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New developments in chemotherapy of advanced breast cancer
Annals of Oncology 10 (Suppl. 6): S139-S146. 1999. © 1999 Kluwer Academic Publishers. Printed in the Netherlands.
Review article New developments in chemotherapy of advanced breast cancer
Clinical Cancer Research, Worldwide Clinical Research and Development. Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, CT USA
Summary Anthracyclines and taxanes are the two most active classes of chemotherapy for the treatment of advanced breast cancer. Recent studies have investigated combination therapy including doxorubicin (Dox) and paclitaxel. The efficacy of this combination has been established in a phase III study conducted by ECOG, comparing Dox/pachtaxel versus Dox versus paclitaxel. The combination is superior to Dox or paclitaxel with respect to response rate and time to disease progression, indicating that the combination provides a new standard for the first line treatment of metastatic breast cancer [1]. Phase II studies using higher doses of Dox and using shorter infusions of paclitaxel have suggested the combination can be further optimised; Gianni reported a 94% objective response rate using Dox 60 mg/m2 followed by paclitaxel 175 mg/m2 given over three hours [2]. The more active regimens are associated with enhanced cardiotoxicity; this toxicity can be avoided, however, by limiting the exposure to doxorubicin. The newer regimens have now been moved into phase III studies. Future progress for this disease will depend on the introduction of new agents. Two novel drugs are currently being investigated in
Background Approximately one in eight women will develop breast cancer in her lifetime [5]. Breast cancer, the most common cancer in women and the second leading cause of cancer deaths in women, in 1996 was estimated to account for 31 % of new cancers and 17% of deaths from cancer in women in the United States [5]. Approximately 43,000 women in the US [5] died as a result of breast cancer in 1992. Even in countries where breast cancer screening programmes are common, only about 50% of patients are diagnosed with localised disease [5]. In addition, a significant number (50% to 75%) diagnosed with early disease will eventually relapse, usually within two years from diagnosis [6]. The median duration of survival of patients with metastatic breast cancer is two to three years [7, 8]. In the absence of an expectation of cure in these patients, the primary goal of therapy is to palliate symptoms and prolong the time to disease progression, while minimising side effects associated with treatment. Systemic chemotherapy can have a palliative benefit greater than its inherent toxicity; more intensive and active
randomised phase III trials as potentiators of Dox and/or paclitaxel. One is a monoclonal antibody from Genentech (Herceptin, trastuzumab) directed at the HER-2/neu oncogene, which is overexpressed in >25% of breast cancers [3]. Recent results indicate that Herceptin in combination with paclitaxel (or with a Dox plus cyclophosphamide regimen) induces a higher response rate (RR) and prolongs the time to disease progression when compared to chemotherapy alone. The second agent N,N-diethyl-2[4(phenylmethyl)-phenoxy] ethanamine.HCl (DPPE, BMS-21738001), when combined with Dox, was associated with a higher RR than previously observed with Dox alone [4]. A randomised trial of Dox versus Dox plus DPPE is ongoing. The possible mechanisms underlying chemo-potentiation by these agents are discussed. As new anthracycline/taxane combinations establish themselves in earlier stages of the disease, the need for effective, non-cross resistant salvage regimens will emerge.
Key words: anthracycline, breast cancer, chemotherapy, HER-2 antibody, N,N-diethyl-2[4-(phenylmethyl)-phenoxy] ethanamine.HCl (DPPE, BMS-217380-01), paclitaxel
regimens have been associated with a better QOL than less intensive ones [7, 9, 10]. In a study of paclitaxel as a single agent, the majority of patients who achieved objective partial response or stable disease experienced stable or improved QOL, while those with progression reported rapid deterioration in QOL measures [10]. The most commonly used cytotoxic agents in treating advanced breast cancer have been cyclophosphamide, methotrexate, 5-fluorouracil (5-FU) and doxorubicin administered in various combinations [7]. Overall response rates with traditional first-line combination chemotherapy vary from 40% to 80%, with complete responses in the range of 5% to 25% and response durations of seven to 13 months [11]. Anthracyclines and taxanes are the two most active classes of cytotoxic antitumour agents for the treatment of metastatic breast cancer. The objective response rates for doxorubicin therapy are in the range of 40%-45% and 30% in untreated and previously treated patients respectively in single institution studies [12]. Randomised clinical trials have demonstrated that first-line treatment with an anthracycline-containing regimen affords greater efficacy than regimens not containing an anthracycline (or taxane) [13, 14]. Anthracycline-containing
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D. E. Lebwohl & R. Canetta
140 60 mg/m2, paclitaxel 175 mg/m2/24 hours, and the combination of doxorubicin 50 mg/m2 and paclitaxel 150 mg/m2/24 hours, with GCSF, as first therapy for metastatic breast cancer [1]. Patients receiving single agent therapy doxorubicin or paclitaxel were crossed-over to the alternative agent at the time of progression. Seven hundred thirty-nine patients were randomised. Grade 4/5 toxicities were seen in 109 patients (six fatal) in the doxorubicin arm, 169 in the paclitaxel arm (two fatal) and 135 in the combination arm (four fatal), with granulocytopenia most commonly the cause of grade 4 toxicity. Cardiac toxicity was similar in the doxorubicin and combination arms (see details below). The objective response rate was 34% with doxorubicin, 33% with paclitaxel and 46% with the combination. The median time to treatment failure was 6.2 months, 5.9 months and 8.0 months in the three arms, respectively. Both response rate and time to treatment failure were superior for the combination compared to either single agent, indicating that the combination of doxorubicin and paclitaxel offers a new standard as first line therapy for metastatic breast cancer. Various other schedules and sequences of paclitaxel combined with doxorubicin or with epirubicin have been evaluated in phase I and II studies with response rates ranging from 42% to 94%, with higher overall and complete response rates observed with short infusion schedules (bolus doxorubicin and 3-hour paclitaxel) [2,29-34] than with paclitaxel administered by prolonged infusion (24 or 72 hours) [1, 35-37]. The objective response rates observed in the short infusion trials using doxorubicin are consistently high, ranging from 69% to 94%, as shown in Table 1. Of note, the complete response rate in the two most mature trials are 38% [2] and 24% [28]. Epirubicin is the 4' epimer of doxorubicin which is less cardiotoxic than its parent compound. Phase II trials with epirubicin in combination with paclitaxel have also shown
Paclitaxel in combination with doxorubicin
Table I Combination trials of taxanes and anthracyclines using short infusion Ref Study no
Dox/paclitaxel (mg/m2)
Max Dox range (mg/m2)
Eval pts
Response rate
Gianni Gehl Amadori Martin Gianni Gianni (neo-adjuvant) 34 Dombernowsky
60/ 125-200 50-60/155-200 50-60 / 220 50/175 60 / 200 60 / 200
490 560 480 511 ±360 ±240
32 29 32 57 47 73
94% 83% 78% 70% 94% 88%
50 / 200
±360
32
69%
38 Luck 39 Kohler 40 Carmichael
60-90/175-225 25-35 / 80 q week 75 / 200
630+ 630 —
68 35 30
68% 51% 43%
400
28
82%
2 29 30 31 32 33
Epi/paclitaxel
The high level of antitumour activity and lack of cross resistance observed with paclitaxel spawned an interest in its use in the first-line setting in combination with doxorubicin [2628]. The superior efficacy of combination therapy including doxorubicin and paclitaxel compared to single agent therapy has been reported in an Intergroup trial comparing doxorubicin
Dox/Docetaxel 41 Nabholtz
50 / 75/ CTX 500
Abbrev: Ref No. reference number; Max Dox Range, maximum cumulative dose range of doxorubicin given; Eval Pts, evaluable patients
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combination chemotherapy (FAC, AC) regimens have produced favourable objective response rates of 60%-85% in the metastatic setting with a small, but not statistically significant, improvement in overall survival [15]. Though anthracycline-containing chemotherapy combinations have good activity, less than 10% of patients experience a complete response; moreover, there is a high relapse rate and a median duration of response of 6 to 12 months [16]. More recently, the taxanes paclitaxel (Taxol) and docetaxel (Taxotere), have been shown to be active as single agents in second-line treatment for advanced breast cancer, with response rates ranging from 28% to 58% [17-20]. Of particular interest, antitumour activity has been observed with taxanes in patients who had developed resistance to prior anthracycline-containing chemotherapy. Two prospective, randomised trials in this setting [18, 21] have demonstrated that single-agent paclitaxel can significantly prolong time to progression when administered at doses of 175 mg/ m2 over three hours. Both trials, however, allowed crossover to paclitaxel 175 mg/m2/3 hours from the control arm, upon progression, and this design might be responsible for the lack of difference in overall survival. A third trial conducted in Australia in patients not previously treated for metastatic disease [22], compared paclitaxel 200 mg/m2/3 hr versus CMFP. No crossover occurred, and the majority of the patients received epirubicin at progression. Despite the lack of difference in response rates and time to progression, a trend towards superior survival favouring paclitaxel (median 17.3 vs 13.9 months, p-value unadjusted = 0.065; adjusted = 0.025) was observed. Two other single-agent first-line trials (ECOG [1] and EORTC [23]) compared paclitaxel versus Dox and achieved similar survival results with the two drugs. In both trials crossover was allowed. In the ECOG trial no differences were observed in response rate and time to progression between the two agents. In the EORTC trial, which adopted a more aggressive doxorubicin regimen (75 mg/m2), response rate and time to progression, as well as toxicity, were increased with doxorubicin. Two randomised trials of single-agent docetaxel confirm these findings. In previously treated patients, docetaxel was superior to mitomycin plus vinblastine [24]. In previously untreated patients, similar time to progression and survival were observed for docetaxel as compared to doxorubicin, although response rates as well as toxicity were higher with the taxane [25]. These single-agent results point to the appeal of combining an anthracycline and a taxane in the treatment of breast cancer.
141 Herceptin in combination with doxorubicin or paclitaxel HER-2/c-erbB2 is the human homolog of the rat protooncogene neu. The gene encodes a 185-kDa transmembrane tyrosine kinase (pl85HER2) which acts as a growth factor receptor [43]. The protooncogene HER-2 may be altered to transform cells to a malignant phenotype by several mechanisms including point mutation leading to increased kinase activity (observed naturally in rat models) and gene amplification leading to high level expression of the unmutated protein (as observed in human cancers, see below). The oncogenic potential of this gene has been demonstrated in several models. Normal fibroblasts which are transfected with the gene and therefore express a high level of the protein exhibit a phenotype typical of malignant cells including growth in soft agar and rumour formation in immunodeficient mice. Similarly, the expression of an activated HER-2 kinase as a transgene in mice leads invariably to the development of mammary adenocarcinoma [44]. Amplification of the HER-2 gene is present in 25% to 30% of human breast cancers [45] and is more common in patients with poorly differentiated cancers, with estrogen receptor negative and node positive cancers. HER-2 amplification predicts for patients with poor prognosis, including a short disease-free and overall survival. This amplification is a significant independent prognostic factor in multivariate analysis, and in many studies is similar in prognostic power to lymph node status [46, 47]. Based on all these observations, a pathogenetic role for the pi 85HER2 protooncogene has been hypothesised in human
Table 2 Cardiac function following doxorubicin and paclitaxel combination therapy (adapted from Ref. 42). Study #
Regimen (mg/m2)
#CHF/ # Total
(%)
6/25 7/30 0/51 0/75 1/44 1/34 0/73 2/57
(24) (23) (0) (0) (2) (3) (0) (4)
0 2 0 0 0 0 0 2
17/389
(4)
0/25 0/25 22/241* 22/242"
(0) (0) (9) (9)
# CHF at cum. A
LVEF (%) at cum. A Base
220-340
340-380
0 1 0 0 1 0 0 0
61 60 64 66 60 63 66 67
59 54 62 62 57 56 63 63
57 50 61 60 55 56 55 —
4
2
64
60
56
0 0 NA NA
0 0 NA NA
63
60
63
61 63
54 56
60 51
220-340
340-380
Single Ann Trials: 1 2 3 4 5 6 7 8
AT:60/l 25-200 AT:50-60/l 55-200 AT:50-60/220 AT:50/l75 AT:60/200 AT:50/200 AT:60/200 AT:60/175
All AT Single Arm: AT:50-60/125-220 Randomised Trials: 9 10
AT:50/220 vs FAC500/50/500 AT:50/150 vsA.60
' Any cardiovascular toxicity of grade III/IV/V. Abbrev: CHF, congestive heart failure; cum A, cumulative dose of doxorubicin in mg/m2; LVEF, left ventricular ejection fraction; A, doxorubicin; AT, doxorubicin plus paclitaxel.
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excellent activity, with response rates ranging from 43% to 68% [38-40]. Other related combination regimens, including doxorubicin or epirubicin and docetaxel, have been reported more recently. A phase II trial of docetaxel and doxorubicin in combination with cyclophosphamide was performed by Nabholtz et al. [41 ] in Canada in 36 patients; among 28 evaluable patients, the overall response rate was 82% with five CR (18%) and 18 PR (64%). There has been concern about using combination therapy with doxorubicin plus paclitaxel due to an increased incidence of cardiac toxicity in the early studies of this combination (Refs. 2, 29-31 in Table 1), where the number of cycles of doxorubicin was eight or more. Subsequent studies have limited the doxorubicin, and heart function has been monitored prospectively. The incidence of congestive heart failure (CHF) and mean values of left ventricular ejection fraction (LVEF) have recently been reported for each study population and for patients after four or six cycles of doxorubicin for a total of 922 patients in 10 trials (Table 2, Ref. 42). The overall incidence of CHF (17 of 389 or 4%) and the well-maintained LVEF for patients who received four to six cycles of doxorubicin plus paclitaxel is similar to historical data and to the control arms in randomised trials (studies 9 and 10 in Table 2) obtained with non-taxane, doxorubicin-containing combinations. In summary, current data suggest that the combination of doxorubicin and paclitaxel is a highly active regimen, particularly using a 3-hour schedule for paclitaxel. The risk of cardiotoxicity is low if the total exposure to doxorubicin is limited. Other combinations of taxanes and anthracyclines are in development.
142 ministered. The primary endpoints of the trial were time to tumour progression (TTP) and safety. The paclitaxel group was more chemotherapy-resistant, as might be expected; 94% percent had recurrence after an anthracycline-containing adjuvant regimen. The results of the trials are listed in Table 3. Both response rate and TTP were superior in the patients receiving both chemotherapy and Herceptin. The improvement in response rate was particularly marked in the more resistant patients who were receiving paclitaxel chemotherapy. An unexpected degree of cardiac toxicity, similar to that observed with anthracyclines, occurred more commonly in patients who received doxorubicin/cyclophosphamide plus Herceptin (18% grade 3/4) than with doxorubicin/cyclophosphamide alone (3%), paclitaxel alone (0%) or paclitaxel plus Herceptin (2%). The mechanism by which Herceptin may enhance cardiotoxicity is not yet understood. In summary, the use of Herceptin in combination with chemotherapy for patients receiving first-line treatment of metastatic breast cancer is associated with a substantial clinical benefit. This represents a major success in the area of rational therapies which are directed at targets involved in the pathogenesis of breast cancer. With this success come a number of questions to be answered: Is the possible synergism between Herceptin and chemotherapy related to immune targeting by antibody or by modulation of growth factor receptor action? What is the origin of the cardiotoxicity and how might it be circumvented?
DPPE in combination with doxorubicin DPPE (BMS-217380-01) is a potent antagonist of a novel intracellular (microsomal and nuclear) histamine receptor (HIC) that appears to be implicated in the mediation of cell proliferation [52]. The mechanism of action has not yet been fully elucidated. Recent work suggests that the target of DPPE is a group of P450 isoenzymes that control the level of eicosanoids and other lipids involved in growth regulation [53]. DPPE is cytoprotective to the gut [54] and normal bone marrow progenitor cells [55], while potentiating chemotherapy-induced cytotoxicity to human tumour cells in model systems [55]. Initial studies demonstrated that DPPE enhances the activity of doxorubicin, daunorubicin, and BCNU; more recent in vitro testing reports potentiation by DPPE of paclitaxel and vinblastine, as well as of doxorubicin [56]. In an initial phase I/II trial, DPPE combined with various agents (e.g., 5- fluorouracil, cyclophosphamide, DTIC) was active in patients previously shown to have failed treatment with the cytotoxic agent alone [57]. More recently, Brandes et al. [4] reported the results of a phase II study of DPPE combined with a standard dose and schedule of doxorubicin (60 mg/m2) in 23 patients with metastatic breast cancer. Sixteen of the patients had received prior non-anthracycline chemotherapy, 13 in the metastatic setting. DPPE (6 mg/kg) was infused intravenously (i.v.) over 80 min-
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breast cancer. This function suggested that specific therapies directed at inhibition of this protein kinase or targeted at cells bearing this receptor may be useful in the treatment of disease. Genentech has developed a monoclonal antibody 4D5 directed against the extracellular domain of the receptor. Early observations suggested that 4D5 inhibits the growth of breast cancer cell lines which express high levels of pl85HER'2 both in vitro and in xenograft systems [48]. The antigen binding regions of 4D5 were genetically engineered into the framework of a human immunoglobulin IgG p for use in clinical development [49]. The IgG, isotype was selected due to its ability to mediate ADCC (antibodydependent cell-mediated cytotoxicity) and complementmediated cytotoxicity. The antibody chosen for clinical development, trastuzumab (Herceptin™) is rarely immunogenic and retains the high affinity for pi 85 of the parent molecule 4DS. The initial phase II trial of trastuzumab as a single agent was performed by Baselga et al. in 46 patients with refractory metastatic breast cancer with overexpression of pi 85HER" 2 [3]. An overall objective response rate of 11.6% (95% C.I. 4.3-25.9) was reported. Of note, women with high serum levels of soluble pl85HER'2 did not respond to trastuzumab. This important observation of antitumour activity was followed by several studies. The single-agent antibody experience was expanded in a phase II study of trastuzumab in 222 women with pl85HER2-overexpressing breast cancers which had progressed on prior chemotherapy [50]. Ninety-four percent of the patients had prior anthracyclines and 64% had prior taxane (notably, 26% of the patients had prior high-dose chemotherapy with stem cell or bone marrow rescue). Infusion of trastuzumab, like other monoclonal antibodies, causes a temporary syndrome of chills, fever, pain, nausea, vomiting and headache, which can be treated with antipyretics and antihistamine. Ten patients in the trial (4.7%) developed cardiac dysfunction; 9 of 10 had previous anthracycline. There was one cardiac death assessed as possibly related to therapy. In this refractory population there was an objective response rate of 16% (95% C.I. 11-22) and a median duration of response of 9.1 months (range 2-26+ months). This study confirms the activity of trastuzumab in refractory disease. The full potential of the antibody, however, may only be realised in combination regimens with chemotherapy in an earlier stage of this disease, as reported by Slamon et al. [51]. These investigators reported on a randomised phase III trial in 469 patients with metastatic breast cancer with no prior chemotherapy in the metastatic setting. Patients were randomised to receive trastuzumab or no trastuzumab until disease progression with systemic cytotoxic chemotherapy. The trastuzumab treatment consisted of a loading dose intravenously of 4 mg/kg over 90 minutes, followed by a weekly dose of 2 mg/kg over 30 minutes. Cytotoxic chemotherapy was given every week concomitantly with trastuzumab therapy for a total of 6 cycles. The regimen for patients with no prior adjuvant anthracycline was doxorubicin 60 mg/m : with cyclophosphamide 600 mg/m2; for patients with prior anthracycline, paclitaxel 175 mg/m2 over three hours was ad-
143 Table 3. Herceptin plus chemotherapy MBC and no prior anthracycline MBC and prior anthracyline
ACx6 AC + weekly Herceptin paclitaxel (3-h) x 6-8 paclitaxel + weekly Herceptin
CRx
CRx+ H
AC
AC + H
234 36 5.5
235 62* 8 6*
66
69
145 42 6.5 18 71
146 65 9.0 3 68
T+H 89 25 4.2 0 59
89 57 7.1 2 70
* Significant differences from CRx alone. Abbrev: MBC = metastatic breast cancer; AC = doxorubicin + cyclophosphamide; T = paclitaxel; CRx : chemotherapy; H = Herceptin; RR = response rate; TTP = time to progression; mo = months; AE = adverse events (any grade)
utes. Doxorubicin was administered i.v. over the last 20 minutes of the DPPE infusion. Premedication included lorazepam and ondansetron; postmedication included metoclopramide. Treatment was repeated every three weeks (maximum, 7 cycles). All patients were evaluable for activity and safety. Sixteen patients (70%; 95% C.I.=47-87%) responded (7 CR and 9 PR). Among 16 patients previously treated with chemotherapy, there were 11 responders, including 6 with CR. Of interest, 5 responders (2 CR, 3 PR) had a poor (ECOG 3/4) performance status pre-treatment. Median CR duration was 11 (range 5-18) months. Hematological toxicity was low; gastrointestinal toxicity (nausea/vomiting/dyspepsia) responded well to anti-emetics, ranitidine and/or dexamethasone in most patients. A mean absolute drop in left ventricular ejection fraction of 8% occurred in 17 patients who received > 300 mg/m2 doxorubicin, similar to historical results in patients treated with doxorubicin alone. The objective response rate in DPPE plus doxorubicin-treated patients is apparently higher than historically reported for doxorubicin alone in this setting, suggesting a chemopotentiating effect of DPPE. A second, confirmatory study of DPPE/doxorubicin (DPPE 6 mg/kg given as 80-minute i.v. infusion; doxorubicin 60 mg/ m2 i.v. over last 20 minutes of DPPE infusion as in the previous series) was performed by the National Cancer Institute of Canada (NCIC), Clinical Trials Group [58]. In the initial cohort (32 patients), the antiemetic regimen was similar to that of Brandes: premedication included lorazepam and ondansetron; postmedication included metoclopramide. In a second cohort (10 patients), premedication included lorazepam, dexamethasone and ondansetron; postmedication included dexamethasone and ondansetron. Eligibility criteria included no previous anthracycline exposure, metastatic or inoperable breast cancer, up to one prior chemotherapy regimen for metastatic disease, bidimensionally measurable disease and six weeks off hormones if previous hormone response. The primary endpoint was complete response (CR) rate. The trial has completed accrual with entry of 42 patients. To date, baseline data is available on all 42. Eight patients had received prior chemotherapy in the metastatic setting and 10 in the adjuvant setting. Most common
sites of disease were nodes (28), bone (23), lung (16), breast (12) and liver (12). Twenty-five of 42 patients had three or more disease sites. More than 70% of patients received > 90% of planned dose intensity of both DPPE and doxorubicin. Thirty-five patients were evaluable for toxicity and response at the time of analysis. Frequent adverse events related to study drugs (all grades, grade 3) included lethargy (77%, grade 3: 23%), anorexia (57%, grade 3: 9%), nausea (80%, grade 3: 17%), vomiting (69%, grade 3: 9%), stomatitis (54%, grade 3: 9%) and alopecia (100%). Frequent neurological toxicities were cerebellar signs (34%, grade 3: 6%), and hallucinations (grade 3: 31%). None of the nonhematologic toxicities were grade 4. Hematologic toxicity included grade 3/4 neutropenia (89%), and grade 3/4 thrombocytopenia (6%). Febrile neutropenia was infrequent (6%). In summary, toxicity is similar to that of doxorubicin single agent in this dose with the exception of the neurologic effects. The neurotoxicity of DPPE was transient, easily managed by sedation during infusion and improved after cycle 1. In this trial, the overall response rate was 49% (95% C l : 31% - 66%), with 11% complete responses (4 of 35 CR) and 37% partial responses (13 of 35 PR). The high activity observed with DPPE plus doxorubicin in this trial supports the findings in the previous single institution trial. In a recently completed, randomised NCIC CTG trial (MA.8), women with metastatic breast cancer (same eligibility criteria as for the NCIC CTG DPPE/doxorubicin phase II trial described above) treated with single agent doxorubicin (60 mg/m2) experienced an objective response rate of 30%, with a complete response rate of 3% [59]. Hence, the response rates with DPPE/ doxorubicin (70% by Brandes and 49% by NCIC CTG) overall objective response rates with 30% and 11% of patients achieving a complete response), when compared with historical data, have stimulated the further development of DPPE, in combination with doxorubicin, as treatment for patients with metastatic breast cancer. In order to investigate the comparative efficacy of doxorubicin plus DPPE, the National Cancer Institute of Canada organised a phase III randomised study, sponsored by Bristol-Myers Squibb, in patients with metastatic breast cancer. Patients are randomised to doxorubicin alone or
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N RR (%) TTP (mo) Cardiotoxicity (% gr 3/4) AE (%)
71 il 71 ^i
144
Future prospects with the new regimens Two of the advances in the treatment of advanced breast cancer described here, the combination of doxorubicin and paclitaxel and the use of Herceptin with chemotherapy, have been demonstrated to prolong the time to disease progression in large trials. The doxorubcin/paclitaxel regimens have shown activity similar to that observed with high dose chemotherapy using stem cell rescue. The confirmation of the superior results with doxorubicin and paclitaxel may be forthcoming, with the results of additional phase III studies. The latter are a trial from EORTC comparing doxorubicin/paclitaxel to doxorubicin/cyclophosphamide and a study in Central and Eastern Europe of comparing doxorubicin/paclitaxel versus doxorubicin/cyclophosphamide/5-fluorouracil, sponsored by Bristol-Myers Squibb. The proof of principle for the third advance, the combination of DPPE with doxorubicin, is being investigated in the ongoing NCIC CTG phase III study. The value of these advances could be increased when the regimens are moved to an earlier stage of the disease, namely for the neo-adjuvant or the adjuvant treatment of breast cancer. The importance of the early application of therapy has again been demonstrated in studies examining the adjuvant use of paclitaxel. The CALGB-led Intergroup study tested whether the sequential use of paclitaxel following a regimen of doxorubicin/cyclophosphamide was more active than doxorubicin/cyclophosphamide alone in their study 9344 . In addition, they investigated the escalation of the doxorubicin dose in the combination regimens, with doxorubicin doses of 60, 75 or 90 mg/m2. 3170 patients were randomised in a 3 x 2 factorial trial design; the doxorubicin was given together with cyclophosphamide 600 mg/m2 every three weeks for four cycles. Patients then received either no paclitaxel or paclitaxel 175 mg/m2 every three weeks for four cycles. At the first preplanned interim analysis (450 events), no differences in disease free survival (DFS) or overall survival (OS) related to doxorubicin dose were observed, but the use of paclitaxel was associated with a significant improvement in both DFS (p=0.0077) and OS (p=0.0390). paclitaxel reduced the recurrence rate by 22% and death rate by 26%, by multivariate analysis. These results are striking: the reduction due to adding paclitaxel to an adjuvant regimen is similar to the reduc-
tion in recurrence rate and death rate observed when comparing the use of adjuvant chemotherapy to no chemotherapy in patients with breast cancer. The early application of the advances described here may also lead to improved survival for patients with breast cancer. Current studies are exploring the neo-adjuvant application of doxorubicin/paclitaxel; the adjuvant use of doxorubicin/paclitaxel is also being investigated. Similarly, studies may be designed to investigate the use of Herceptin with paclitaxel (and potentially doxorubicin, if the Herceptinrelated cardiotoxicity can be managed or reduced) for adjuvant therapy of the subset of patients with high levels of HER2. Finally, if DPPE/doxorubicin is found to be superior to doxorubicin alone, this drug would also be incorporated into adjuvant and/or neo-adjuvant breast cancer regimens. Despite the current advances, there still will be patients with disease refractory to these new combinations with doxorubicin and taxanes in the adjuvant and/or metastatic setting. New salvage therapies for this population are needed. Currently, activity has been observed in the refractory setting with agents directed at thymidylate synthetase, such as infusional 5-fluorouracil, capecitabine [61] and UFT [62,63]. In addition, agents such as vinorelbine [64] and a large array of novel agents now in early clinical development are of interest. Recent results in breast cancer, with taxane combinations and Herceptin indicate the value of careful studies of new therapies to the treatment of breast cancer, and might change the standard of care in the treatment of the disease.
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doxorubicin plus DPPE. Eligible patients have measurable disease and will be either patients who are newly diagnosed with metastatic breast cancer (first-line), patients who have relapsed subsequent to hormonal or non-anthracycline containing chemotherapy in the adjuvant setting (first-line; predicted to be the majority of patients) or those who have received first-line, non-anthracycline containing chemotherapy for advanced disease (second-line). The study is powered to show a 50% improvement in the primary endpoint of timeto-progression (TTP; from 6 to 9 months) and response rate (from 30% to 45%) , which would demonstrate that DPPE acts as a chemopotentiator of doxorubicin in this setting. In addition, quality of life, using the EORTC QLQ-C30 and BR23 (breast specific module), will be assessed.
145
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Correspondence to • David Lebwohl, M.D. Bristol-Myers Squibb Pharmaceutical Research Institute 5 Research Parkway Wallingford, CT 06492 USA
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Review article New developments in chemotherapy of advanced breast cancer
Clinical Cancer Research, Worldwide Clinical Research and Development. Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, CT USA
Summary Anthracyclines and taxanes are the two most active classes of chemotherapy for the treatment of advanced breast cancer. Recent studies have investigated combination therapy including doxorubicin (Dox) and paclitaxel. The efficacy of this combination has been established in a phase III study conducted by ECOG, comparing Dox/pachtaxel versus Dox versus paclitaxel. The combination is superior to Dox or paclitaxel with respect to response rate and time to disease progression, indicating that the combination provides a new standard for the first line treatment of metastatic breast cancer [1]. Phase II studies using higher doses of Dox and using shorter infusions of paclitaxel have suggested the combination can be further optimised; Gianni reported a 94% objective response rate using Dox 60 mg/m2 followed by paclitaxel 175 mg/m2 given over three hours [2]. The more active regimens are associated with enhanced cardiotoxicity; this toxicity can be avoided, however, by limiting the exposure to doxorubicin. The newer regimens have now been moved into phase III studies. Future progress for this disease will depend on the introduction of new agents. Two novel drugs are currently being investigated in
Background Approximately one in eight women will develop breast cancer in her lifetime [5]. Breast cancer, the most common cancer in women and the second leading cause of cancer deaths in women, in 1996 was estimated to account for 31 % of new cancers and 17% of deaths from cancer in women in the United States [5]. Approximately 43,000 women in the US [5] died as a result of breast cancer in 1992. Even in countries where breast cancer screening programmes are common, only about 50% of patients are diagnosed with localised disease [5]. In addition, a significant number (50% to 75%) diagnosed with early disease will eventually relapse, usually within two years from diagnosis [6]. The median duration of survival of patients with metastatic breast cancer is two to three years [7, 8]. In the absence of an expectation of cure in these patients, the primary goal of therapy is to palliate symptoms and prolong the time to disease progression, while minimising side effects associated with treatment. Systemic chemotherapy can have a palliative benefit greater than its inherent toxicity; more intensive and active
randomised phase III trials as potentiators of Dox and/or paclitaxel. One is a monoclonal antibody from Genentech (Herceptin, trastuzumab) directed at the HER-2/neu oncogene, which is overexpressed in >25% of breast cancers [3]. Recent results indicate that Herceptin in combination with paclitaxel (or with a Dox plus cyclophosphamide regimen) induces a higher response rate (RR) and prolongs the time to disease progression when compared to chemotherapy alone. The second agent N,N-diethyl-2[4(phenylmethyl)-phenoxy] ethanamine.HCl (DPPE, BMS-21738001), when combined with Dox, was associated with a higher RR than previously observed with Dox alone [4]. A randomised trial of Dox versus Dox plus DPPE is ongoing. The possible mechanisms underlying chemo-potentiation by these agents are discussed. As new anthracycline/taxane combinations establish themselves in earlier stages of the disease, the need for effective, non-cross resistant salvage regimens will emerge.
Key words: anthracycline, breast cancer, chemotherapy, HER-2 antibody, N,N-diethyl-2[4-(phenylmethyl)-phenoxy] ethanamine.HCl (DPPE, BMS-217380-01), paclitaxel
regimens have been associated with a better QOL than less intensive ones [7, 9, 10]. In a study of paclitaxel as a single agent, the majority of patients who achieved objective partial response or stable disease experienced stable or improved QOL, while those with progression reported rapid deterioration in QOL measures [10]. The most commonly used cytotoxic agents in treating advanced breast cancer have been cyclophosphamide, methotrexate, 5-fluorouracil (5-FU) and doxorubicin administered in various combinations [7]. Overall response rates with traditional first-line combination chemotherapy vary from 40% to 80%, with complete responses in the range of 5% to 25% and response durations of seven to 13 months [11]. Anthracyclines and taxanes are the two most active classes of cytotoxic antitumour agents for the treatment of metastatic breast cancer. The objective response rates for doxorubicin therapy are in the range of 40%-45% and 30% in untreated and previously treated patients respectively in single institution studies [12]. Randomised clinical trials have demonstrated that first-line treatment with an anthracycline-containing regimen affords greater efficacy than regimens not containing an anthracycline (or taxane) [13, 14]. Anthracycline-containing
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D. E. Lebwohl & R. Canetta
140 60 mg/m2, paclitaxel 175 mg/m2/24 hours, and the combination of doxorubicin 50 mg/m2 and paclitaxel 150 mg/m2/24 hours, with GCSF, as first therapy for metastatic breast cancer [1]. Patients receiving single agent therapy doxorubicin or paclitaxel were crossed-over to the alternative agent at the time of progression. Seven hundred thirty-nine patients were randomised. Grade 4/5 toxicities were seen in 109 patients (six fatal) in the doxorubicin arm, 169 in the paclitaxel arm (two fatal) and 135 in the combination arm (four fatal), with granulocytopenia most commonly the cause of grade 4 toxicity. Cardiac toxicity was similar in the doxorubicin and combination arms (see details below). The objective response rate was 34% with doxorubicin, 33% with paclitaxel and 46% with the combination. The median time to treatment failure was 6.2 months, 5.9 months and 8.0 months in the three arms, respectively. Both response rate and time to treatment failure were superior for the combination compared to either single agent, indicating that the combination of doxorubicin and paclitaxel offers a new standard as first line therapy for metastatic breast cancer. Various other schedules and sequences of paclitaxel combined with doxorubicin or with epirubicin have been evaluated in phase I and II studies with response rates ranging from 42% to 94%, with higher overall and complete response rates observed with short infusion schedules (bolus doxorubicin and 3-hour paclitaxel) [2,29-34] than with paclitaxel administered by prolonged infusion (24 or 72 hours) [1, 35-37]. The objective response rates observed in the short infusion trials using doxorubicin are consistently high, ranging from 69% to 94%, as shown in Table 1. Of note, the complete response rate in the two most mature trials are 38% [2] and 24% [28]. Epirubicin is the 4' epimer of doxorubicin which is less cardiotoxic than its parent compound. Phase II trials with epirubicin in combination with paclitaxel have also shown
Paclitaxel in combination with doxorubicin
Table I Combination trials of taxanes and anthracyclines using short infusion Ref Study no
Dox/paclitaxel (mg/m2)
Max Dox range (mg/m2)
Eval pts
Response rate
Gianni Gehl Amadori Martin Gianni Gianni (neo-adjuvant) 34 Dombernowsky
60/ 125-200 50-60/155-200 50-60 / 220 50/175 60 / 200 60 / 200
490 560 480 511 ±360 ±240
32 29 32 57 47 73
94% 83% 78% 70% 94% 88%
50 / 200
±360
32
69%
38 Luck 39 Kohler 40 Carmichael
60-90/175-225 25-35 / 80 q week 75 / 200
630+ 630 —
68 35 30
68% 51% 43%
400
28
82%
2 29 30 31 32 33
Epi/paclitaxel
The high level of antitumour activity and lack of cross resistance observed with paclitaxel spawned an interest in its use in the first-line setting in combination with doxorubicin [2628]. The superior efficacy of combination therapy including doxorubicin and paclitaxel compared to single agent therapy has been reported in an Intergroup trial comparing doxorubicin
Dox/Docetaxel 41 Nabholtz
50 / 75/ CTX 500
Abbrev: Ref No. reference number; Max Dox Range, maximum cumulative dose range of doxorubicin given; Eval Pts, evaluable patients
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combination chemotherapy (FAC, AC) regimens have produced favourable objective response rates of 60%-85% in the metastatic setting with a small, but not statistically significant, improvement in overall survival [15]. Though anthracycline-containing chemotherapy combinations have good activity, less than 10% of patients experience a complete response; moreover, there is a high relapse rate and a median duration of response of 6 to 12 months [16]. More recently, the taxanes paclitaxel (Taxol) and docetaxel (Taxotere), have been shown to be active as single agents in second-line treatment for advanced breast cancer, with response rates ranging from 28% to 58% [17-20]. Of particular interest, antitumour activity has been observed with taxanes in patients who had developed resistance to prior anthracycline-containing chemotherapy. Two prospective, randomised trials in this setting [18, 21] have demonstrated that single-agent paclitaxel can significantly prolong time to progression when administered at doses of 175 mg/ m2 over three hours. Both trials, however, allowed crossover to paclitaxel 175 mg/m2/3 hours from the control arm, upon progression, and this design might be responsible for the lack of difference in overall survival. A third trial conducted in Australia in patients not previously treated for metastatic disease [22], compared paclitaxel 200 mg/m2/3 hr versus CMFP. No crossover occurred, and the majority of the patients received epirubicin at progression. Despite the lack of difference in response rates and time to progression, a trend towards superior survival favouring paclitaxel (median 17.3 vs 13.9 months, p-value unadjusted = 0.065; adjusted = 0.025) was observed. Two other single-agent first-line trials (ECOG [1] and EORTC [23]) compared paclitaxel versus Dox and achieved similar survival results with the two drugs. In both trials crossover was allowed. In the ECOG trial no differences were observed in response rate and time to progression between the two agents. In the EORTC trial, which adopted a more aggressive doxorubicin regimen (75 mg/m2), response rate and time to progression, as well as toxicity, were increased with doxorubicin. Two randomised trials of single-agent docetaxel confirm these findings. In previously treated patients, docetaxel was superior to mitomycin plus vinblastine [24]. In previously untreated patients, similar time to progression and survival were observed for docetaxel as compared to doxorubicin, although response rates as well as toxicity were higher with the taxane [25]. These single-agent results point to the appeal of combining an anthracycline and a taxane in the treatment of breast cancer.
141 Herceptin in combination with doxorubicin or paclitaxel HER-2/c-erbB2 is the human homolog of the rat protooncogene neu. The gene encodes a 185-kDa transmembrane tyrosine kinase (pl85HER2) which acts as a growth factor receptor [43]. The protooncogene HER-2 may be altered to transform cells to a malignant phenotype by several mechanisms including point mutation leading to increased kinase activity (observed naturally in rat models) and gene amplification leading to high level expression of the unmutated protein (as observed in human cancers, see below). The oncogenic potential of this gene has been demonstrated in several models. Normal fibroblasts which are transfected with the gene and therefore express a high level of the protein exhibit a phenotype typical of malignant cells including growth in soft agar and rumour formation in immunodeficient mice. Similarly, the expression of an activated HER-2 kinase as a transgene in mice leads invariably to the development of mammary adenocarcinoma [44]. Amplification of the HER-2 gene is present in 25% to 30% of human breast cancers [45] and is more common in patients with poorly differentiated cancers, with estrogen receptor negative and node positive cancers. HER-2 amplification predicts for patients with poor prognosis, including a short disease-free and overall survival. This amplification is a significant independent prognostic factor in multivariate analysis, and in many studies is similar in prognostic power to lymph node status [46, 47]. Based on all these observations, a pathogenetic role for the pi 85HER2 protooncogene has been hypothesised in human
Table 2 Cardiac function following doxorubicin and paclitaxel combination therapy (adapted from Ref. 42). Study #
Regimen (mg/m2)
#CHF/ # Total
(%)
6/25 7/30 0/51 0/75 1/44 1/34 0/73 2/57
(24) (23) (0) (0) (2) (3) (0) (4)
0 2 0 0 0 0 0 2
17/389
(4)
0/25 0/25 22/241* 22/242"
(0) (0) (9) (9)
# CHF at cum. A
LVEF (%) at cum. A Base
220-340
340-380
0 1 0 0 1 0 0 0
61 60 64 66 60 63 66 67
59 54 62 62 57 56 63 63
57 50 61 60 55 56 55 —
4
2
64
60
56
0 0 NA NA
0 0 NA NA
63
60
63
61 63
54 56
60 51
220-340
340-380
Single Ann Trials: 1 2 3 4 5 6 7 8
AT:60/l 25-200 AT:50-60/l 55-200 AT:50-60/220 AT:50/l75 AT:60/200 AT:50/200 AT:60/200 AT:60/175
All AT Single Arm: AT:50-60/125-220 Randomised Trials: 9 10
AT:50/220 vs FAC500/50/500 AT:50/150 vsA.60
' Any cardiovascular toxicity of grade III/IV/V. Abbrev: CHF, congestive heart failure; cum A, cumulative dose of doxorubicin in mg/m2; LVEF, left ventricular ejection fraction; A, doxorubicin; AT, doxorubicin plus paclitaxel.
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excellent activity, with response rates ranging from 43% to 68% [38-40]. Other related combination regimens, including doxorubicin or epirubicin and docetaxel, have been reported more recently. A phase II trial of docetaxel and doxorubicin in combination with cyclophosphamide was performed by Nabholtz et al. [41 ] in Canada in 36 patients; among 28 evaluable patients, the overall response rate was 82% with five CR (18%) and 18 PR (64%). There has been concern about using combination therapy with doxorubicin plus paclitaxel due to an increased incidence of cardiac toxicity in the early studies of this combination (Refs. 2, 29-31 in Table 1), where the number of cycles of doxorubicin was eight or more. Subsequent studies have limited the doxorubicin, and heart function has been monitored prospectively. The incidence of congestive heart failure (CHF) and mean values of left ventricular ejection fraction (LVEF) have recently been reported for each study population and for patients after four or six cycles of doxorubicin for a total of 922 patients in 10 trials (Table 2, Ref. 42). The overall incidence of CHF (17 of 389 or 4%) and the well-maintained LVEF for patients who received four to six cycles of doxorubicin plus paclitaxel is similar to historical data and to the control arms in randomised trials (studies 9 and 10 in Table 2) obtained with non-taxane, doxorubicin-containing combinations. In summary, current data suggest that the combination of doxorubicin and paclitaxel is a highly active regimen, particularly using a 3-hour schedule for paclitaxel. The risk of cardiotoxicity is low if the total exposure to doxorubicin is limited. Other combinations of taxanes and anthracyclines are in development.
142 ministered. The primary endpoints of the trial were time to tumour progression (TTP) and safety. The paclitaxel group was more chemotherapy-resistant, as might be expected; 94% percent had recurrence after an anthracycline-containing adjuvant regimen. The results of the trials are listed in Table 3. Both response rate and TTP were superior in the patients receiving both chemotherapy and Herceptin. The improvement in response rate was particularly marked in the more resistant patients who were receiving paclitaxel chemotherapy. An unexpected degree of cardiac toxicity, similar to that observed with anthracyclines, occurred more commonly in patients who received doxorubicin/cyclophosphamide plus Herceptin (18% grade 3/4) than with doxorubicin/cyclophosphamide alone (3%), paclitaxel alone (0%) or paclitaxel plus Herceptin (2%). The mechanism by which Herceptin may enhance cardiotoxicity is not yet understood. In summary, the use of Herceptin in combination with chemotherapy for patients receiving first-line treatment of metastatic breast cancer is associated with a substantial clinical benefit. This represents a major success in the area of rational therapies which are directed at targets involved in the pathogenesis of breast cancer. With this success come a number of questions to be answered: Is the possible synergism between Herceptin and chemotherapy related to immune targeting by antibody or by modulation of growth factor receptor action? What is the origin of the cardiotoxicity and how might it be circumvented?
DPPE in combination with doxorubicin DPPE (BMS-217380-01) is a potent antagonist of a novel intracellular (microsomal and nuclear) histamine receptor (HIC) that appears to be implicated in the mediation of cell proliferation [52]. The mechanism of action has not yet been fully elucidated. Recent work suggests that the target of DPPE is a group of P450 isoenzymes that control the level of eicosanoids and other lipids involved in growth regulation [53]. DPPE is cytoprotective to the gut [54] and normal bone marrow progenitor cells [55], while potentiating chemotherapy-induced cytotoxicity to human tumour cells in model systems [55]. Initial studies demonstrated that DPPE enhances the activity of doxorubicin, daunorubicin, and BCNU; more recent in vitro testing reports potentiation by DPPE of paclitaxel and vinblastine, as well as of doxorubicin [56]. In an initial phase I/II trial, DPPE combined with various agents (e.g., 5- fluorouracil, cyclophosphamide, DTIC) was active in patients previously shown to have failed treatment with the cytotoxic agent alone [57]. More recently, Brandes et al. [4] reported the results of a phase II study of DPPE combined with a standard dose and schedule of doxorubicin (60 mg/m2) in 23 patients with metastatic breast cancer. Sixteen of the patients had received prior non-anthracycline chemotherapy, 13 in the metastatic setting. DPPE (6 mg/kg) was infused intravenously (i.v.) over 80 min-
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breast cancer. This function suggested that specific therapies directed at inhibition of this protein kinase or targeted at cells bearing this receptor may be useful in the treatment of disease. Genentech has developed a monoclonal antibody 4D5 directed against the extracellular domain of the receptor. Early observations suggested that 4D5 inhibits the growth of breast cancer cell lines which express high levels of pl85HER'2 both in vitro and in xenograft systems [48]. The antigen binding regions of 4D5 were genetically engineered into the framework of a human immunoglobulin IgG p for use in clinical development [49]. The IgG, isotype was selected due to its ability to mediate ADCC (antibodydependent cell-mediated cytotoxicity) and complementmediated cytotoxicity. The antibody chosen for clinical development, trastuzumab (Herceptin™) is rarely immunogenic and retains the high affinity for pi 85 of the parent molecule 4DS. The initial phase II trial of trastuzumab as a single agent was performed by Baselga et al. in 46 patients with refractory metastatic breast cancer with overexpression of pi 85HER" 2 [3]. An overall objective response rate of 11.6% (95% C.I. 4.3-25.9) was reported. Of note, women with high serum levels of soluble pl85HER'2 did not respond to trastuzumab. This important observation of antitumour activity was followed by several studies. The single-agent antibody experience was expanded in a phase II study of trastuzumab in 222 women with pl85HER2-overexpressing breast cancers which had progressed on prior chemotherapy [50]. Ninety-four percent of the patients had prior anthracyclines and 64% had prior taxane (notably, 26% of the patients had prior high-dose chemotherapy with stem cell or bone marrow rescue). Infusion of trastuzumab, like other monoclonal antibodies, causes a temporary syndrome of chills, fever, pain, nausea, vomiting and headache, which can be treated with antipyretics and antihistamine. Ten patients in the trial (4.7%) developed cardiac dysfunction; 9 of 10 had previous anthracycline. There was one cardiac death assessed as possibly related to therapy. In this refractory population there was an objective response rate of 16% (95% C.I. 11-22) and a median duration of response of 9.1 months (range 2-26+ months). This study confirms the activity of trastuzumab in refractory disease. The full potential of the antibody, however, may only be realised in combination regimens with chemotherapy in an earlier stage of this disease, as reported by Slamon et al. [51]. These investigators reported on a randomised phase III trial in 469 patients with metastatic breast cancer with no prior chemotherapy in the metastatic setting. Patients were randomised to receive trastuzumab or no trastuzumab until disease progression with systemic cytotoxic chemotherapy. The trastuzumab treatment consisted of a loading dose intravenously of 4 mg/kg over 90 minutes, followed by a weekly dose of 2 mg/kg over 30 minutes. Cytotoxic chemotherapy was given every week concomitantly with trastuzumab therapy for a total of 6 cycles. The regimen for patients with no prior adjuvant anthracycline was doxorubicin 60 mg/m : with cyclophosphamide 600 mg/m2; for patients with prior anthracycline, paclitaxel 175 mg/m2 over three hours was ad-
143 Table 3. Herceptin plus chemotherapy MBC and no prior anthracycline MBC and prior anthracyline
ACx6 AC + weekly Herceptin paclitaxel (3-h) x 6-8 paclitaxel + weekly Herceptin
CRx
CRx+ H
AC
AC + H
234 36 5.5
235 62* 8 6*
66
69
145 42 6.5 18 71
146 65 9.0 3 68
T+H 89 25 4.2 0 59
89 57 7.1 2 70
* Significant differences from CRx alone. Abbrev: MBC = metastatic breast cancer; AC = doxorubicin + cyclophosphamide; T = paclitaxel; CRx : chemotherapy; H = Herceptin; RR = response rate; TTP = time to progression; mo = months; AE = adverse events (any grade)
utes. Doxorubicin was administered i.v. over the last 20 minutes of the DPPE infusion. Premedication included lorazepam and ondansetron; postmedication included metoclopramide. Treatment was repeated every three weeks (maximum, 7 cycles). All patients were evaluable for activity and safety. Sixteen patients (70%; 95% C.I.=47-87%) responded (7 CR and 9 PR). Among 16 patients previously treated with chemotherapy, there were 11 responders, including 6 with CR. Of interest, 5 responders (2 CR, 3 PR) had a poor (ECOG 3/4) performance status pre-treatment. Median CR duration was 11 (range 5-18) months. Hematological toxicity was low; gastrointestinal toxicity (nausea/vomiting/dyspepsia) responded well to anti-emetics, ranitidine and/or dexamethasone in most patients. A mean absolute drop in left ventricular ejection fraction of 8% occurred in 17 patients who received > 300 mg/m2 doxorubicin, similar to historical results in patients treated with doxorubicin alone. The objective response rate in DPPE plus doxorubicin-treated patients is apparently higher than historically reported for doxorubicin alone in this setting, suggesting a chemopotentiating effect of DPPE. A second, confirmatory study of DPPE/doxorubicin (DPPE 6 mg/kg given as 80-minute i.v. infusion; doxorubicin 60 mg/ m2 i.v. over last 20 minutes of DPPE infusion as in the previous series) was performed by the National Cancer Institute of Canada (NCIC), Clinical Trials Group [58]. In the initial cohort (32 patients), the antiemetic regimen was similar to that of Brandes: premedication included lorazepam and ondansetron; postmedication included metoclopramide. In a second cohort (10 patients), premedication included lorazepam, dexamethasone and ondansetron; postmedication included dexamethasone and ondansetron. Eligibility criteria included no previous anthracycline exposure, metastatic or inoperable breast cancer, up to one prior chemotherapy regimen for metastatic disease, bidimensionally measurable disease and six weeks off hormones if previous hormone response. The primary endpoint was complete response (CR) rate. The trial has completed accrual with entry of 42 patients. To date, baseline data is available on all 42. Eight patients had received prior chemotherapy in the metastatic setting and 10 in the adjuvant setting. Most common
sites of disease were nodes (28), bone (23), lung (16), breast (12) and liver (12). Twenty-five of 42 patients had three or more disease sites. More than 70% of patients received > 90% of planned dose intensity of both DPPE and doxorubicin. Thirty-five patients were evaluable for toxicity and response at the time of analysis. Frequent adverse events related to study drugs (all grades, grade 3) included lethargy (77%, grade 3: 23%), anorexia (57%, grade 3: 9%), nausea (80%, grade 3: 17%), vomiting (69%, grade 3: 9%), stomatitis (54%, grade 3: 9%) and alopecia (100%). Frequent neurological toxicities were cerebellar signs (34%, grade 3: 6%), and hallucinations (grade 3: 31%). None of the nonhematologic toxicities were grade 4. Hematologic toxicity included grade 3/4 neutropenia (89%), and grade 3/4 thrombocytopenia (6%). Febrile neutropenia was infrequent (6%). In summary, toxicity is similar to that of doxorubicin single agent in this dose with the exception of the neurologic effects. The neurotoxicity of DPPE was transient, easily managed by sedation during infusion and improved after cycle 1. In this trial, the overall response rate was 49% (95% C l : 31% - 66%), with 11% complete responses (4 of 35 CR) and 37% partial responses (13 of 35 PR). The high activity observed with DPPE plus doxorubicin in this trial supports the findings in the previous single institution trial. In a recently completed, randomised NCIC CTG trial (MA.8), women with metastatic breast cancer (same eligibility criteria as for the NCIC CTG DPPE/doxorubicin phase II trial described above) treated with single agent doxorubicin (60 mg/m2) experienced an objective response rate of 30%, with a complete response rate of 3% [59]. Hence, the response rates with DPPE/ doxorubicin (70% by Brandes and 49% by NCIC CTG) overall objective response rates with 30% and 11% of patients achieving a complete response), when compared with historical data, have stimulated the further development of DPPE, in combination with doxorubicin, as treatment for patients with metastatic breast cancer. In order to investigate the comparative efficacy of doxorubicin plus DPPE, the National Cancer Institute of Canada organised a phase III randomised study, sponsored by Bristol-Myers Squibb, in patients with metastatic breast cancer. Patients are randomised to doxorubicin alone or
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N RR (%) TTP (mo) Cardiotoxicity (% gr 3/4) AE (%)
71 il 71 ^i
144
Future prospects with the new regimens Two of the advances in the treatment of advanced breast cancer described here, the combination of doxorubicin and paclitaxel and the use of Herceptin with chemotherapy, have been demonstrated to prolong the time to disease progression in large trials. The doxorubcin/paclitaxel regimens have shown activity similar to that observed with high dose chemotherapy using stem cell rescue. The confirmation of the superior results with doxorubicin and paclitaxel may be forthcoming, with the results of additional phase III studies. The latter are a trial from EORTC comparing doxorubicin/paclitaxel to doxorubicin/cyclophosphamide and a study in Central and Eastern Europe of comparing doxorubicin/paclitaxel versus doxorubicin/cyclophosphamide/5-fluorouracil, sponsored by Bristol-Myers Squibb. The proof of principle for the third advance, the combination of DPPE with doxorubicin, is being investigated in the ongoing NCIC CTG phase III study. The value of these advances could be increased when the regimens are moved to an earlier stage of the disease, namely for the neo-adjuvant or the adjuvant treatment of breast cancer. The importance of the early application of therapy has again been demonstrated in studies examining the adjuvant use of paclitaxel. The CALGB-led Intergroup study tested whether the sequential use of paclitaxel following a regimen of doxorubicin/cyclophosphamide was more active than doxorubicin/cyclophosphamide alone in their study 9344 . In addition, they investigated the escalation of the doxorubicin dose in the combination regimens, with doxorubicin doses of 60, 75 or 90 mg/m2. 3170 patients were randomised in a 3 x 2 factorial trial design; the doxorubicin was given together with cyclophosphamide 600 mg/m2 every three weeks for four cycles. Patients then received either no paclitaxel or paclitaxel 175 mg/m2 every three weeks for four cycles. At the first preplanned interim analysis (450 events), no differences in disease free survival (DFS) or overall survival (OS) related to doxorubicin dose were observed, but the use of paclitaxel was associated with a significant improvement in both DFS (p=0.0077) and OS (p=0.0390). paclitaxel reduced the recurrence rate by 22% and death rate by 26%, by multivariate analysis. These results are striking: the reduction due to adding paclitaxel to an adjuvant regimen is similar to the reduc-
tion in recurrence rate and death rate observed when comparing the use of adjuvant chemotherapy to no chemotherapy in patients with breast cancer. The early application of the advances described here may also lead to improved survival for patients with breast cancer. Current studies are exploring the neo-adjuvant application of doxorubicin/paclitaxel; the adjuvant use of doxorubicin/paclitaxel is also being investigated. Similarly, studies may be designed to investigate the use of Herceptin with paclitaxel (and potentially doxorubicin, if the Herceptinrelated cardiotoxicity can be managed or reduced) for adjuvant therapy of the subset of patients with high levels of HER2. Finally, if DPPE/doxorubicin is found to be superior to doxorubicin alone, this drug would also be incorporated into adjuvant and/or neo-adjuvant breast cancer regimens. Despite the current advances, there still will be patients with disease refractory to these new combinations with doxorubicin and taxanes in the adjuvant and/or metastatic setting. New salvage therapies for this population are needed. Currently, activity has been observed in the refractory setting with agents directed at thymidylate synthetase, such as infusional 5-fluorouracil, capecitabine [61] and UFT [62,63]. In addition, agents such as vinorelbine [64] and a large array of novel agents now in early clinical development are of interest. Recent results in breast cancer, with taxane combinations and Herceptin indicate the value of careful studies of new therapies to the treatment of breast cancer, and might change the standard of care in the treatment of the disease.
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