby preventing the formation of thymidine nucleosides for DNA synthesis. In addition,

349

the 5-FU metabolite, FUTP, is incorporated into RNA as a fraudulent base, producing functional inhibitions which also contribute to its cytotoxic effects. Given as an intravenous bolus, 5-FU has a short half-life (10 to 20 minutes). Prolonged exposure to 5-FU, achieved through continuous intravenous infusion, has been explored as a means of improving both the clinical activity and tolerability of 5-FU. A variety of studies in women with metastatic breast cancer have shown that continuous infusion 5-FU is an active chemotherapy treatment (response rates typically = 25% to 30%).62-e+ Principal side effects include mucocutaneous reactions such as rashes, hand-foot syndrome, mucositis, diarrhea, and, to a mild degree, neutropenia. Oral administration of 5-FU therapy affords the favorable pharmocokinetic features of continuous intravenous infusion, without the requirement of parenteral administration. The development of oral 5-FU therapy has required overcoming barriers such as limited oral bioavailability and rapid degradation of 5-FU by the enzyme dihydropyrimidine dehydrogenase (DPD) located in the gastrointestinal tract and liver. However, the use of prodrugs of 5-FU with good oral absorption and the development of inhibitors of DPD have led to the emergence of a variety of oral compounds that deliver 5-FU at clinically effective systemic concentrations.65,66 Table 5 identifies these new agents and their results in phase II/III studies in advanced breast cancer. Capecitabine (Xeloda; Roche, Nutley, NJ) is a prodrug of 5-FU, easily absorbed from the gut and converted through enzymatic steps in th.e liver and in the tumor into 5-FU. Tegafur (Ftorfur; with leucovorin and uracil as Orzel, Bristol-Myers Squibb) is also a prodrug, metabolized peripherally into 5-FU. In the case of tegafur, 5-FU is delivered with uracil as an inhibitor of DPD to enhance systemic levels. Glaxo Wellcome has developed an oral 5-FU preparation including eniluracil, an irreversible inhibitor of DPD. Because of the potency of this inhibition, significantly lower doses of oral 5-FU are needed to achieve comparable systemic levels. Many patients like the convenience of oral chemotherapy, although there is a tendency to assume than the oral route will yield fewer side effects than parenteral therapy. These newer agents are not wholly free of side effects, however, and generally share similar toxicities as infusional 5-FU.

350

BURSTEIN,

Table

5. Oral

5-FU

I

Theraljy

! ;, 6 ,.,

for

Line Agent 5-FU

Dose

(IV)

200-300 t

Schedule

mg/m*/d

of Therapy/

Prior infusion

Breast

Response

Therapy

, @&54%

divided

orally

Days

I - 14, every

3rd; prior

21 days

prior

5-FU

doses

I mglm’

eniluracil mg/m* twice

36%13’*

&

Days

orally

I-28,

every

prior

orally Various

diarrhea, bilirubin,

fatigue,

mucositis,

neutropenia

1 ~~~~~lj~,01w34

anthracycline,

Diarrhea,

taxane

rash, neutropenia

I St

55%‘35

Various

I7~%43~% IV- 14 I

daily

syndrome, elevated

25%‘=*

3rd, prior

35 days

IO

rash,

diarrhea

nausea,

anthracycline

Effects

syndrome,

20~o~24~y,‘29.‘30 Hand-foot

anthracycline,

2nd, prior

300- 1,200 mg/d

Tegafur

Hand-foot

taxanes

I st 5-FUiEniluracil

Side 124. 128

mucositis.

per day in 2

WINER

Rates

64

Various

AND

Cancer

leucovorin

2,5 IO mgld

Capecitabine

Continuous

M&&tic

BUNNELL,

Nausea/vomiting,

* uracil

diarrhea,

mucositis

i- leucovorin *Randomized

trial,

capecitabine

arm.

Mucocutaneous reactions are the most common side effect of oral 5FU analogs, and patients should be advised not to ignore early symptoms as these often require dose adjustment. Neutropenia is less common, but still observed, particularly in patients who have been heavily pretreated with chemotherapy. For such patients, initiation of therapy at a lower dose is suggested, with subsequent dose escalation if the first cycle is well tolerated. OTHER

drugs target several of the enzymes involved in the synthetic pathway for DNA precursors. Many have broad antitumor activities, and are generally well tolerated. Table 6 summarizes the principal products being currently studied. As has been historically true for 5-FU and methotrexate, these newer antimetabolites are being investigated in combination with other cytotoxic chemotherapy, including taxanes, vinorelbine, camptothecins, and alkylators. VINORELBINE

ANTIMETABOLITES

In addition to the oral 5-FU analogues, a variety of newer antimetabolites are being developed as treatments for advanced breast cancer. These

6. Newer

Table

Target

Edetrexate

i

Amtimetabolites

for’T&kwm&t

Common Neutropenia,

DHFR TS

(Zene~a)‘~~

(LY231514;

DHFR,

TS,

GARFT

Eli Lilly)147

Cancer

Line

of Therapy

Thrombocytopenia,

Side Effects

stomatitis,

LFT abnormalities, neutropenia,

MTA

Breast

Metastatic

abnormalities, Tomudex

of Advanced

Enzyme(s)

for Inhibition

Drug

Vinorelbine (Navelbine; Glaxo Wellcome, Research Triangle Park, NC) is a semisynthetic vinca alkaloid with broad antitumor efficacy.67268 Like

rash,

LFT

for

Breast

Phase

II

CWlCW

Response

Rates

I St-line

therapy

34%~4 [ 0%142.143

I St-line

therapy

26%lq6

thrombocytopenia asthenia, diarrhea,

NN145

neutropenia,

rash, LFT abnormalities,

anemia,

skin NN

I St-or Znd-line

2nd~line therapy,

therapy prior

3 I%‘48 22%‘49

anthracyclines Abbreviations: ventricular

function:

DHFR, NN,

dihydrofolate nausea

reductase;

and vomiting.

TS, thymidylate

synthase;

GARFT,

glycinamide

ribonucleoticle

formyltransferase;

LFT, left

CYTOTOXIC

CHEMOTHERAPY

FOR ADVANCED

BREAST

other vinca alkaloids, vinorelbine acts by inhibiting microtubule assembly within the tumor cell preventing cell division. In comparison to other vinca drugs, vinorelbine is less neurotoxic, and appears to have less effect on axonal microtubules at standard doses. Vinorelbine is metabolized primarily in the liver by the P450A system, and can have drug interactions with such agents as ketoconazole and erythromycin. Despite its hepatic metabolism, patients with liver metastases can generally tolerate vinorelbine without increased toxicity. Pharmacologic studies have shown that more than 75% of the liver must be replaced with tumor before mean clearance is affected.69 Nonetheless, dose reduction is generally warranted in patients with advanced hepatic disease. The principal side effects of vinorelbine are myelosuppression and neuropathy. At higher doses, alopecia, constipation, fatigue, and phlebitis are more common. Multiple studies have established the efficacy of single-agent vinorelbine in the treatment of metastatic breast cancer.70171 These studies are summarized in Table 7. As a single agent, vinorelbine has first-line response rate activity of 35% to 45%, and second-line activity of 15% to 30%. Vinorelbine has been incorporated into a variety of combination chemotherapy regimens. An orally available formulation of vinorelbine is in development, which appears to have a safety and efficacy profile similar to the intravenous drug.

Table Weekly Dosing Study Cannobio Fun&au

Prior Chemotherapy Regimens

(wM et allSo et alIS’

Romero Twelves

et al152 et aI’=

Gasparini

et al’+’

Barni et alIs Weber et alI=

7. Activity

30 30

o- I 0

30

et al’s’

* Vinorelbine Abbreviations:

No. of Patients

Gemcitabine (Gemzar; Eli Lilly, Indianapolis, IN) is a cytidine nucleoside analog that is phosphorylated in cells. Once phosphorylated, it inhibits ribonucleotide reductase, therby limiting production of deoxynucleotide triphosphosphates for DNA synthesis. It is also incorporated into DNA, instead of deoxycytidine, causing strand termination. Gemcitidine has activity against a wide variety of solid tumors. The most common toxicities are neutropenia, liver function test abnormalities such as transaminitis, nausea/vomiting, and mild alopecia. Less common side effects include peripheral edema and diarrhea. Gemcitabine is typically given as a weekly intravenous infusion for 3 consecutive weeks, foll.owed by 1 week off of therapy. Gemcitabine has activity in advanced breast cancer and is generally well tolerated. In patients with extensive prior chemotherapy or pelvic irradiation, neutropenia can be a problem. Several phase II studies have documented response rates between 14% and 46% for first- or second-line therapy (Table 8). Gemcitabine is being studied in a variety of combination regimens for advanced breast cancer.T2 TOPOISOMERASE

The camptothecins such as topotecan (Hycamtin; SmithKline Beecham, Philadelphia, PA) and irinotecan (Camptosar; Pharmacia) are inhibitors

in Metastatic Mean Dose Intensity (w/m2

PW)

Breast

Cancer

CR/PR/OR

0

145 45

20.6 22.4

713414 I 713414 I

25 20-25

0 l-4

34 67

19.8 15.7

6/44/50 413 I135

20 30

I 0

30

na

3/33/36

60 47 II5

19.4 20.7 19.3

white

blood

trial. cell; Hgb, hemoglobin.

Major (>5%

(“/-) 2 I125146

30

INHIBITORS

Camptothecins

“a

arm of randomized WBC,

of Vinorelbine

GEMCITABINE

26

I Jones

351

CANCER

Toxicities grade

3 or 4)

WBC, WBC,

constipation constipation

WBC, WBC,

Hgb, alopecia, N/V, alopecia

WBC, WBC

phlebitis,

stomatitis

I5/20/35 612513 I

WBC,

asthenia,

constipation.

5/l III6

WBC,

anemia,

asthenia

stomatitis

352

BURSTEIN,

Prior Study Carmichael

Chemotherapy

Metastatic et al15s

Breast

for

Dose

Cancer

(m&n*,

8, 15 every

I,

Response

AND

Principal

Rate

800

25%

WBC,

N/V,

et al Is9

0

1,200

46%

WBC,

NN

Possinger

et al160

0

1,000

14%

WBC,

NN

WBC,

neutropenia;

NN,

nausea/vomiting;

LFT, liver

of the enzyme topoisomerase I. The major side effect of topotecan is myelosuppression, although other hematologic and gastrointestinal toxicities can occur. For irinotecan, the most common side effect is diarrhea, with other gastrointestinal and hematologic side effects being less problematic. Camptothecins have modest clinical activity in advanced breast cancer. In several phase II trials of topotecan, administered as either second- or thirdline chemotherapy, response rates have averaged between 10% and 15% (range, 0% to 31%).73-77 There is very little clinical experience with irinotecan in breast cancer. A single phase II study reported a 23% response rate.78

The epidophyllotoxin etoposide also has modest activity in advanced breast cancer. Oral etoposide (Vepisid; Bristol-Myers Squibb) may be more active that etoposide given as an intravenous bolus. Sustained oral etoposide dosed at 50 mg/m2/d for 21 days on a 28-day cycle has been extensively evaluated in women with metastatic breast cancer. Response rates of 10% to 35% have been reported when oral etoposide is used as first- or second-line therapy.79~sz Among more heavily pretreated patients, response rates are less than 5%.83 HER-2 overexpression may be associated with relative resistance to oral etoposide.84 While oral etoposide may be convenient for patients, the toxicity can be significant, especially bone marrow suppression with severe neutropenia. PLATINUM

ANALOGS

Cisplatin (Platinol; Bristol-Myers Squibb) and carboplatin (Paraplatin; Bristol-Myers Squibb) have been widely used to treat metastatic breast cancer, and have historically been incorporated into highdose chemotherapy regimens.sss6 The paclitaxel/

function

WINER

Side

Effects

Blackstein

Abbreviation:

O-I

days 28 days)

BUNNELL,

LFT

test.

carboplatin combination that has been widely used to treat a variety of malignancies also has activity in patients with metastatic breast cancer, with response rates of 62% reported when used as first-line therapy. 87 The report of clinical activity using trastuzumab in combination with cisplatin has rekindled some enthusiasm for using platinumbased agents in women with metastatic breast canis a new-generation platinum cer. ** Oxaliplatin compound with different biological properties than either cisplatin or carboplatin.89 Nonhematologic toxicities associated with oxaliplatin include neuropathy, nausea/vomiting, and diarrhea. Hematologic toxicities include thrombocytopenia and anemia, although myelosuppression is uncommon. Clinical experience among patients with breast cancer is limited. In a single phase II study of women with anthracycline-resistant metastatic breast cancer, a response rate of 21% was reported for oxaliplatin at a dose of 130 mg/m2 every 3 weeks.90 TRASTUZUMAB

AND

CHEMOTHERAPY

The availability of trastuzumab and the demonstration that trastuzumab in combination with chemotherapy improves survival for women with metastatic breast cancer14 represent important advances in the management of this disease. A determination of HER-2 expression status is required for adequate treatment of women with advanced breast cancer. Trastuzumab has activity against advanced breast cancer as a single agent.91-93 Response rates of 30% to 35% have been observed among patients HER-Z-positive on fluorescence in situ hybridization (FISH) without prior chemotherapy treatment for advanced breast cancer, with response rates of 15% to 20% among women with previous chemotherapy treatment for meta-

CYTOTOXIC

CHEMOTHERAPY

Table

FOR

9. Trestuzumab

Trastuzumab

ADVANCED

in Combination

BREAST

With

& Chemotherapy

Chemotherapy No.

(drugs/schedule)

353

CANCER

for HER-Z-Overexpressing of Prior

Metastatic

Doxorubicin/cyclophosphamide’6*

0

Paclitaxel

every

0 (adjuvant

Paclitaxel

weekly”6

Regimens Breast

Metestatic

Breast

Cancer

for

Cancer

Response

Rates

o-3

50* 38* N-75*

o-2

24 75

Docetaxel/carboplatin’63

o-2 0

60 54

Docetaxellcisplatin’b4

0

76

3 weeks’*

Cisplatin**

>I

Vinorelbine’61 Docetaxel

weekly’62

*Randomized t Range

anthracycline)

reflects

trial,

trastuzumab

different

HER-2

(%)

arm. testing

methodologies.

static disease. The optimal timing and duration of trastuzumab therapy is not known. HER-2-overexpressing tumors respond differently, and less well, to standard chemotherapy regimens than do HER-2-negative tumoq94 a finding that renders most phase II and phase III studies in metastatic breast cancer obsolete. Trastuzumab has been studied in combination with several chemotherapeutic agents (Table 9). In randomized trials and phase II studies of women with HER-2-overexpressing breast cancer, trastuzumab plus chemotherapy has generated higher response rates than seen or expected with chemotherapy alone.16 Excess cardiac toxicity was observed when trastuzumab was used in conjunction with an anthracycline-containing chemotherapy regimen.95 Ongoing trials are evaluating trastuzumab in combination with a variety of chemotherapeutic regimens. It is not known if continuing trastuzumab and chemotherapy is clinically valuable once patients have progressed on trastuzumab-based regimens. CONCLUSIONS

A variety of new cytotoxic agents are entering use in the management of advanced breast cancer. The past 5 years have seen a remarkable number of new chemotherapy drugs identified with significant activity in metastatic breast cancer patients, broadly extending the number of treatment options. Many of these drugs show high levels of efficacy even in patients with extensive prior therapy and seem to have a more favorable side effect profile than some of the older agents. In addition, through the use of new delivery vehicles such as

liposome encapsulation, or through different treatment schedules, such as oral 5FU analogs or weekly taxanes, the tolerability of traditional drugs has been enhanced. These improvements represent genuine advances for women with metastatic breast cancer, and it is likely that these newer agents and schedules will be incorporated into evolving adjuvant therapy regimens. Treatment with chemotherapy is also guided by an understanding of tumor biology. Patients with advanced breast cancer will have their treatment determined by tumor expression of such biological markers as estrogen/progesterone receptors and the HER-2 oncogene. In this regard, advanced breast cancer has become the paradigm for the rational use of new biological therapeutic agents. REFERENCES 1. Geels

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