Combined chemo-endocrine adjuvant therapy for patients with operable breast cancer: Still a question?

CANCER

TREATMENT

REVIEWS

1998: 24: 15-26

CONTROVERSY

m

Combined chemo-endocrine ad’uvant therapy for patients with opera b le breast cancer: still a question? M. Colleoni*,

A. Coates+,

0. Pagani* and A. Goldhirsch**

*Division of Medical Oncology, European Institute of Oncology, Milan, Italy +Australian New Zealand Breast Cancer Trials Group, Departments of Medicine, and Medical Oncology, Royal Prince Alfred Hospital, Sydney, Australia %ervizio Oncologico Cantonale, Ospedale Beata Vergine, Mendrisio, Switzerland

INTRODUCTION Adjuvant systemic therapy for early breast cancer began in the early 1970s. Local-regional treatment was frequently insufficient to control disease, leading investigators to suggest the presence of occult micrometastases at the time of diagnosis (l-3). This was supported by experimental findings in tumourbearing mice where surgery followed by chemotherapy yielded a survival advantage when compared to each modality alone (4). There was an inverse relationship between the number of viable tumour cells in the animal and efficacy of treatment with cytotoxic agents. (5). The biological hypothesis concerning a potential benefit from adjuvant chemotherapy was first tested in randomized clinical trials by the National Surgical Adjuvant Breast Project (NSABP) (3) and the Milan National Cancer Institute (6). Subsequent trials have established that polychemotherapy is superior to the use of a single agent, and this has become the standard chemotherapeutic approach for patients at higher risk of relapse, especially those of premenopausal age. On the other hand, controversy has persisted regarding the treatment of postmenopausl patients with chemotherapy. For these patients, endocrine treatment with tamoxifen has been clearly shown to increase survival. The Overview of the Early Breast Cancer Trialists’ Correspondence: European Institute Italy. 0305-7372/98/O

M. Colleoni, of Oncology,

IO0 I5 + I2 $I2.00/0

Division of Medical Oncology, Via Ripamonti 435,20141, Milan,

University of Sydney

Collaborative Group also clearly demonstrated the efficacy of ovarian ablation (7) in producing improved survival in patients aged 50 years or less. There is also evidence for the effectiveness of tamoxifen in premenopausal patients with nodenegative disease, mainly in patients with tumours expressing oestrogen receptors (OR) (8, 9). Tamoxifen has therefore become widely used, especially in postmenopausal patients, although its value in patients wth OR-poor tumours remains uncertain. The combination of endocrine manipulations and chemotherapy was an empirical attempt to improve treatment results by overcoming resistance to one of the two modalities. However, it is conceivable that such combined therapy may be sub-additive or even antagonistic. Theoretically, an endocrine therapy might decrease cell turnover by forcing cells in the Go phase of the cell cycle, thus reducing susceptibility to cytotoxics (10). Moreover, treatment results in advanced disease with the combination of the two modalities were not encouraging (11, 12). Results of combined chemotherapy and endocrine therapies in the adjuvant setting remain controversial (13-16). The uncertainty surrounding these results was reflected in the conclusions of the International Consensus Panel, St. Gallen, 1995 (17) (Table l), in which chemo-endocrine therapy was not definitely recommended for any patient group. During the past 3 years, several new trials have matured, yielding results which shed light upon the use of combined chemo-endocrine therapy in several patient groups, especially those with primary tumours classified as OR-positive (18-20). 0

1998 W.B. SAUNDERS

COMPANY

LTD

M. COLLEONI

16

Table Patient

I

St Gallen

guidelines

for the adjuvant

treatment

group

Node Low

Premenopausal OR positive

OR negative Postmenopausal OR positive OR negative Elderly

OR, oestrogen

risk

Good

No treatment vs tamoxifen+

Not

applicable

No treatment vs tamoxifen+ Not applicable No treatment vs tamoxifen+

of breast

cancer

negative

risk

Node High

ETAL.

positive

risk

Tamoxifen*+ Oophorectomy+ Chemotherapy+ Gn-Rht Not applicable

Chemotherapy Oophorectomy+ Gn-Rht

ftamoxifen+

Tamoxifen

Tamoxifen

Not applicable Tamoxifen

Chemotherapy Tamoxifen;

f tamoxifen if OR negative:

Chemotherapy

f tamoxifen

Chemotherapy

f chemotherapy

Chemotherapy+ Oophorectomy Gn-Rht

tamoxifen+ f tamoxifen+

Chemotherapy tamoxifen+

+ oophorectomy

f

Chemotherapy Tamoxifen

f chemotherapy+

Chemotherapy Tamoxifen; Chemotherapy

+tamoxifen+ if OR negative: f tamoxifen+

receptor

* Bold entries are treatments t Treatments still being tested

accepted for routine use or baseline in randomized clinical trials.

in clinical trials.

Pending the results of studies in progress, the present systematic review seeks to clarify the role of combined modality chemo-endocrine therapy in the management of surgically resected breast cancer, both in order to aid treatment selection and to clarify the unanswered questions for further trials.

therapy or chemo-endocrine DS cytotoxic therapy), then by the age group or menopausal status (as defined in each trial) and, when available, by tumour receptor content (positive, negative or unknown). Within each of these groups, trials were ordered by the type of endocrine therapy and where the information was available by the patient risk group.

MATERIALS AND METHODS RESULTS The authors undertook a systematic review (21) of published clinical trials comparing combined modality chemo-endocrine therapy with either of its component modalities alone. A Medline search strategy yielded 268 potential publications. The abstracts of these publications were then reviewed, allowing the elimination of 228 articles which clearly did not contribute original clinical trial data on these questions. The full text of the remaining 40 articles was then reviewed, allowing further exclusions, and leaving 28 articles describing 28 clinical trials which addressed one or both of the target comparisons. Additional sources (Early Breast Cancer Trialists Group, 1992; Cancerlit; American Society of Clinical Oncology abstracts, 1997; European Society of Medical Oncology abstracts, 1997; text books), led to the inclusion of three additional studies recently presented in abstract form (20,22,23). Although the inclusion of such studies may risk publication bias, the authors felt that it contributed important information to the subject of this review. The studies identified were next classified by the question addressed (chemo-endocrine ZISendocrine

Chemo-endocrine

vs endocrine

therapy

The trials identified which compared endocrine therapy alone to the same endocrine therapy plus chemotherapy are summarized in Table 2.

Oophorectomy f chemotherapy No published trials comparing ovarian ablation to ablation plus chemotherapy were identified, although several are known to be ongoing.

Tamoxifen f chemotherapy Whether chemotherapy adds to the benefits achieved with tamoxifen has been addressed in the subset of patients with node-positive tumours by 11 randomized trials involving 7301 patients that compared chemo-endocrine therapy with endocrine tamoxifen alone. Seven of them (four focused on postmenopausal patients) reported an advantage in

ADIUVANT Table

2

CHEMO-ENDOCRINE Trials

comparing

Group/ endocrinotherapy

THERAPY

adjuvant

chemo-endocrine Trial

Premenopausal Ablation Tamoxifen 5 years concomitant

No

ID (ref)

trials

IBCSG

Ill (I 5)

IBCSG

VII (I 8)

2 years concomitant 3 years concomitant I year sequential

NCI-C Pearson SWOG

(19) (27) (25)

Anthracycline based 5 years concomitant

NASBP

B-16

ICCG FASG INT-0

(23) (26) IO0 (22)

concomitant

4 years concomitant 3 years concomitant 5 years concomitant MAP 5 months concomitant Pre-postmenopausal 5 yean concomitant DFS, disease-free

survival:

therapy

with

(20)

endocrine

17 therapy No. of patients

Outcome (% DFS at 5 years)

(14)

MF CMF

767 768

89 vs 84, p
CMF + prednisone OR+ ORCMF early + delay OR+ ORCMF CMFVP CMFVP

327

58 60 63 64 62 48 84 NR, 61

vs 42, p = 0.003 vs 55, p = 0.65 vs 20, p = 0.02 vs 57, p=O.OI vs 53, p = 0.05 vs 50, p=O.lS vs 82, p=O.E p=O.O4 vs 59, p=O.l

84 p = p = NR, 85 79

vs 67, p = 0.004* 0.04 0.0003 ~~0.05 vs 69, p = 0.04* vs 72, p=O.OI

AC(L-pamA, OROR+ Epi FEC CAF

Hupperets

(28)

CAF

GROCTA

(13)

CMFx6

NR, not reported;

CANCER

reported B-20

5 years

BREAST

Chemotherapy

NSABP

Postmenopausal Tamoxifen I year concomitant

IN

I-pam

1212

705 94 966 FA)

II24

604 374 I558 408 Epix4

339

(I 83 post)

59 vs 49, p = 0. I 66 vs 63, p = 0.23

$3 yean.

disease-free survival for the combined modality therapy. In the subset of node-negative tumours, one trial from NSABP investigators reported an advantage for the combination (20). Few trials have reported separate results for pre- and postmenopausal women. Several older trials used additional chemotherapy which was substantially adapted from the standard CMF (cyclophosphamide, methotrexate, fluorouracil) regimen (24), and which compromised the dose intensity. These trials failed to show any superiority to tamoxifen alone (19, 25). In contrast, all trials which used standard CMF or regimens based on an anthracycline obtained results superior to tamoxifen alone (15, 20) (Table 2). Overall, the results strongly suggest that the addition of standard cytotoxic chemotherapy to tamoxifen is advantageous. Several of the trials report separately on subgroups of patients with OR-positive or ORnegative tumours. With the exception of IBCSG Study III, in which the OR status of many patients was unknown, these trials show that the benefit of adding chemotherapy is still seen in patients with OR-positive tumours. The International Breast Cancer Study Group (IBCSG; formerly the Ludwig Breast Cancer Study

Group) Trial III included postmenopausal women 65 years old or younger, receptor-positive or -negative and node-positive (15). A total of 327 patients was included between 1978 and 1981, and randomized to receive no adjuvant therapy, tamoxifen (20 mg/day plus prednisone for 12 months) or the combination of chemotherapy according to the CMF plus prednisone schedule plus tamoxifen for 12 months. After a median follow-up of 15 years, the chemo-endocrine therapy continued to provide significantly better disease-free survival than endocrine therapy alone or no adjuvant treatment. In the ORpositive group, hormone treatment and chemo-endocrine treatment were superior to observation only, but there was no difference between chemoendocrine therapy and endocrine therapy (p = 0.65). Fifteen-years, overall survival was 44% for chemoendocrine therapy, 33% for endocrine therapy and 28% for no adjuvant therapy. In this early trial, definition of hormone-receptor status was incomplete, and a large benefit favouring chemo-endocrine therapy was seen among patients with unknown OR status. A subsequent trial of the IBCSG (Trial VII) incorporated OR status as a stratification factor, thus

18 allowing analysis separately for OR-positive and OR-negative cohorts. This trial randomized nodepositive, postmenopausal patients to tamoxifen alone, tamoxifen plus three cycles of early CMF, tamoxifen plus three cycles of delayed CMF, or the combination of both (18). On 1212 accessible patients, it was observed that those who received chemotherapy did better than those who received tamoxifen alone. The addition of CMF, early, delayed or both, reduced the risk of relapse by 19,13 and 22%, respectively. The reduction was particularly marked for patients with OR-positive tumours (risk of relapse reduced by 24, 26 and 31%, respectively, for early, delayed or both). Negative results were reported by a Canadian Study that randomly assigned 705 receptor-positive patients to receive tamoxifen for 1 year vs CMF plus tamoxifen. No difference among the three arms was noted for either disease-free survival or overall survival that are nearly identical (19). The results of the South West Oncology Group (SWOG) trial, which included 966 postmenopausal, OR-positive patients, showed no significant difference between the group given tamoxifen for 1 year (295 patients), and the group given CMFVP (cyclophosphamide, methotrexate, fluorouracil, vincristine, prednisone) weekly for 1 year plus tamoxifen (303 patients) (25). However, the chemotherapy regimen in these trials were different from the classical CMF regimen described by Bonadonna et al. (1) and this data may have affected the results. The French Adjuvant Study group evaluated 714 postmenopausal patients randomized to receive FEC (fluorouracil, epirubicin, cyclophosphamide) for six cycles, tamoxifen, the combination of FEC plus tamoxifen or control (26). Disease-free survival was better in the tamoxifencontaining groups than in the other arms, with the best survival for the chemo-endocrine group (27 recurrences vs 40 for tamoxifen alone, vs 48 for chemotherapy alone, vs 58 for observation), but the difference between chemo-endocrine (192 patients) and endocrine (182 patients) therapy was not significant. The NSABP B-16 randomized 1296 nodepositive, receptor-positive or negative patients to tamoxifen alone for 5 years, AC (doxorubicin, cyclophosphamide) plus tamoxifen or PAF (melphalan, doxorubicin, fluorouracil) plus tamoxifen (14). An advantage in disease-free survival was observed for the chemo-endocrine treatment over tamoxifen alone. Moreover, an overall survival benefit was observed for combining AC with tamoxifen vs tamoxifen alone. It was observed that this trial included 20% of patients that were OR-negative, which possibly reduced the effectiveness of tamoxifen alone. Pearson et al. reported better disease-free survival on 94 postmenopausal patients with CMFVP plus tamoxifen vs tamoxifen alone (26). The

M. COLLEONI

ET AL.

GROCTA study, which included 504 patients with OR-positive tumours and positive nodes, randomized in a three-arm design to tamoxifen for 5 years (168 patients), chemotherapy for six cycles of CMF followed by four cycles of epirubicin (165 patients), or a combination of both treatments (171 patients) (12). The comparison between chemo-endocrine therapy did not improve outcome compared with tamoxifen alone, although some benefit was seen in postmenopausal patients with four or more positive nodes. A study from the International Collaborative Cancer Group has been reported recently in nodepositive, receptor-positive or -negative tumours. Although no clear overall survival advantage was detected, a significant increase in disease-free survival was observed (23). Another study from the U.S. Intergroup has been reported in abstract form and produced evidence of an advantage with FAC plus tamoxifen vs FAC in node-positive, OR-positive patients. Only recently have chemo-endocrine trials focused on patients with node-negative tumours. Since there are relatively fewer recurrences and deaths, many more patients must be studied to establish differences between treatment arms. However, lowerrisk patients with OR-positive tumours can be regarded as a crucial test of the value of adding chemotherapy to tamoxifen alone, since in this group, the efficacy of tamoxifen might be expected to be optimal. The NSABP Trial B-20 was reported recently. It included 2363 pre-and postmenopausal patients with OR-positive, node-negative tumours. They were randomly assigned to three arms: two comprised chemo-endocrine therapy with tamoxifen plus either CMF or a regimen consisting of mediumdose methotrexate followed by fluorouracil. The third group received tamoxifen alone, and served as a control for both chemo-endocrine therapies. A significant advantage in relapse-free survival and overall survival was observed for both the combined treatment arms, compared to tamoxifen alone (20). This effect was seen both in patients older and younger than 50 years. There are limited data available in patients with OR-negative, node-positive tumours. The International Breast Cancer Study Group Trial III described above included postmenopausal women, receptor-positive or -negative and node-positive, randomized to receive no adjuvant therapy, tamoxifen (20 mg/day plus prednisone for 12 months) or the combination of chemotherapy according to the CMF plus prednisone schedule plus tamoxifen for 12 months (15). In the group of OR-negative patients (82 patients), CMF plus prednisone plus tamoxifen was superior to observation (p = 0.03) and hormone therapy (p =0.02). The IBCSG Trial VII

ADIUVANT

CHEMO-ENDOCRINE

THERAPY

IN BREAST

described above included 279 patients with ORnegative tumours (18), who demonstrated a complex interaction between tamoxifen and chemotherapy. Early CMF alone showed a small, non-significant benefit, delayed CMF showed an increased risk of 28%, while for patients with OR-negative tumours allocated both early and delayed CMF, the results were almost identical to those in the tamoxifen-alone control arm.

Medroxypugesterone

acetate (MFA) + chemotherapy

In the only trial comparing MPA to MPA plus anthracycline containing chemotherapy (FAC regimen), Hupperets et al. reported no significant difference in disease-free survival on 408 patients (28), although older patients (>55 years old) benefitted from the combined modality in terms of survival.

Chemo-endocrine

vs chemotherapy

The trials comparing chemotherapy alone to the same chemotherapy plus an endocrine therapy are summarized in Table 2. Overall, the results are less clear than those of trials adding chemotherapy to endocrine therapy. Whether tamoxifen or MPA adds to the benefits achieved with chemotherapy has been addressed in 8965 patients by 18 randomized trials. Thirteen trials produced no evidence of benefit, although in three of them, subgroups had evidence of benefit, and five trials demonstrated an advantage for combined therapy. Two trials evaluated the issue of chemotherapy plus oophorectomy vs chemotherapy alone, and no evidence of a benefit was observed.

ChemotheraQy f tamoxifen The ECOG group randomized 553 premenopausal, node-positive patients to CMF vs CMF plus prednisone (40mg/m* daily for 14 days each 28-day cycle) vs CMF plus prednisone and tamoxifen with chemotherapy (28). The outcome was similar for all subgroups. A second ECOG study compared CMF plus prednisone alone or with the addition of tamoxifen to surgery alone in 265 node-positive, receptor-positive or -negative patients (30). No improved disease-free nor overall survival was observed for OR-positive patients, although ORnegative patients had improved disease-free survival. Another negative study was presented by the German Breast Cancer Study Group, which randomized patients with any hormone-receptor status and node-positive disease to CMF for three or six cycles with or without tamoxifen (31). After three

CANCER

19

cycles of CMF, patients were further randomized to receive three additional cycles of CMF or no additional CMF, and to receive tamoxifen for 2 years or no tamoxifen. Although there was no difference between treatment arms after a median follow-up of 56 months, the small sample size of the subgroups (pre-post menopausal patients either OR-positive or OR-negative) may have reduced the possibility to detect small differences. The SWOG trial described above included 966 postmenopausal, OR-positive patients, and found no significant difference between the groups given CMFVP for 1 year with (303 patients) or without (303 patients) tamoxifen (24). The three-arm GROCTA study described above included a comparison of chemotherapy using sixcycles of CMF followed by four cycles of epirubicin, with the same chemotherapy plus tamoxifen (13). Overall, the combined chemo-endocrine therapy significantly improved outcome compared with chemotherapy alone. The Gynecologic Adjuvant Breast Group randomized 471 pre- and postmenopausal patients at high risk of recurrence (node positive) to receive AC every three weeks for eight cycles or AC plus tamoxifen. The combination treatment was equivalent to AC alone for patients aged 49 years or younger (32). A small study from Italy randomized 125 premenopausal patients with nodepositive disease to CMF for nine cycles alone or combined with tamoxifen 30 mg daily for 2 years. After a median follow-up of 63 months, there was a trend to better disease-free survival with combined modality therapy but there was no difference in overall survival (33). The NSABP Trial B-09 randomized 1858 patients (779 premenopausal) with positive nodes to melphalan plus fluorouracil, or the same combination plus tamoxifen (34). There was a tendency of a positive effect for the combination in postmenopausal patients, whereas a shorter diseasefree and overall survival was observed for premenopausal patients, who had either oestrogen or progesterone receptor-negative tumours. Such data may be related to an antagonism between tamoxifen and melphalan, which has been demonstrated in animal models (lo), that is more relevant in premenopausal patients where the activity of chemotherapy is essential. In another large study performed by the Danish Breast Cancer Study Group, 1308 patients (811 premenopausal), nodepositive and OR positive in the majority of cases, were randomized to receive CMF for 9 months or CMF and tamoxifen for 1 year. The tamoxifen-CMF arm was closed prematurely because of a significant survival detriment (35), although at 4 years of followup, researchers saw only a non-significant trend for tamoxifen-treated patients to do worse. A study that included 314 pre- and postmenopausal patients, either OR-positive and OR negative and compared

20

M. COLLEONI

Table

3

Trials

comparing

adjuvant

Group/ chemotherapy

Trial

Premenopausal CMF variants CMF+ prednisone

CMFVP PF

CMF ‘CFP

x I2

x 12 months

(+/-

CMF CMF

prednisone)

x9

IBCSG

SWOG NSABP

(I 6) B-09 (34)

ECOG (29) lngle (42)

B-09

chemotherapy

(34)

(25)

No. of patients

Oophorectomy OR+ OROophorectomy Tamoxifen 2 years OR+ ORTamoxifen I year Tamoxifen OE+ _ ORTamoxifen MAP

Tamoxifen OR+ ORTamoxifen Tamoxifen Tamoxifen Tamoxifen

356

314 779

553 400 202 136 125 I51

( + / - RT)

I079 299 vs 299 146 vs 145 966 265 261 427

Outcome (% DFS at 5 years)

48 45 40 58 NR 74 53 5 I 6 I

vs vs vs vs

43, 40, 39, 56,

p =0.4 I p = 0. I p=O.8 p = 0.7*

vs vs vs vs

71. 61, 49, 53,

p=O.6 p=O.l p =0.42 p =0.06

p=o.20 p=o.30 60 vs 50, p=O.l3 53 vs 61, p=O.7

54 54 45 59 63 61 47

vs vs vs vs vs vs vs

48, 48, 36, 55, 54, 59, 3 I,

p>O.OOO I p = 0.007 p = 0.2 p = 0.23 p=O.31 p=O.58 p=O.O6

based FASG

(26)

GBSG (3 I) Mauriac (40) Hubay (39) Crowe (36)

(+/-RT)

Anthracycline AC x8

with Endocrine therapy

II (44)

SWOG ECOG ECOG (30) lngle (37) Rutqvist (38)

Pre-postmenopausal CMF variants “CMF x 3-6 CMF + prednisone CMF CMG + beg

CMF CAFR

ID (ref)

NSABP

CMFVP CMFP CFP CMF Anthracycline FEC x6

therapy

GUN (33) Pannuti (43)

Postmenopausal CMF variants L-pam FU

CMF

chemo-endocrine

ET AL.

Tamoxifen

365

85 vs 63, p=O.O04

473 334 312 31 I I308

48 71 NR, 78 86 47

471

DABG

(35)

Tamoxifen Tamoxifen Tamoxifen Tamoxifen OR+ Tamoxifen

GABG

(32)

Tamoxifen

vs 53, vs 59, p=O.l vs 48, vs 49, vs 5 I,

p = 0.32 p=O.OI I p =O. I2 p =o.oo I p = 0.8+

based

x6Epi (+Rl-)

x4

GROCTA Blomqvist

(13) (4 I)

Tamoxifen Tamoxifen

336 (40 mg)

49 vs 38, p=O.l3 (pO.0 I >50 years) 66 vs 43, p>O.cOI 66 vs 64, p=O.7

(I I 72pZm) DFS, disease-free

survival;

NR, not reported;

*7 years; +4 years.

CMF plus tamoxifen ZJSCMF alone, demonstrated an advantage in both disease-free and overall survival (36). Ingle et al. found no difference between chemotherapy and the combination with tamoxifen in 261 postmenopausal patients (37), whereas Rutqvist described a significant advantage in terms of disease-free survival for the combination of CMF and tamoxifen US chemotherapy (38). Two other groups reported on CMF plus or minus tamoxifen on 312 and 334 patients, respectively, and failed to observe significant difference between the two groups (39, 40). Blomqvist et al. failed to observe a difference on 200 patients treated with CAFt (cyclophosphamide, adriamycin, fluorouracil and ftorafur)

plus tamoxifen US chemotherapy (41), and similar results have been described by Ingle et ~2. in premenopausal patients (42). CM F and derivatives f MPA A small of CMF patients. ease-free

study from Italy tested the combination plus MPA vs CMF in 151 premenopausal No significant difference in terms of disor overall survival was noted (43).

Chemotherapy f ovarian ablation Two trials (IBCSG Trial II and SWOG) involving 670 patients have addressed the important question of

ADlUVANT

CHEMO-ENDOCRINE

THERAPY

IN BREAST

whether oophorectomy adds to the efficacy of chemotherapy in premenopausal patients with nodepositive breast cancer. In IBCSG Trial II, 356 patients with four or more involved axillary lymph nodes were randomized to receive either adjuvant chemotherapy (12 cycles of the CMF plus prednisone combination described above) alone or after surgical oophorectomy (44). After 15 years of median followup, the disease-free survival of patients who had an oophorectomy prior to chemotherapy was not significantly different from that for patients given chemotherapy alone. There was a trend to superior disease-free survival among the 107 patients with OR-positive tumours who received an oophorectomy (55 DS 40%, p = 0.14). Among the subgroup of patients with OR-positive tumours and age >40 years, the advantage in disease-free survival at 15 years was conventionally statistically significant (22 ns lo%, p=O.O5). The difference in overall survival was not statistically significant (34 vs 28%, HR= 0.85; p = 0.23). The SWOG study included 314 patients with nodepositive disease recruited over a lo-year period (16). Patients were randomized to CMFVP for 1 year, or to the same treatment preceded by surgical oophorectomy. At a median follow-up of 5 years, there was no significant difference between the two treatments.

DISCUSSION The present review complements rather than replaces the overview process of the Early Breast Cancer Trialists’ Collaborative Group published in 1992 (7). The published overview data provide information relevant to several of the questions addressed by the present review. The overview provides a structured review, including unpublished as well as published data, and provides a quantitative synthesis which is not appropriate in the present systematic review. Nevertheless, the overview provided conclusions similar to those of the present review. No significant reductions in the odds of recurrence or death were observed in the overview for the addition of tamoxifen to chemotherapy in women aged less than 50 years (7). It suggested that prolonged tamoxifen therapy (2 years or more) may be better in women younger than 50 years, and that OR-positive patients would be expected to have the greatest benefit from endocrine therapy (7). Conversely, the overview indicated that in women older than 50 years of age, chemotherapy combined with tamoxifen was better than chemotherapy alone, and that chemotherapy combined with tamoxifen yields a better disease-free survival than tamoxifen alone. However, at least as far as has been published, the overview is limited to trials which commenced

CANCER

21

randomization before 1985. The present review includes 11 newer trials that add relevant information to all the questions being addressed. There are data supporting the hypothesis that the combination treatment may yield superior results than any modality given alone. Postmenopausal patients, node-positive and OR-positive patients should be considered as candidates for chemoendocrine therapy. In particular, patients with ORpositive tumours benefit substantially from chemoendocrine therapy as compared to tamoxifen alone (12, 13, 17,22, 25) or vs chemotherapy alone (9, 36). Postmenopausal patients with OR-negative tumours may also benefit from chemotherapy and tamoxifen (13,14), but results are less clear. Moreover, recently reported results from NSABP Trial B-20 with chemotherapy and tamoxifen in node-negative, OR-positive patients support the combination, and stimulate further studies in this patient population. In premenopausal patients, there is little although increasing evidence that chemo-endocrine therapy is superior to chemotherapy alone. The frequent development of amenorrhea in patients treated with adjuvant chemotherapy, especially regimens containing alkylating agents, has led some investigators to hypothesize that much of the benefit of adjuvant chemotherapy is due to a medical castration effect (44-47). In the Milan Trial (6), more than 70% of the patients developed amenorrhea. This was more frequent in women older than40 yers (only4.5% resumed menses after cessation of chemotherapy), whereas in women younger than 40 years, the normal menstrual cycle was re-established in 42% (47). There was a difference in disease-free survival for patients with CMF-induced amenorrhea vs the others (73 vs 56%) that was not statistically significant. In the NSABP trial, no association between disease-free survival and melphalan-induced ovarian suppression was observed (45). In fact, 73% of the patients aged 40 years or older had amenorrhea, compared to only 22% of younger patients. Since the improvement in disease-free survival was greater for the younger group, it was concluded that suppression of ovarian function did not play a major role. A significant difference between patients with no menses and patients who continued to menstruate was observed in the IBCSG Trial I (45). Using CMF and CMF plus prednisone therapy in patients younger than 40 years, an association between amenorrhea and disease-free survival was observed, especially in OR-positive patients. It may be argued, analysing these results, that the induction of amenorrhea may be an important target in premenopausal patients, but that the activity of chemotherapy may not be solely attributed to the induction of amenorrhea. The best timing for combining hormone therapy and chemotherapy remains to be established. There

22

are data indicating that many breast cancers are composed of a heterogeneous population of receptor-positive and receptor-negative cells. The former group of cells responds more favourably to chemotherapy (34), whereas receptor-positive cells respond more often to endocrine therapy. The introduction of chemotherapy may induce reduction of OR-negative cells and overgrowth of receptorpositive, chemoresistant cells, thus supporting the sequential use of chemotherapy and endocrine therapy. There are theoretical arguments against the simultaneous administration of chemotherapy and enEndocrine manipulations are docrine therapy. cytostatic and may decrease cell turnover, whereas many chemotherapeutic agents are cell-cycle active and therefore require DNA synthesis to exert their maximum activity (14). Tamoxifen antagonizes calmodulin, is a Ca’+-channel antagonist, and can inhibit multidrug resistance (47,48). The drug can alter membrane lipids and therefore could alter diffusion rates of certain drugs. More specifically, it inhibits P-glycoprotein-mediated drug resistance (49). Tamoxifen demonstrated an additive effect when it was combined with doxorubicin and cyclophosphamide in vitro (50). Studies in advanced disease comparing chemotherapy alone USchemotherapy combined with oestrogens, tamoxifen or progestins did not show a survival advantage for the combination treatment (10, 11). As reported previously, results from Trial VII of the IBCSG suggested that the simultaneous administration of chemo-endocrine therapy may be detrimental in receptor-positive postmenopausal patients (14). This observation was particularly true for delayed administration of chemotherapy after starting tamoxifen. The same results were reported from the NSABP Trial B-09 in premenopausal patients, where a detrimental effect was observed for OR-negative patients (9). It may be argued that in the subset of premenopausal patients with ORnegative tumours in whom chemotherapy is important, antagonism between chemotherapy and tamoxifen may reduce the effect of chemotherapy and negatively influences survival. The antagonism is probably enhanced when chemotherapy is administered late, as in IBCSG Trial VII, or for a prolonged time as in NSABP Trial B-09. From a conceptual point of view, ‘endocrine maintenance’ consisting of hormone therapy administered only after the completion of chemotherapy may be preferred. However, the NSABP Trial B-20 reported a benefit for the CMF combination with concurrent tamoxifen, and anthracycline-based chemotherapy with concurrent tamoxifen has also yielded positive results (13,22,23). The optimal use of tamoxifen and chemotherapy represents one of the most intriguing

M. COLLEONI

ET AL.

points in chemo-endocrine therapy and deserves further investigation. A further major issue is represented by the optimal chemotherapy regimen to be used. A beneficial effect of adding CMF to tamoxifen was seen in the three trials in which CMF was administered for 2 successive weeks every 4 weeks, with cyclophosphamide given orally during the first 14 days of each course (13,17,19). The trials in which CMF was given either on Day 1 every 3 or 4 weeks, or at a low continuous dosage as in the CMFVP regimen showed no benefit (18, 24). In fact, the lack of significant differences in disease-free survival conferred by combined modality CMF plus tamoxifen vs tamoxifen alone in the Grocta (12), SWOG (24), the Danish Trial 82C (35) and the NCIC trial (18) are associated with either reduced chemotherapy dose intensity and/or an altered schedule, compared to standard CMF. Several trials have compared complex variations in CMF regimens in patients with advanced or recurrent disease. In particular, the trial conducted by the EORTC with 254 eligible patients, comparing the two regimens (i.e. CMF Day 1 q 3 weeks and the standard CMF Days 1 and 8 q 4 weeks) (24) concluded that the standard CMF was superior in terms of response rate and overall survival. The authors attributed the superiority to the higher dose intensity. The results of combined endocrine therapy and chemotherapy which contains anthracyclines are less conflicting. In fact, three recently published trials, in which the combination of adriamycin or epirubicin with or without cyclophosphamide and tamoxifen was prescribed, demonstrated a significant advantage in terms of treatment outcome as compared to tamoxifen alone (16, 22, 23). Improvement of the results achieved to date can be reasonably expected from new endocrine and chemotherapeutic agents (51). New antioestrogens with different toxicity profiles, different pharmacokinetics or biological effects are currently being tested. Toremifene is characterized by a lower carcinogenic profile. Droloxifene, which has a short half-life, has been tested in phase II trials. ICI 182780 has no oestrogenic effect and idoxifene is an agent with reduced oestrogenic effect. New steroidal and non-steroidal aromatase inhibitors have been demonstrated in phase II-III trials to be significantly active, more selective and less toxic than aminoglutetimide. They include formestane (4-OH androstendione) (type I), exemestane (FCE 24304) (type I), fadrozole (CGS 16949A) (type II), letrozole (CGS 20267) (type II), vorozole (R83842) (type II), Arimidex (anastrozole; ZD1033) (type II), and Rogletimide (pyridoglutethimide) (type II). Some of them, including exemestane, letrozole and vorozole, will soon be tested as adjuvant therapy in breast cancer.

ADJUVANT Table

4

CHEMO-ENDOCRINE Ongoing

trials

THERAPY

of adjuvant

chemo-endocrine

IN

BREAST

therapy

Trial

CANCER

vs endocrine

23 therapy

Regimen

Oophorectomy + CT f T INT 0142 SCTN-BR940 I FRE-FNCLCC-9456 UKCCCR-ABC CT + tamoxifen IBCSG I l-93 SCTN-BR940 I IUKCCCR-ABC IBCSG 12-94 IBCSG IX SCTN-BR9402 SWOG 88 I4 IBCSG

14-94

Patient

cT+ET

ET

OOPH + CT T+CMF+OOPH CT+OOPH CTfT+OOPH

OOPH+T+CT T+OOPH OOPH TfOOPH

Pre-N, Pre Pre/N,OR+/N,ORPn?

T+OOPH+AC T f OOPH + CMF T+OOPH+CT T or toremifene + AC T+CMF T+CMF T+CAF (with delayed vs concurrent T) T or toremifene after or with AC-CMF

T+OOPH TIf:OOPH TfOOPH T or toremifene T T TvsCAF (with delayed vs concurrent T or toremifene

P&N, Pt-e Pre/post Pen/post/N, Post/N0 Post Post/N, Post/N,

Pre, premenopausal; ~0% postmenopausal; OOPH, oophomctomy; therapy: N, no difference; R hormone receptor; OCT, octreotide.

T, tamoxifen;

Table

vs chemotherapy

5

Ongoing

trials

of adjuvant

chemo-endocrine

therapy

Trial

Oophorectomy+ IBCSG-VIII Tamoxifen + CT IBCSG 13-93 ECOG NSABP B-23 SCTN-BR9403 CAN-NCIC-MA

group

CT, chemotherapy,

T)

ET, endocrine

therapy;

Regimen

Patient

CT+ET

CT

CMF+Gos

CMF

AC-CMF+T CMFPNATH +T T after CMF or AC T after CMF T after CMF, FEC, AC

AC-CMF+/I6 week CMFP or CMFPNATH CMF or AC CMF CMF, CEF or AC

CE, chemo-endocrine

group

CT

I2

Pm, PmmenoPausal: poti postmenopausal: OOPH, oophorectomy; therapy; N, no difference; R, hormone receptor; Gos, goserelin: OCr,

vs Gos

T tamoxifen; octreotide.

Several new cytotoxics have been considered for extensive testing in the adjuvant setting. The most promising cytotoxics include taxanes, already shown to be effective agents in metastatic and locally advanced disease. There are several open questions about the proper schedule of administration for these agents and about their association with other active cytotoxics, especially anthracyclines. The use of taxanes in the adjuvant setting is currently being tested. A second new agent with promising potential in the adjuvant setting is vinorelbine. The interactions of these cytotoxics with endocrine therapy will require further evaluation. Many of the open questions on combined chemoendocrine therapy may be resolved by the ongoing trials listed in Tables 4 and 5. An important point being investigated by the IBCSG in node-positive,

CT, chemotherapy

Pm/pen/N, gap

P&N, P&N, Any/N,,ER Any/& Any/N, ET, endocrine

therapy;

-

CE, chemo-endncnne

premenopausal patients is whether chemotherapy is required in patients treated by ovarian ablation. Trial 11-93 tests the addition of four cycles of AC given immediately after oophorectomy and followed by tamoxifen DSoophorectomy and tamoxifen alone. Four other trials (SCTN-BR9401, UKCCCR-ABC, Int 0142 and FRE-FNCLCC-9456) are currently investigating the issue of combined oophorectomy and chemotherapy plus or minus tamoxifen, whereas the CRC 88002 trial is currently evaluating the addition of tamoxifen to oophorectomy. These trials involve a long accrual period and a long follow-up to observe significant effects of the combination modality in this subset of patients, both because of the relative rarity of such patients, and the large difference between the treatment arms, which may reduce accrual.

24

A second important point that deserves further investigation in premenopausal patients is represented by the combination of chemotherapy and maintenance with tamoxifen, especially for patients at low risk of relapse. IBCSG is evaluating, in a target population of 1200 premenopausal patients, node-positive and not suitable for endocrine therapy alone, the role of four cycles of AC followed by three cycles of CMF plus or minus tamoxifen. A further question evaluated in the trial is the influence of the gap between the two chemotherapy schedules. Three other trials are evaluating the role of tamoxifen after chemotherapy, whereas the ECOG group evaluated the combination of tamoxifen and chemotherapy given simultaneously. Trial VIII of the IBCSG has accrued over 900 patients with node-negative disease, and compares CMF given for six cycles followed by the gonadotropin-releasing hormone analogue goserelin for 18 months with either modality alone. A total of 1200 patients will be enrolled (52). Similar issues are addressed by the Intergroup Trial INT 0142 comparing tamoxifen plus oophorectomy ZISthe same combination plus chemotherapy. In receptor-negative patients, the NSABP Trial B23 is evaluating tamoxifen after chemotherapy DS chemotherapy alone. In postmenopausal patients, there are, as discussed previously, several firmly established points. Chemo-endocrine therapy has been shown to be very effective in reducing recurrence and prolonging survival in both nodepositive and -negative, receptor-positive patients. However, there are still some doubts about the best way to combine the two modalities and the optimal agent to be used. The question of delayed or concurrent tamoxifen was evaluated in Trial SWOG 8814, which also studied the role of the combination treatment ‘us monotherapy, whereas SCTN-BR9402 investigated the combination of CMF plus tamoxifen ZIStamoxifen alone. A second interesting point is addressed by the IBCSG IX Trial, where only three cycles of chemotherapy given plus or minus tamoxifen to OR-positive, node-negative patients. One of the major problems is the identification of subsets of patients most likely to benefit from a combined chemo-endocrine approach. There is evidence of lack of a response to endocrine therapy, not only in receptor-negative patients but also according to new markers such as c-erbB-2 (52), whereas a plethora of new markers of poor response to chemotherapy have been identified including DNA ploidy, S-phase fraction, p53 and Bcl-2 (53-56). More recently, a trend of a better response to neoadjuvant chemo-endocrine therapy was observed for tumours positive for OR, PgR, and Bcl-2, whereas a significantly lower response rate was observed for c-erbB-2-positive tumours (56).

M. COLLEONI

ET AL.

Clinical trials over more than two decades have established many solid facts about adjuvant systemic therapy with cytotoxic and endocrine agents, but many questions remain to be resolved. These unresolved issues are the subjects of ongoing investigations which will continue to improve our management of early breast cancer.

SUMMARY AND CONCLUSIONS Adjuvant systemic treatment delays relapse and prolongs survival in patients with operable breast cancer. However, the relative wealth of available agents and the heterogeneity of the target population contribute to considerable uncertainty about the optimal approach to particular patient groups. Systematic review and meta-analysis of the results of trials testing polychemotherapy have clearly established the value of such treatment. Endocrine treatment with tamoxifen was to be especially useful in patients with hormone-receptor positive tumours. Research in recent years has therefore concentrated on secondary questions, such as scheduling, dose intensity and new combinations of chemotherapeutic agents. Combined chemo-endocrine treatments, using polychemotherapy plus tamoxifen, ovarian ablation or both, have been compared with either modality alone. Other endocrine agents such as fluoxymesterone acetate, medroxyprogesterone acetate and, recently, LH-RI-I analogues have also received attention. The systematic review presented here suggests that combined cytotoxic and endocrine therapies might be the most effective use of available treatments for most, if not all, patients, and highlights the unresolved questions requiring further research.

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