Download Paclitaxel Versus Doxorubicin as First-Line Single

Paclitaxel Versus Doxorubicin as First-Line Single-Agent
Chemotherapy for Metastatic Breast Cancer: A European
Organization for Research and Treatment of Cancer
Randomized Study With Cross-Over
By R. Paridaens, L. Biganzoli, P. Bruning, J.G.M. Klijn, T. Gamucci, S. Houston, R. Coleman, J. Schachter,
A. Van Vreckem, R. Sylvester, A. Awada, J. Wildiers, and M. Piccart on behalf of the European Organization for Research
and Treatment of Cancer-Investigational Drug Branch for Breast Cancer/Early Clinical Studies Group
Purpose: To compare the efficacy of paclitaxel versus doxorubicin given as single agents in first-line therapy of advanced breast cancer (primary end point,
progression-free survival [PFS]) and to explore the degree of cross-resistance between the two agents.
Patients and Methods: Three hundred thirty-one patients were randomized to receive either paclitaxel 200
mg/m2, 3-hour infusion every 3 weeks, or doxorubicin
75 mg/m2, intravenous bolus every 3 weeks. Seven
courses were planned unless progression or unacceptable toxicity occurred before the seven courses were
finished. Patients who progressed within the seven
courses underwent early cross-over to the alternative
drug, while a delayed cross-over was optional for the
remainder of patients at the time of disease progression.
Results: Objective response in first-line therapy was
significantly better (P ⴝ .003) for doxorubicin (response
rate [RR], 41%) than for paclitaxel (RR, 25%), with
doxorubicin achieving a longer median PFS (7.5 months
for doxorubicin v 3.9 months for paclitaxel, P < .001).
In second-line therapy, cross-over to doxorubicin (91
patients) and to paclitaxel (77 patients) gave response
rates of 30% and 16%, respectively. The median survival durations of 18.3 months for doxorubicin and
15.6 months for paclitaxel were not significantly different (P ⴝ .38). The doxorubicin arm had greater toxicity,
but this was counterbalanced by better symptom control.
Conclusion: At the dosages and schedules used in
the present study, doxorubicin achieves better disease
and symptom control than paclitaxel in first-line treatment. Doxorubicin and paclitaxel are not totally crossresistant, which supports further investigation of these
drugs in combination or in sequence, both in advanced
disease and in the adjuvant setting.
J Clin Oncol 18:724-733. © 2000 by American
Society of Clinical Oncology.
LTHOUGH ADVANCED breast cancer may be considered incurable, efficient palliation can be achieved
with the optimal use of therapeutic resources, ie, radiotherapy, hormonotherapy, biphosphonates, and chemotherapy.
In this setting, chemotherapy is generally prescribed after
failure of endocrine therapy. However, it is prescribed as
first-line treatment for patients with receptor-negative tumors or with life-threatening visceral metastases.
Among the presently available cytotoxic drugs, doxorubicin is generally considered as the most active agent in
advanced breast cancer.1 Although the best chemotherapy
regimen remains a matter of debate, the results of several
studies indicate that there is a dose-response relationship for
this agent and that, at the maximum-tolerated dose of 75
mg/m2, the results obtained with monotherapy are comparable with those achieved with a standard combination such
as cyclophosphamide, methotrexate, and fluorouracil.2-5
When progression occurs after first-line chemotherapy, the
response to salvage treatment is generally disappointing,
indicating that similar mechanisms of resistance affect most
conventional regimens. In this regard, paclitaxel represents
a major advance. This cytotoxic compound, originally
extracted from the bark of the Pacific yew (Taxus brevifolia), stabilizes polymerized microtubules, thereby disrupting
mitosis.6,7 It was selected in 1977 by the National Cancer
Institute (NCI) for further development as an antitumor drug
and proved, subsequently, to be active in a broad panel of
tumors, including ovarian and breast cancer.8 In breast
cancer, paclitaxel seemed particularly promising because it
elicited impressive response rates in phase II studies as
second- or third-line therapy in patients with demonstrated
resistance to anthracyclines.9-20
A
From the University Hospital Gasthuisberg, Leuven; and Investigational Drug Branch for Breast Cancer; and European Organization for
Research and Treatment of Cancer Data Center; and Institut Jules
Bordet, Brussels, Belgium; and Netherlands Cancer Institute, Amsterdam; and Daniel den Hoed Klinik and Academic Hospital, Rotterdam,
The Netherlands; and Istituto Regina Helena, Rome, Italy; and Guy’s
Hospital, London; and Weston Park Hospital, Sheffield, United Kingdom; and Rabin Medical Centre, Tel Aviv, Israel.
Submitted April 12, 1999; accepted October 29, 1999.
Address reprint requests to Robert Paridaens, MD, Department of
Oncology, University Hospital Gasthuisberg, Herestraat 49, B-3000
Leuven, Belgium; email [email protected].
© 2000 by American Society of Clinical Oncology.
0732-183X/00/1804-724
724
Journal of Clinical Oncology, Vol 18, No 4 (February), 2000: pp 724-733
725
PACLITAXEL v DOXORUBICIN IN BREAST CANCER
The purpose of the present phase III trial was to compare
the efficacy of paclitaxel and doxorubicin given as single
agents in first-line therapy of advanced breast cancer. A
cross-over applied systematically on demonstrated progression during first-line treatment, unless contraindicated or
refused by the patient, intended to explore further the degree
of cross-resistance between the two agents.
PATIENTS AND METHODS
Eligibility Criteria
To be eligible, patients were required to have histologically or
cytologically proven adenocarcinoma of the breast and metastatic
disease in overt progression with uni- or bidimensionally measurable
lesions. Prior hormonotherapy, radiotherapy, or immunotherapy for
adjuvant or neoadjuvant purposes or for advanced disease was allowed
but had to be stopped at study entry. No prior chemotherapy for
advanced disease was permitted. Prior adjuvant chemotherapy with
cyclophosphamide, methotrexate, and fluorouracil or comparable regimens was authorized on the provision that patients had never been
exposed to anthracyclines or to taxanes and that all cytotoxic drugs
were stopped at least 3 months before study entry. Other requirements
for eligibility were an age greater than 18 years, a World Health
Organization performance status of 0 to 2, a life expectancy of at least
3 months, adequate hematologic parameters (absolute neutrophil
count ⬎ 1.5 ⫻ 109/L, platelets ⬎ 100 ⫻ 109/L), adequate renal and
hepatic functions (total bilirubin and creatinine ⬍ 1.25 ⫻ upper normal
limit), a normal cardiac function, and absence of cardiac disease or
significant arythmia as demonstrated by ECG and left ventricular
ejection fraction (LVEF) measurement (echocardiography or multiple
gated aquisition scan). Men and pregnant or lactating women were
excluded. The protocol was approved by the European Organization for
Research and Treatment of Cancer (EORTC) Protocol Review Committee and by the ethics committee of each participating center; all
patients gave their written informed consent to participate in the trial.
(grade 3 or 4) nonhematologic toxicity persisting at the scheduled
retreatment date, treatment was delayed until recovery. If treatment
could not be administered on day 43, patients went off study. Three
dose reduction levels were foreseen for each regimen (60, 50, and 40
mg/m2 for doxorubicin; 175, 135, and 110 mg/m2 for paclitaxel) if the
patient experienced severe toxicity during the previous cycle. This
included grade 3 nonhematologic toxicity (other than nausea, vomiting,
alopecia, or diarrhea), prolonged myelosuppression (ANC ⬍ 0.5 ⫻
109/L or platelets ⬍ 50 ⫻ 109/L for ⱖ 7 days), febrile neutropenia, or
documented infection during neutropenia. No subsequent dose reescalation was permitted. Patients who could not tolerate the lowest
dose level went off study.
In first-line treatment, a maximum of seven cycles of doxorubicin
were planned (cumulative dose 525 mg/m2), whereas paclitaxel therapy
could be either stopped after seven cycles or pursued in responding
patients at the discretion of the treating physician. Patients progressing
during their seven courses were to undergo early cross-over to the
alternative drug, whereas a delayed cross-over was optional for the
remainder at the time of disease progression.
Pretreatment and Follow-Up Studies
At baseline, standard evaluations including physical examination,
performance status, routine hematology, and biochemistry parameters,
ECG and tumor assessments were performed. Toxicity was assessed in
each cycle of therapy using the NCI common toxicity criteria (NCI
CTC).21 Tumor response was assessed after cycles 3, 5, and 7, and
every 2 months thereafter. A full re-evaluation of disease extension was
performed within 2 weeks of cross-over. A multiple gated aquisition
scan or an echocardiography for the evaluation of the LVEF was
mandatory at study entry and at completion of the fifth and seventh
course of treatment during doxorubicin administration. Quality of life
(QOL) was assessed by the EORTC Quality-of-Life Questionnaire C30
(EORTC QLQ-C30) and the Rotterdam Symptom Checklist22 at
baseline, at the completion of cycles 3, 5, and 7 of both first-line and
cross-over therapy, and during follow-up at every 2 months until
disease progression.
Treatment Allocation and Administration
Criteria of Evaluation
All participating institutions were affiliated with the EORTC and
were members of the Investigational Drug Branch for Breast Cancer
(IDBBC) of the Breast Cancer Cooperative Group and/or the Early
Clinical Studies Group (ECSG). Randomization was performed centrally at the EORTC Data Center located in Brussels (Belgium) by
telephone, fax, or computer. After stratification for the institution and
for prior adjuvant chemotherapy (no; yes with relapse earlier than 1
year after completion; or yes with relapse 1 year or more after
completion), patients were randomly assigned to receive either doxorubicin (75 mg/m2, administered as a short infusion over 5 to 15
minutes) or paclitaxel (200 mg/m2, administered as a continuous
infusion during 3 hours) as first-line therapy. For patients receiving
paclitaxel, a premedication of dexamethasone (20 mg orally, 12 and 6
hours before paclitaxel), diphenhydramine (50 mg intravenous 30
minutes before paclitaxel), and cimetidine (300 mg intravenous 30
minutes before paclitaxel) was systematically given. For patients
receiving doxorubicin, a premedication of dexamethasone and a 5-hydroxytryptamine-3 antagonist was administered.
Cycles were repeated every 3 weeks, with weekly monitoring of
hematology. For patients who did not achieve hematologic recovery
(ANC ⱖ 1.5 ⫻ 109/L and platelets ⱖ 100 ⫻ 109/L) or in case of severe
Tumor response was assessed according to the Union Internationale
Contre le Cancer criteria.23 Complete remission (CR) was defined as
the disappearance of all known disease determined by two observations
not less than 4 weeks apart. Partial remission (PR) was defined, for
bidimensionally measurable disease, as the decrease of at least 50% of
the sum of the products of the largest perpendicular diameters of all
measurable lesions as determined by two observations not less than 4
weeks apart or, for unidimensionally measurable disease, a decrease of
at least 50% of the sum of the largest diameters of all lesions. It was not
necessary for all lesions to have regressed to qualify for a partial
response, but no lesion should have progressed and no new lesion
should have appeared. Serial evidence of appreciable change documented by radiography or photography was obtained for external
review. The stable disease category was defined as a less than 50%
decrease and a less than 25% increase either in the sum of the products
of the largest perpendicular diameters of all measurable lesions, in case
of bidimensionally measurable disease, or in the sum of the diameters
of all lesions for unidimensionally measurable disease, maintained at
least 2 months after treatment initiation. In addition, no lesion should
have progressed and no new lesion should have appeared. Progressive
disease (PD) was defined as a 25% or greater increase in the size of at
726
PARIDAENS ET AL
least one bidimensionally measurable lesion or the appearance of a new
lesion.
All case report forms were regularly reviewed and source verified. A
large proportion of the objective remissions (CR or PR) (85% and 90%
for first- and second-line treatment, respectively) and a sample of
disease stabilizations (22% of first-line stable disease) were reviewed.
The cases were presented by the local investigators to two independent
radiologists who were blinded to treatment arm.
Study End Points and Statistical Methods
The primary end points of the study were progression-free survival
(PFS, calculated from the day of randomization until the date of PD or
death, if it occurred before documentation of PD) in first-line chemotherapy and response rate (RR) in second-line chemotherapy. RR to
first-line therapy, QOL, and overall survival (OS) were secondary end
points.
Results were analyzed according to the intent-to-treat principle. The
␹2 test and Fisher’s exact test were used to compare response rate and
toxicity. The duration of response was computed from the date of
randomization until documentation of PD. OS and PFS were estimated
using the Kaplan-Meier method24 and compared using a two-sided
log-rank test.25 Logistic regression and Cox’s proportional hazards
regression model was used to assess treatment effect after adjustment
for important prognostic variables.26 When a patient was crossed over
to the alternative drug or started a new therapy without documented
progression, this patient was counted as a treatment failure at the start
of this unauthorized therapy.
RESULTS
Treatment Delivery
Between August 1993 and May 1996, 331 patients from
14 institutions were randomized to receive either paclitaxel
(166 patients) or doxorubicin (165 patients) as first-line
chemotherapy. Sixteen patients were considered not eligible
because of the absence of measurable lesions (n ⫽ 9),
inadequate organ function (n ⫽ 4), the presence of brain
metastases (n ⫽ 2), or prior chemotherapy for metastatic
disease (n ⫽ 1). Patient characteristics were similar in the
two groups, and, as listed in Table 1, there was no
significant imbalance in classical prognostic factors. The
details of treatment delivery in both first- and second-line
treatments are given in Table 2. Two patients in each group
never started first-line treatment, leaving 164 and 163
patients who received at least one course of paclitaxel and
doxorubicin, respectively.
First-line treatment. A median of seven cycles was
administered per patient in both the paclitaxel arm (range,
one to 22 cycles) and the doxorubicin arm (range, one to
nine cycles). Twenty-one patients versus one patient received more than seven cycles of therapy in the paclitaxel
and doxorubicin arms, respectively. However, because dose
reductions and treatment delays were more frequent in the
doxorubicin arm, the average dose-intensity achieved with
doxorubicin (93% of planned dose-intensity; range, 53% to
Table 1.
Age, years
Median
Range
WHO performance status
0
1
2
DFI, months
Median
Range
Prior radiotherapy
Prior hormonotherapy
Prior adjuvant chemotherapy
Dominant site of disease
Soft tissue only
Bone ⫹/⫺ soft tissue
Single visceral
Multiple visceral
No. of metastatic sites
1
2
3 or more
Hormone receptor status
ER⫽positive
ER⫽negative
ER unknown
Patient Characteristics
Patients Treated
With Paclitaxel
(n ⫽ 166)
Patients Treated
With Doxorubicin
(n ⫽ 165)
No.
No.
%
54
31-74
69
83
14
%
55
26-75
42
50
8
68
82
15
24
0-212
41
50
9
33
0-383
130
126
53
78
76
32
124
122
54
75
74
33
10
26
105
25
6
16
63
15
18
23
93
31
11
14
56
19
47
73
46
28
44
28
43
70
52
26
42
32
45
64
57
27
39
34
40
64
61
24
39
37
Abbreviation: DFI, disease-free interval; WHO, World Health Organization.
103%) was lower than with paclitaxel (99% of planned
dose-intensity; range, 72% to 107%). In patients receiving
paclitaxel, the most frequent reasons for delaying treatment
were neutropenia, neutropenic fever, and neurotoxicity, and
infection was the most frequent reason for dose reduction.
In the doxorubicin arm, neutropenia and stomatitis were the
principal causes of treatment delay, and neutropenia, stomatitis, and neutropenic fever were the principal causes of
dose reduction. The most frequent toxicities leading to
treatment interruption were gastrointestinal (four patients),
hematologic (three patients), infection (two patients), and
cardiac function (17 patients) with doxorubicin, and neurotoxicity (four patients) with paclitaxel.
The most frequent reasons for stopping first-line paclitaxel were disease progression, including death caused by
malignancy (90 patients; 55%), treatment completion (57
patients; 35%), and excessive toxicity and/or patient refusal
(12 patients; 7%). Eighty-one doxorubicin patients (50%)
ended first-line therapy because of treatment completion, 37
(23%) because of excessive toxicity and/or patient refusal,
and 36 (22%) because of PD.
727
PACLITAXEL v DOXORUBICIN IN BREAST CANCER
Table 2.
Drug Administration in First- and Second-Line Treatment
First-Line Treatment
Total no. of patients
Total no. of cycles
No. of cycles per patient
Median
Range
No. of patients ⬎ 7 cycles
Relative DI, %
Median
Range
Dose reduction, % of cycles
Not reduced
Reduced by 1 dose level
Reduced by 2 dose levels
Reduced by 3 dose levels
Dose reduction, % of patients
Not requiring dose
reduction
Delay, % of cycles
Delay, % of patients
cycles of paclitaxel and 18% of doxorubicin cycles were
delayed, mainly for neutropenia and neutropenic fever.
Approximately 10% of the cycles were dose-reduced in the
two treatment arms. The most frequent reasons for stopping
second-line therapy were disease progression (61% of
patients) under paclitaxel and treatment completion (47% of
patients) under doxorubicin.
Data on second-line therapy are available for 95% and
91% of the first-line paclitaxel and first-line doxorubicin
patients, respectively, who did not cross over. Fifty-five
percent of paclitaxel first-line patients received a further
systemic treatment (hormonotherapy 20% and chemotherapy 80%); 60% of the second-line regimens were anthracycline-based. A second-line chemotherapy was received by
62% of the patients previously treated with doxorubicin. A
taxane-based regimen was received by 21% of these patients.
Second-Line Treatment
Paclitaxel
Doxorubicin
Paclitaxel
Doxorubicin
164
949
163
908
77
382
91
485
7
1-22
21
7
1-9
1
5
1-15
7
6
1-8
1
99
72-107
93
53-103
97
67-104
92
68-106
94
5
1
-
80
17
2
1
89
10
1
-
87
11
2
-
90
68
85
75
5
20
19
44
5
16
18
42
Response and Efficacy Data
Abbreviation: DI, dose-intensity.
Second-line treatment. Among those patients eligible
for early cross-over, 65 (76%) out of 86 paclitaxel-resistant
patients received doxorubicin, whereas 24 (75%) out of 32
doxorubicin-resistant patients received paclitaxel. Overall,
168 patients have been crossed to the alternate drug, for a
total of 77 patients receiving paclitaxel and 91 patients
receiving doxorubicin. Late cross-over was performed in 26
(46%) out of 57 patients previously exposed to paclitaxel
and in 53 (65%) out of 81 patients first treated with
doxorubicin.
Overall, a median of five cycles (range, one to 15 cycles)
were administered per patient in the paclitaxel arm, and a
median of six cycles (range, one to eight cycles) were
administered in the doxorubicin arm. Five percent of the
Table 3.
In first-line therapy, 15 paclitaxel patients and 17 doxorubicin patients were not assessable for response, but all
were included in the analyses of response rate, time to
progression, and survival according to the intent-to-treat
principle. As previously stated, four patients received no
trial therapy. The main reasons for failure of response
evaluation in the eligible patients were insufficient documentation of response under treatment (paclitaxel, n ⫽ 2;
doxorubicin, n ⫽ 3), drop out from study for toxicity/refusal
(four patients in each treatment arm), and early death from
nonmalignant conditions (paclitaxel, n ⫽ 3; doxorubicin,
n ⫽ 1) or from toxicity (two patients on doxorubicin).
The patterns of response achieved under paclitaxel or
doxorubicin in first- and in second-line treatment are depicted in Table 3. The objective remission rate (CR ⫹ PR)
was significantly better for doxorubicin than for paclitaxel
in first-line treatment (41%; 95% confidence interval, 33.1%
to 48.1% v 25%; 95% confidence interval, 18.7 to 31.9%,
Best Response in First- and Second-Line Treatment
Second-Line Treatment
First-Line Treatment
Patients Treated
With Paclitaxel
(n ⫽ 166)
CR
PR
SD
PD
Not assessable
Early Cross-Over
Patients Treated
With Doxorubicin
(n ⫽ 165)
No.
%
No.
%
3
39
58
51
15
2
23
35
31
9
10
57
60
21
17
6
35
36
13
10
Abbreviation: SD, stable disease.
P
}
.003
Late Cross-Over
Patients Treated
With Paclitaxel
(n ⫽ 24)
Patients Treated
With Doxorubicin
(n ⫽ 65)
Patients Treated
With Paclitaxel
(n ⫽ 53)
Patients Treated
With Doxorubicin
(n ⫽ 26)
No.
%
No.
%
No.
%
No.
%
0
3
10
9
2
0
13
42
38
8
0
17
34
10
4
0
26
52
15
7
0
9
20
23
1
0
17
38
43
2
0
10
10
3
3
0
38
38
12
12
728
PARIDAENS ET AL
Fig 1. PFS on first-line treatment with paclitaxel (solid line) or
with doxorubicin (dashed line).
respectively; P ⫽ .003). In second line treatment, the
response rates were 30% for doxorubicin and 16% for
paclitaxel. Response by disease site (number of responses/
number of sites) for first-line doxorubicin and paclitaxel,
respectively, was as follows: soft tissue, 67% (76 of 114)
versus 38% (36 of 95); liver, 42% (32 of 77) versus 19% (14
of 72); lung, 34% (12 of 35) versus 43% (20 of 46); and
bone, 0% (zero of 14) versus 14% (two of 14). Response by
disease site for second-line doxorubicin and paclitaxel,
respectively, was as follows: soft tissue, 33% (15 of 45)
versus 40% (14 of 35); liver, 38% (17 of 45) versus 18%
(seven of 39); lung, 26% (six of 23) versus 25% (three of
12); and bone, 43% (three of seven) versus 0% (zero of
eight).
The median duration of objective response in first-line
treatment was 9.7 months (range, 3.4 to 45.8⫹ months) for
doxorubicin and 7.7 months (range, 3.8 to 55.5⫹ months)
for paclitaxel. In second-line treatment, median duration of
response was 8.3 months (range, 3.0 to 25.3 months) for
doxorubicin, and 5.6 months (range, 4.4 to 11.5 months) for
paclitaxel. PFS curves for first-line therapy are presented in
Fig 1. PFS in first-line therapy was significantly longer for
doxorubicin than for paclitaxel (median, 7.5 months v 3.9
months, respectively; P ⫽ .0001). We did not compare the
time to disease progression in patients who stopped after
seven cycles with those who continued beyond seven cycles
because this is a subgroup analysis of two groups of patients
that were not determined by randomization and, therefore,
are almost certainly not comparable. There was no significant difference in OS between the two study arms (P ⫽ .38),
with a median survival of 18.3 months in the doxorubicin
arm and 15.6 months in the paclitaxel arm (Fig 2).
The relationship between treatment and prognostic factors on response, PFS, and OS has been examined. The
prognostic factors selected by univariate analyses were age,
performance status, dominant site, number of sites, prior
adjuvant chemotherapy, and disease-free interval. After
adjusting for these factors, doxorubicin remained more
active than paclitaxel in terms of RR and PFS; again, no
difference in OS was demonstrated (Table 4).
Toxicity
Toxicities and clinically relevant adverse events encountered during treatment in first- and second-line therapy are
presented in Tables 5 and 6, respectively. As expected, the
toxicity profiles of the two drugs were different. Doxorubicin was more toxic than paclitaxel in terms of hematologic,
gastrointestinal, and cardiac side effects. In contrast, paclitaxel elicited more neurotoxicity (mainly sensory) and
arthralgia/myalgia. Neutropenia, febrile neutropenia (fever ⱖ 38.5°C, associated with an ANC of ⬍ 0.5 ⫻ 109/L,
and requiring hospitalization and intravenous antibiotic
treatment), documented infections, and hospital admission
for serious adverse events were more frequently observed in
the doxorubicin arm. No severe hypersensitivity reaction
729
PACLITAXEL v DOXORUBICIN IN BREAST CANCER
Fig 2. OS in patients treated in
first-line treatment with paclitaxel
(solid line) or with doxorubicin
(dashed line).
necessitating prolongation of the 3-hour paclitaxel infusion
was reported.
Six toxic deaths were encountered: three after doxorubicin in first-line therapy (two patients died as a result of a
neutropenic sepsis and one patient suffered an episode of
acute dyspnea and died at home 2 weeks after the first cycle
of chemotherapy); two in second-line therapy (two myocardiopathies after a cumulative dose of 525 mg/m2 of doxorubicin); and one after paclitaxel was encountered in second-line treatment (neutropenic sepsis).
Regarding cardiotoxicity, a total of 12 patients developed
congestive heart failure, six patients (4%) on first-line
doxorubicin, two on second-line paclitaxel, and four on
second-line doxorubicin. Of all these patients, the median
Table 4. Cox Proportional Hazards Regression Analysis of Prognostic
Factors for Response, Progression, and Survival: Unadjusted and Adjusted
Results
Response
Unadjusted
Adjusted
PFS
Unadjusted
Adjusted
OS
Unadjusted
Adjusted
Risk Ratio
(doxorubicin/paclitaxel)
95% CI
P
0.49
0.50
0.31-0.79
0.31-0.81
.003
.005
0.60
0.59
0.48-0.75
0.47-0.75
.001
.001
0.92
0.86
0.72-1.19
0.67-1.11
.38
.25
Abbreviation: OS, overall survival.
age was 60 years (range, 42 to 69 years), and the median
cumulative dose of doxorubicin was 480 mg/m2 (range, 300
to 675 mg/m2). Twenty-nine patients (17 on first-line
doxorubicin and 12 on second-line doxorubicin) ceased
therapy because of a drop in LVEF of ⱖ 20% of the
baseline value. Myocardial ischemic events were reported in
an additional three patients (two on doxorubicin and one on
paclitaxel).
QOL
Two QOL questionnaires (EORTC QLQ-C30 and the
Rotterdam Symptom Checklist) were completed by patients
at fixed intervals during first-line and cross-over therapy
until disease progression. The results will be the subject of
a separate paper, but, in brief, 176 patients completed a
baseline QOL questionnaire (85 patients receiving first-line
paclitaxel and 91 patients receiving first-line doxorubicin).
Baseline QOL was strongly associated with survival. An
analysis based on the assessment after the third cycle on
first-line treatment showed no difference in global health
status/QOL between the two treatment groups. A more
detailed analysis showed that the greater toxicity of doxorubicin at this time point was compensated by better
symptom control, particularly pain, compared with that
achieved with paclitaxel.
DISCUSSION
This study demonstrates that, in advanced breast cancer,
monotherapy with doxorubicin given at the dose of 75
730
PARIDAENS ET AL
Table 5. Main Clinically Relevant Adverse Events and Grade 3 to 4 NCI
CTC Toxicity Observed Per Patient During First-Line Treatment
Patients
Treated With
Doxorubicin
(n ⫽ 163)
Patients
Treated With
Paclitaxel
(n ⫽ 164)
Toxicity
No.
%
No.
%
Neutropenia grade 4
Febrile neutropenia
Documented infection
Vomiting
Stomatitis
Arthralgia/myalgia
Sensory neurotoxicity
CHF
Myocardial infarction
Hospitalization (any cause)
Toxic death
66
11
6
4
2
7
14
0
1
46
0
40
7
4
2
1
4
9
0
1
28
0
139
33
10
22
25
0
0
6
2
61
3
85
20
6
13
15
0
0
4
2
37
3
P
⬍.001
⬍.001
.319
⬍.001
⬍.001
.015
⬍.001
.015
.62
.07
.123
Abbreviation: CHF, congestive heart failure.
mg/m2 every 3 weeks achieves better disease control than
paclitaxel 200 mg/m2 given as a 3-hour infusion every 3
weeks. In first-line treatment, therapy with doxorubicin
results in a higher objective RR and almost twice the
median PFS achieved after therapy with paclitaxel (7.5
months with doxorubicin v 3.9 months with paclitaxel). No
significant survival difference was observed between the
two treatment groups; however, the cross-over design of the
study may reduce the likelihood of observing such a
difference.
The greater efficacy of doxorubicin is associated with
better pain control but is counterbalanced by higher hematologic, gastrointestinal, and cardiac toxicity. Doxorubicin
should, therefore, be proposed as first-line therapy to patients who are symptomatic or affected by life-threatening
disease. In asymptomatic patients, however, paclitaxel remains a reasonable first-line option because of its favorable
Table 6. Main Clinically Relevant Adverse Events and Grade 3 to 4 NCI
CTC Toxicity Observed Per Patient During Second-Line Treatment
Patients Treated
With Paclitaxel
(n ⫽ 77)
Patients Treated
With Doxorubicin
(n ⫽ 91)
Toxicity
No.
%
No.
%
Neutropenia grade 4
Febrile neutropenia
Documented infection
Vomiting
Stomatitis
Arthralgia/myalgia
Sensory neurotoxicity
CHF
Toxic death
35
6
4
2
3
4
8
2
1
45
8
5
3
4
5
10
3
1
70
18
3
9
7
0
1
4
2
77
20
3
10
8
0
1
4
2
Abbreviation: CHF, congestive heart failure.
toxicity profile and the observation that the efficacy of
doxorubicin is sufficiently maintained in second-line therapy and that the paclitaxel followed by doxorubicin sequence does not adversely affect survival.
Another randomized trial conducted by the American
Intergroup has compared paclitaxel with doxorubicin in
first-line treatment for metastatic disease. In that three-arm
study, reported by Sledge et al.27 at the American Society of
Clinical Oncology meeting in 1997, 739 patients were
randomized to receive either doxorubicin (60 mg/m2) or
paclitaxel (175 mg/m2) continuous infusion over 24 hours
or the combination of doxorubicin (50 mg/m2) and paclitaxel (150 mg/m2) over 24 hours plus granulocyte colonystimulating factor support. Patients receiving single-agent
chemotherapy were crossed to the alternate drug at the time
of progression. RRs and median durations of PFS in
first-line therapy were almost identical for paclitaxel (33%
RR; 5.9 months) and doxorubicin (34% RR; 6.2 months) but
were significantly better for the combination of doxorubicin
and paclitaxel (46% RR; 8 months). There was no significant difference in OS between the three arms of the study.
Cross-over from doxorubicin to paclitaxel yielded a 20%
RR, whereas the alternate sequence resulted in a 16% RR
(P ⫽ .06).
The results of the monotherapy arms of the American
trial are difficult to compare with those of the present study
because the Intergroup used a lower dose of doxorubicin (60
instead of 75 mg/m2) and a different dose and schedule of
administration of paclitaxel (175 mg/m2 over 24 hours
instead of 200 mg/m2 over 3 hours).
The ideal dose and schedule of paclitaxel are yet to be
defined. Using the 3-hour infusion, increasing the dose of
paclitaxel from 175 up to 250 mg/m2 does not significantly
improve efficacy but does increase toxicity.28 Prolonging
the duration of infusion of paclitaxel, at a fixed dose of 250
mg/m2, from 3 to 24 hours results in higher RRs but does
not improve PFS or OS.29 A randomized trial comparing
paclitaxel 250 mg/m2 as a 3-hour infusion with paclitaxel
140 mg/m2 as a 96-hour infusion did not demonstrate any
difference between the schedules in terms of RR, median
duration of response, and OS.30 However, prolonged infusion of 120 to 140 mg/m2 over 96 hours may still elicit
responses in patients who have become refractory to higher
doses given over 3 hours.31
Finally, new strategies, such as the weekly administration
of lower doses of paclitaxel, are under investigation.32
However, the above-mentioned data would suggest that the
3-hour infusion and the dose of 175 mg/m2 are an adequate
way of administering paclitaxel in advanced breast cancer
patients. Should we assume that the superiority of doxorubicin over paclitaxel in our study is because of the use of a
731
PACLITAXEL v DOXORUBICIN IN BREAST CANCER
higher dose of doxorubicin? The role of dose-intensity in
anthracycline-based therapy is still an open question. Several studies have shown that an increased dose of anthracycline per course correlates with a higher RR; however, only
a few of the studies were randomized, and they did not
demonstrate an impact of higher doses on time to progression.5,33-39
Doxorubicin 75 mg/m2 has been used as the control
arm of a phase III study in which metastatic breast cancer
patients, who failed an alkylating-containing regimen,
were randomized to receive either the doxorubicin treatment or docetaxel at the dose of 100 mg/m2 as a 1-hour
infusion every 3 weeks.40 Among 196 assessable patients, docetaxel showed a higher response rate than the
anthracycline. The results of that trial affect neither the
interpretation of our study (because we are dealing with
two different compounds and a different patient population) nor our conclusions. In fact, we do not believe that
the main issue in the future will be which drug, either the
anthracycline or the taxane, should be used as first-line
treatment but what will be the best way of administering
the two drugs together. The essential question to be
addressed, therefore, is whether it would be preferable to
combine reduced doses of paclitaxel and doxorubicin
within a combination regimen or to give each drug at full
dose in a sequential schedule. The American Intergroup
Trial has shown that the combination of doxorubicin and
paclitaxel 24-hour infusion is superior to both single
agents in terms of RR and median time to treatment
failure.27 Although very high remission rates were observed in pilot studies of paclitaxel given as a 3-hour
infusion plus doxorubicin, a surprisingly high incidence
of congestive heart failure was also reported.41,42 This
was unexpected in view of the lack of cardiotoxicity
reported in early studies with paclitaxel, in which only
anecdotal asymptomatic cardiac rhythm disturbances
were reported.43 Subsequent pharmacokinetic studies
provided a plausible explanation for this phenomenon,
suggesting a 30% increase in doxorubicin exposure when
given before paclitaxel.44,45
Recent data suggest that the combination is safe provided
that a total dose of 360 mg/m2 of doxorubicin is not
exceeded.46 A recently completed IDBBC-ECSG randomized study has compared the safety and efficacy of six
courses of doxorubicin 60 mg/m2 plus paclitaxel 175 mg/m2
(3-hour infusion) with a standard doxorubicin/cyclophosphamide combination. If the doxorubicin/paclitaxel combination proves superior to the control arm, single-agent paclitaxel could be offered as consolidation therapy to
responding patients.47 Gianni et al47 have evaluated the
cumulative response in 47 patients treated with doxorubicin
plus paclitaxel in a 3-hour infusion for six or eight cycles
followed by single-agent paclitaxel. Six treatment cycles
were sufficient to achieve at least a partial response in all the
responding patients, but continuing treatment with the
taxane after the combination increased the patients’ chances
of complete response.
The sequential administration of doxorubicin and paclitaxel is very attractive as a strategy for overcoming the
pharmacokinetic interaction between these two agents.
Moreover, the data presented by Henderson et al48 at the
American Society of Clinical Oncology in 1998 strongly
suggest the benefit of using paclitaxel in sequence with a
standard anthracycline-containing regimen in the adjuvant setting.48 At present, we can assert that single-agent
doxorubicin, given at the dose of 75 mg/m2 every 3
weeks, is more active in terms of RR and PFS than
paclitaxel 200 mg/m2 given as a 3-hour infusion every 3
weeks, as first-line treatment of metastatic breast cancer.
No matter what sequence doxorubicin and paclitaxel are
administered in, no total cross-resistance has been observed.
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