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2137
Response to Second-Line Chemotherapy in Patients
with Metastatic Breast Carcinoma Previously
Responsive to First-Line Treatment
Prognostic Factors
Bernard Brun, M.D.1
Mohamed Benchalal, M.D.2
Christelle Lebas, M.D.3
Pascal Piedbois, M.D.4
Ma Lin, M.D.3
Jean-Paul Lebourgeois, M.D.4
BACKGROUND. The aim of this retrospective study was to determine those prognos-
1
Cancer Department, University Hospital Pitie
Salpetriere, Paris, France.
2
Cancer Department, Centre Hospitalier Intercommunal, Montfermeil, France.
3
Statistics Department, University Hospital
Saint Louis, Paris, France.
4
Cancer Department, University Hospital Henri
Mondor, Creteil, France.
tic factors associated with response to a second-line chemotherapy in patients
with metastatic breast carcinoma (MBC) that was previously responsive to a firstline chemotherapy.
METHODS. The 70 MBC patients studied had previously responded to a first-line
chemotherapy, mainly anthracycline or anthracenedione-containing regimens.
During first-line chemotherapy they had received treatment until the maximum
response was obtained, at which time treatment was discontinued. Second-line
chemotherapy regimens were of several types (48.5% with anthracycline). A study
of prognostic factors associated with response to second-line chemotherapy was
performed by univariate and multivariate analysis.
RESULTS. Second-line chemotherapy achieved a 44% response rate, with a median
response duration of 10 months. Survival was 13 months in the entire patient
group, 22 months in responders, and 8 months in nonresponders. Univariate analysis identified seven factors related to patient response rate to second-line treatment. A better response rate to second-line chemotherapy was observed in patients
with the following features: 1) chemotherapy free time (time between onset of
metastatic disease and initiation of first-line) õ 12 months (P Å 0.03); 2) complete
response to first-line chemotherapy (P Å 0.013); 3) response duration to first-line
chemotherapy ú 14 months (P Å 0.0001); 4) progression free interval (time between
end of first-line treatment and initiation of second-line chemotherapy) ú 11
months (P Å 0.0001); 5) performance status at second-line treatment õ 2 (P Å
0.04); 6) tumor index at second-line chemotherapy õ 4 (P Å 0.05); and 7) treatment
with an anthracycline-containing second-line regimen (P Å 0.03). In multivariate
analysis, only progression free interval was identified as being associated with
response rate to second-line chemotherapy (P Å 0.0001).
CONCLUSIONS. Retained chemosensitivity appeared to be an important characteristic in patients responding to second-line chemotherapy. Cancer 1997;79:2137–46.
q 1997 American Cancer Society.
KEYWORDS: breast carcinoma, salvage, chemotherapy, chemosensitivity.
Address for reprints: Bernard Brun, M.D., Cancer Department, (Pr Baillet) Hopital Pitie-Salpetriere 47 Boulevard de l’hopital, 75013 Paris,
France.
Received November 4, 1996; revision received
January 22, 1997; accepted January 22, 1997.
I
n patients with metastatic breast carcinoma (MBC), combination
cytotoxic chemotherapy has been considered to constitute a major
therapeutic advance.1 – 5 Approximately 60% of all patients will have
an objective response,1 – 5 with subsequent palliation of symptoms,
and perhaps an improved survival,6 – 12 although this last point remains
controversial.3,13 – 15 However, most patients recur, with a median time
to progression ranging from 5 to 13 months.1,2 Investigations are on-
q 1997 American Cancer Society
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W: Cancer
2138
CANCER June 1, 1997 / Volume 79 / Number 11
going to improve these results, focusing in particular
on dose intensity,16 schedules,17 high dose chemotherapy,18 and the optimum duration of treatment.6,19 – 23
When disease is refractory to the delivered regimen or at second recurrence after response, patients
are often offered a ‘‘second-line’’ or ‘‘salvage’’ chemotherapy. This approach has yielded disappointing results in so far as only 33% of patients obtain a clinically
significant response. Henderson2 complained about
the rudimentary information available with regard to
prognostic factors related to response and survival in
this situation. Salvage chemotherapy may be given in
two distinct situations: in patients initially refractory
to combination chemotherapy and in patients who
recur after an initial response. Two subsets should also
be distinguished within the latter group: those who
recur during continuous chemotherapy and are therefore refractory to the on-going regimen and those who
recur after the discontinuation of a chemotherapy
schedule in whom a new treatment challenge may be
expected to be of value, possibly even using the same
regimen.
The authors performed a retrospective study restricted to the last subset of patients: MBC patients
who had responded to a first-line regimen, recurred
thereafter and received a second-line regimen. The
main purpose of this study was to identify the predictive factors statistically related to a response to salvage chemotherapy in this precise situation.
TABLE 1
Characteristics of the Study Cohort
Characteristics
No.
%
No. of patients entered
Excluded from analyses
Adjuvant chemotherapy
Previous endocrine therapy
First-line therapy containing anthracyclin
First-line therapy without anthracyclin
Alive at the end of follow-up
Follow-up (mos)
Median
Range
Age (yrs)a
Median
Range
Disease free interval (mos)
Median
Range
Chemotherapy-free time (? mos)
Median
Range
Sites of diseasea
Bone
Liver
Lung
Othersb
Tumor indexa
1
2
3
4
5
6
75
5
14
56
68
2
4
7
20
80
97
3
6
a
PATIENTS AND METHODS
b
Patient Population
Between 1979 and 1990, 231 women with MBC received first-line combination chemotherapy: 176 a
combination of 5-fluorouracil, doxorubicin, cyclophosphamide, and vincristine (FACV), 43 other anthracycline- or anthracenedione-containing regimens,
and 12 regimens without anthracycline. All patients
were treated according to the same general treatment
design. One hundred thirty-eight patients (59.7%) experienced a response; 134 of them recurred thereafter.
At their second recurrence, 75 women (54%) received
second-line chemotherapy. Five patients were excluded because of poor evaluation or incomplete
treatment records. Thus, 70 patients could be fully
assessed for the current study. Their baseline characteristics are summarized in Table 1. MBC was defined
on the basis of both previous biopsy-proven adenocarcinoma of the breast and evidence of metastatic disease. Patients who had received prior endocrine therapy, either as adjuvant treatment or for the treatment
of MBC, were also eligible.
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100
(12–172)
48
(28–67)
39
(0–240)
1
(0–109)
55
28
14
24
79
40
20
34
2
14
17
26
9
2
3
20
24
37
13
3
At the time of second-line chemotherapy.
Soft tissue, brain, and skin.
Evaluation
Pretreatment evaluation included a physical examination with tumor measurements, chest X-ray and/or
chest computerized tomography (CT), bone scintiscan
and bone X-ray, liver echogram or CT scan, complete
blood cell counts, serum creatinine, baseline liver
chemistry, and determination of carcinoembryonic
antigen (CEA) and CA 15-3 when available. This evaluation was repeated every 3 months.
When metastatic sites were measurable, tumor response was evaluated according to the International
Union Against Cancer criteria.24 In patients with no
measurable disease, response was assessed on the basis of the summary of Miller et al. of World Health
Organization recommendations.25 Complete response
(CR): complete disappearance of all known disease for
at least 4 weeks; partial response (PR): estimated decrease in tumor size of ¢50% for at least 4 weeks; and
no change: no significant change for at least 4 weeks.
W: Cancer
Breast Carcinoma Salvage Chemotherapy/Brun et al.
This includes stable disease (SD), an estimated decrease of õ50%, and lesions with an estimated increase of õ25%; and progressive disease (PD): the appearance of any new lesions not previously identified,
or an estimated increase of ¢25% in known lesions.
A separate set of response criteria were necessary for
bone metastases: CR: complete disappearance of all
lesions on X-ray or scan for at least 4 weeks; PR: partial
decrease in size of lytic lesions, recalcification of lytic
lesions, or decreased density of blast lesions for at least
4 weeks; NC: because of the slow response of bone
lesions, the designation of no change was not be applied until at least 8 weeks elapsed from start of therapy; and PD: increase in size of known lesions or appearance of new lesions. A recurrence was indicated
by the appearance of new lesions, the recurrence of
old lesions, or a 25% increase in the size of lesions
over that observed at the time of maximum regression.
These criteria were used to assess both first-line and
second-line responses.
Characteristics of Chemotherapy
The chemotherapy regimens used are listed in Table
2. The chemotherapy regimens employed as first-line
treatment were FACV or slight variations of this schedule if: 1) the patients had received no prior adjuvant
chemotherapy at all; 2) the patients had received adjuvant chemotherapy without anthracycline; or 3) the
patients had received adjuvant chemotherapy with anthracycline, but the interval between the completion
of adjuvant chemotherapy and the onset of metastatic
disease was longer than 1 year. In other cases, the
chemotherapy regimen did not include anthracyclines. Second-line chemotherapy regimens included
several programs described in Table 2. Thirty-four patients received as second-line treatment an anthracycline or anthracenedione-containing regimens (Table
3). The choice between these regimens was made
without specific guidelines but on the basis of the patient status, previous total dose of doxorubicin limited
to 450 mg/m2 , and previous duration of response. In
patients with a previous response of long duration, the
same regimen as that used in the first-line treatment
(mainly FACV) was often, but not systematically, employed.
In all cases, both for first-line and second-line chemotherapy, treatment duration was decided according
to sequential evaluations. Response was assessed after
three courses of chemotherapy. The same treatment
was continued for three additional courses if at least
a PR was demonstrated. Treatment was only pursued
3 months later if an objective improvement was
achieved by comparison with previous assessment.
Otherwise, chemotherapy was discontinued.
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2139
Prognostic Characteristics
Using the data collected prior to salvage chemotherapy, the authors studied the predictive value of several
baseline characteristics for second-line response: demographic data (age at start of second-line chemotherapy), extent of disease, and types of therapy. These
characteristics were assessed: 1) before the onset of
metastatic disease (previous adjuvant chemotherapy,
previous adjuvant endocrine therapy); 2) at the time of
first-line chemotherapy (metastatic disease sites [five
sites of tumor involvement were recorded: bone, liver,
lung, pleura, and others]); tumor mass (it was scored
according to an arbitrary tumor index, which was calculated as follows: for each common site of involvement [i.e., bone, lung and pleura, liver, pelvis, and soft
tissues], the number of lesions was noted as 0 Å no
lesion, 1 Å 1 lesion, or 2 Å ¢2 lesions; the sum of all
recorded involved sites was the tumor index); type
of regimen; dose intensity; number of cycles; level of
response; and duration of response; 3) at the initiation
of salvage therapy (metastatic; sites, performance status, change of metastatic pattern, CEA and CA 15-3,
and tumor index), and 4) time intervals: disease free
interval (time between primary carcinoma diagnosis
and onset of metastatic disease); chemotherapy free
time (defined as the time interval between diagnosis
of metastatic disease and the initiation of first-line
chemotherapy); and progression free interval (defined
as the time from the end of first-line chemotherapy to
the onset of disease progression).
Statistical Analysis
Analysis was based on a reference date of January
1995. Overall survival from the initiation of first-line
chemotherapy and salvage chemotherapy was estimated using the Kaplan – Meier method.26 Patient
characteristics were evaluated for their prognostic
value by determining the response rate associated with
each characteristic. P values were determined using
the chi-square or Fisher’s exact tests to compare response rates. Continuous variables were categorized
according to the median value computed on the entire
sample. Second, variables found to be associated with
outcome at the 5% level, and that influenced the response rate, were simultaneously introduced into a
logistic regression model. A step-down procedure allowed the iterative selection of variables significantly
related to the occurrence of remission, as tested by
the likelihood ratio test. Levels of significance were
represented by P values derived from two-sided tests.
A P value of °0.05 was considered to indicate statistical significance. Statistical analyses were performed
using the SAS (Statistical Analysis System, Inc., Carey,
NC) and BMDP (Biomedical Computers Programs,
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2140
CANCER June 1, 1997 / Volume 79 / Number 11
TABLE 2
Chemotherapy Regimens Used as First-Line and Second-Line Treatment
Regimens
FACV
Day 1
Day 2
Days 3, 4, and 5
Days 3, 4, and 5
FEC
Day 1
FNC
Day 1
FIP
EeVCM
VBM
FUC
VMFM
Days 1 and 14
Days 1, 2, and 3
Days 1, 2, and 3
Days 1 and 14
Days 2 and 15
Days 1–5
Days 1–14
Days 1 and 14
Days 1–7
Days 1, 3, 5, 7, and 9
Days 1–21
Day 1
Day 2
Day 3 and 4
Day 3 and 4
Drugs
Doses
Route
Doxorubicin
Vincristine
Cyclophosphamide
5-fluorouracil
Epiadriamycin
Cyclophosphamide
5-fluorouracil
Mitoxantrone
Cyclophosphamide
5-fluorouracil
Cisplatin
Ifosfamide
5-fluorouracil
Ellipticinium
Methotrexate (/folinic acid)
Etoposide
Chlorambucil
Vinblastine
Methotrexate
Bleomycin
5-fluorouracil
(continuous infusion)
Teniposide
Mitomycin-C
5-fluorouracil
Methotrexate
45 mg/m2
1.4 mg/m2
350 mg/m2
500 mg/m2
60 mg/m2
600 mg/m2
750 mg/m2
12 mg/m2
600 mg/m2
600 mg/m2
60 mg/m2
1500 mg/m2
500 mg/m2
120 mg/m2
350 mg/m2
100 mg
4 mg
5 mg/m2
5 mg/m2
5 mg/m2
250 mg/m2
IV
IV
IV
IV
IV
IV
IV
IV
IV
IV
IV
IV
IV
IV
IV
Oral
Oral
IV
Oral
SC
IV
60 mg/m2
10 mg/m2
500 mg/m2
10 mg/m2
IV
IV
IV
IV
Others
Schedule
(weeks)
No. used at
first-line
No. used at
second-line
4
60
24
4
6
3
4
4
4
1
4
4
0
13
4
0
8
4
0
6
4
0
3
1
2
3
IV: intravenous; SC: subcutaneous; FACV: doxorubicine, vincristine, cyclophosphamide, and 5-fluorouracil; FEC: epiadriamycin, cyclophosphamide, and 5-fluorouracil; FNC: mitoxantrone, cyclophosphamide, and
5-fluorouracil; FIP: cisplatin, ifosfamide, and 5-fluorouracil; VBM: vinblastine, methotrexate, and bleomycin; EeVCM: ellipticine, methotrexate, etoposide, and chlorambucil; VMFM: teniposide, mitomycin-C, 5fluorouracil, and methotrexate; FUC: 5-fluorouracil (continuous infusion).
University of California, Los Angeles, CA) statistical
software packages.
RESULTS
Seventy evaluable patients, who achieved a PR or CR
to first-line chemotherapy for the treatment of MBC,
experienced a recurrence and received second-line
chemotherapy (Table 1). At the initiation of first-line
cytotoxic chemotherapy, 14 patients (20%) had received prior adjuvant chemotherapy, and 56 (80%) had
received prior endocrine therapy. Endocrine therapy
was given as adjuvant therapy in 23 patients, and 33
received it as treatment for metastatic disease (10 had
been responders to this treatment). The disease free
interval ranged from 0 to 240 months (median, 39
months). The chemotherapy free time ranged from 0
to 77 months (median, 1 month). Bone, liver, lung,
and soft tissue involvement was observed in 74%, 27%,
20%, and 37% of patients, respectively. The tumor index score was 1, 2, or 3 in 66%, and 4, 5, or 6 in 34%
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of patients. First-line chemotherapy contained anthracycline (N Å 64), or anthracenedione (N Å 4), and a
regimen without anthracycline or anthracenedione
was given to 2 patients. Patients received between 4
to 19 cycles (median, 6 cycles) (Table 4). Thirteen patients (19%) experienced a CR, and 57 patients (81%)
a PR (Table 4). Duration of response ranged from 4 to
118 months (median, 12 months). The CR duration
(range, 10 – 118 months; median, 55 months) was significantly better than the PR duration (range, 4 – 60
months; median 12 months) with P value õ0.001.
At initiation of second-line chemotherapy, the
median age was 48 years (range, 28 – 67 years); the
tumor index was 1, 2, or 3 in 47%, and 4, 5, or 6 in
53% of patients. Bone, liver, lung, and soft tissue
involvement was observed in 78%, 40%, 20%, and 34%
of patients, respectively. A change in the metastatic
pattern had occured in 18 patients (26%). The performance status was 1 in 22 patients (31%), and 2 or ú2
in 47 patients (67%). Progression free intervals ranged
W: Cancer
Breast Carcinoma Salvage Chemotherapy/Brun et al.
2141
TABLE 3
Results of Second-Line Treatment According to Chemotherapy Regimens
Regimens
Regimens with
anthracycline or
anthracedione
FACV
FEC
FNC
Regimens without
anthracycline or
anthracedione
FIP
VBM
EeVCM
VMFM
FUC
Others
No.
CR
34
24
6
4
0
2
0
36
4
8
13
3
6
2
0
0
0
0
0
0
0
CR duration
(mos)
range
PR duration (mos)
24,22
PR
Median
Mean
Range
Overall
response
%
14
2
2
8
9,5
6–18
9,29
10,21
58
66
50
6
6–18
12
8–39
0
12,5
38
33
66
0
1
5
1
4
0
CR: complete response, PR: partial response; FACV: doxorubicin, vincristine, cyclophosphamide, and 5-fluorouracil; FEC: epiadriamycin, cyclophosphamide, and 5-fluorouracil; FNC: mitoxantrone, cyclophosphamide, and 5-fluorouracil; FIP: cisplatin, ifosfamide, and 5-fluorouracil; VBM: vinblastine, methotrexate, and bleomycin; EeVCM: ellipticine, methotrexate, etoposide, and chlorambucil; VMFM: teniposide, mitomycinC, 5-fluorouracil, and methotrexate; FUC: 5-fluorouracil (continuous infusion).
TABLE 4
Results of First-Line Regimens
CR duration
(mos)
PR duration
(mos)
First-line regimens
No.
CR
õ14
¢14
Median
Mean
Range
PR
õ14
¢14
Median
Mean
Range
FACV
FEC
FNC
Neither anthracycline
nor anthracenedione
60
4
4
13
0
0
1
12
55
56
10–118
47
4
4
26
4
3
21
0
1
12
16,5
6–60
6–10
6–15
2
0
2
2
12,36
CR: complete response; PR: partial response; FACV: doxorubicin, vincristine, cyclophosphamide, and 5-fluorouracil; FEC: epiadriamycin, cyclophosphamide, and 5-fluorouracil; FNC: mitoxantrone, cyclophosphamide, and 5-fluorouracil.
from 1 to 109 months (median, 11 months). The number of second-line cycles ranged from 2 to 32 (median,
3). A response to second-line chemotherapy (Table 3)
was achieved in 31 patients (44%) with a CR in 3%.
Of the 36 patients (51.4%) retreated with a regimen
without anthracycline or anthracenedione, 11
achieved a PR, and 25 experienced no response.
Thirty-four patients (48.6%) were treated with an anthracycline-containing regimen, with 2 patients
achieving a CR, 18 patients a PR, and 14 no response.
The duration of response to second-line chemotherapy ranged from 2 to 39 months (median, 10 months).
The follow-up period ranged from 12 to 172 months
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(median, 100 months). Table 5 shows different subgroups according to the patterns of response to firstline chemotherapy. A trend toward an increased response rate to second-line therapy was apparent for
patients treated with anthracycline regimens, and patients with CR at first-line chemotherapy. Response
duration was not statistically different between these
subgroups.
The authors selected 31 variables and studied their
relationship to the response to salvage chemotherapy
using univariate analysis. These variables could be divided in two groups. The first group included data
available at the time of first-line chemotherapy (previ-
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CANCER June 1, 1997 / Volume 79 / Number 11
TABLE 5
Second-Line Response According to Patterns of First-Line Therapy
Response duration (mos)
Patterns of response to
first-line therapy
No.
Retreatment regimens
No.
Response
%
Median
Mean
Range
CR ¢ 14
12
7
3
0
88
75
0
17
7–29
10,14,39
1
PR ¢ 14
23
FACV regimen
60
56
43
44
20
61
31
10
34
10
12
13
15
6–18
8,12,25
6,10,11,12
6,6,8,8,12
6–29
6–39
FEC or FNC regimens
8
9
3
4
5
19
9
0
1
9
PR õ 14
8
4
1
0
16
7
9
25
31
29
1
7
21
CR õ 14
With anthracycline
Without anthracycline
With anthracycline
Without anthracycline
With anthracycline
Without anthracycline
With anthracycline
Without anthracycline
With anthracycline
Without anthracycline
With anthracycline
Without anthracycline
14
8
With anthracycline
Without anthracycline
1
1
0
1
Regimens without
anthracycline or
anthracenedione
2
8
CR: complete response; PR: partial response; FACV: doxorubicin, vincristine, cyclophosphamide, and 5-fluorouracil; FEC: epiadriamycin, cyclophosphamide, and 5-fluorouracil; FNC: mitoxantrone, cyclophosphamide, and 5-fluorouracil.
ous treatment, clinical data, and time intervals). The
second group included data available at the time of
second-line chemotherapy (clinical data, results of
first-line chemotherapy, and time intervals).
Disease free interval, previous adjuvant chemotherapy, previous endocrine therapy, previous response to endocrine therapy, dose intensity, number
of cycles under first-line chemotherapy, changes in
the metastatic pattern, CEA, CA 15-3, metastatic sites,
and the tumor index at first-line chemotherapy were
not associated with response to salvage chemotherapy
by univariate analysis.
Seven variables (Table 6) were statistically related
to response (P õ 0.05). Chemotherapy free time õ 12
months (P Å 0.03), CR to first-line chemotherapy (P
Å 0.013), response duration to first-line chemotherapy
ú 14 months (P Å 0.0001), progression free interval ú
11 months (P Å 0.0001), performance status õ 2 at
salvage chemotherapy (P Å 0.04), tumor index õ 4
at second-line chemotherapy (P Å 0.05), and salvage
chemotherapy with anthracycline (P Å 0.03), were all
associated with a higher response rate to second-line
chemotherapy. Progression free intervals and response rates to salvage chemotherapy were statistically linked in patients retreated with a regimen regardless of whether or not it contained anthracycline
(P Å 0.045, and P Å 0.01, respectively). A multivariate
analysis was performed on these seven variables. Only
the progression free interval was statistically relevant
for predicting salvage response (P Å 0.0001). No addi-
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tional predictive information could be obtained from
the six remaining variables. Thus no predictive logistic
model was available by statistical analysis. However,
a correlation was demonstrated between the number
of poor prognostic factors and the response rate to
second-line treatment. In the patients whose number
of poor prognostic factors were 0, 1 – 2, 3 – 4, and 5 – 7,
respectively, the response rates were. 4 of 4 (100%),
16 of 24 (67%), 9 of 21 (43%), and 2 of 21 (10%), respectively (P Å 0.0016).
By the time the reference date was reached, 66
patients had died and 4 were alive. Median survival
from the initiation of salvage chemotherapy was 13
months for the whole group. Median survival times
for responders (CR or PR) and nonresponders (SD or
PD) were 22.3 months and 8.1 months, respectively.
These differences in survival distribution were statistically significant (P Å 0.0001). Median survival from the
initiation of first-line chemotherapy was 60 months
in patients responsive to the salvage regimen, and 28
months in patients with refractory disease (P Å
0.0001).
DISCUSSION
Standard dose chemotherapy regimens in previously
untreated patients produced a 40 – 75% objective response rate and a median duration of response of 5
to 13 months.1,2 However MBC virtually always recurs,
and despite optimistic reports,7,8 a beneficial effect on
survival is still controversial.3 To improve these results,
W: Cancer
Breast Carcinoma Salvage Chemotherapy/Brun et al.
2143
TABLE 6
Univariate Statistical Analysis
Prognostic factors at first-line treatment
Chemotherapy-free time (mos)
ú12
õ12
Response
Complete response
Partial response
Response duration (mos)
õ14
ú14
Progression-free interval (mos)
õ11
ú11
Prognostic factors at second-line treatment
Performance status
1
2,3
Tumor index (at second-line treatment)
1,2,3
4,5,6
Type of salvage therapy
No anthracycline
Anthracycline
a
b
No. patients
No. responses
Response
rate %
29
41
8
23
28
56
13
57
10
21
77
37
P valuea
0.03
0.013
0.0001b
36
34
9
22
25
65
36
34
6
25
17
74
22
47
14
16
64
34
33
37
19
12
58
32
36
34
11
20
31
59
0.0001
0.04
0.05
0.03
Based on chi-square test and Fisher’s exact test.
Based on Wilcoxon signed rank test.
recent research has focused on four points. 1) The
search for new agents. Several promising agents have
demonstrated significant clinical activity, such as epirubicin,27 platinum analogs,28 vinorelbine,29 taxoids:
paclitaxel,30 and docetaxel31 ; 2) schedule has been systematically studied. Blomquist et al.17 suggested the
superiority of a 4-week schedule compared with a
weekly schedule; 3) duration of therapy: Several randomized studies have suggested that prolonging therapy may delay recurrence,6,20,22,23 and thus improve
quality of life, although overall length of survival is
probably only marginally improved; 4) high dose intensity16,18,32 – 34 and high dose chemotherapy18,35 – 38
have been extensively investigated, especially with the
systematic use of stem cell support.39 It is commonly
admitted that patients with advanced refractory disease are unlikely to benefit from high dose chemotherapy. However, high dose chemotherapy after a good
response to standard dose therapy yields a CR rate
substantially higher than the 10 – 20% reported with
standard dose therapy.40 A recent randomized study
described a benefit on both response and survival.41
Points 3 and 4 outline the same idea: the role of more
chemotherapy after a response. Consequently, it
would be useful to know which patients may benefit
from more chemotherapy. The current study was
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based on this question, because a response to retreatment after a previous response may demonstrate
retained chemosensitivity. The authors investigated
whether this persistent chemosensitivity could be predicted from the clinical features of patients. The current study focused on a selected series of patients homogeneously treated until maximum response and retreated when they recurred after an interruption of
treatment. Prognostic factors related to response to
second-line treatment were mainly features available
at the time of second-line therapy. Only one factor
chemotherapy free time, was a feature available at the
time of first-line treatment, and its significance is
doubtful. Thus, if the six second-line factors may permit prediction of the ability of patients to respond to
second-line therapy, nothing at the time of first-line
treatment could be detected to predict long term chemosensitivity.
The authors were unable to find any study in the
literature devoted to this subject. Retreatment of patients recurring after a previous response11,23,42 – 46 has
been studied in few articles. The numbers of patients
in these series ranged from 25 to 70. The response rate
ranged from 6.5%23 to 40%.11 The duration of response
ranged from 2.5 months to 37.9 months.11 No systematic analysis of prognostic factors was attempted in
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these articles. However, Hart et al.42 noted a relationship between the first-line tretment response and second-line treatment response. Gregory et al.43 found a
higher response rate to second-line treatment in patients with a previous CR. In a subset of patients with
a previous CR Decker et al. found a 40% response
rate and impressive durations of response.11 Ro et al.44
studied 39 patients previously responsive to doxorubicin, who were retreated at recurrence with doxorubicin and experienced a 28% response rate with a median survival of 17 months in responders. These findings are quite similar to those in the current study.
Many authors have studied prognostic factors in patients receiving first-line chemotherapy for MBC.9,43,46–53
Many factors related to response rate and survival
were identified. These factors could be considered to
be of four types: 1) indicators of tumor growth (disease
free interval, initial features of primary tumor, and
biologic properties of the tumor); 2) measurement of
tumor mass (tumor index,9,49 number of sites,48,50,51
liver involvement,43,46,48,50 performance status, and biologic parameters); 3) disabling factors (previous chemotherapy, previous radiotherapy, and performance
status); and 4) type of treatment. These studies were
mainly focused on response rate and survival; the
search for predictive factors related to the duration
of response were not a major endpoint. However an
increased duration of response was described in older
patients,48 in patients with no lymph node, lung, or
liver involvement,48 in patients with a long disease free
interval,50 in patients with a good performance status,50 in patients with few disease sites,50 in patients
receiving an anthracycline regimen,50 and the achievement of a CR.48 Patients with factors predicting long
response duration to first-line chemotherapy may be
thought to be candidates to further retained chemosensitivity. The main factors identified in the current
study (CR, response duration, and progression free interval) are obviously linked and are indicators of retained chemosensitivity. However, in the current
study, factors predicting long first-line response duration were not found to be related to second-line response. Therefore, it appears that retained chemosensitivity cannot be fully known in a first-line context
and appears to be an independent factor. The ability
of the patients in the current study to respond to a
second chemotherapy course appeared to be mainly
(if not solely) linked to this factor.
The authors’ observation could be helpful in two
respects: 1) the decision to retreat a patient recurring
after a response, according to the number of poor
prognostic factors; and 2) the selection of patients
when a new drug is offered for evaluation. In several
recent and major studies dealing with new agents, pa-
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05-05-97 13:23:24
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tients were described as having received only one regimen, either as adjuvant therapy or for metastatic disease, without available documentation concerning
their previous response and its duration.29,30 The current extensive use of high dose chemotherapy draws
attention to the question of retained chemosensitivity.
One of the purposes of the current study was to detect
factors related to long term chemosensitivity available
at the time of first-line chemotherapy, but none was
found and consequently, the current study offers no
guideline for the selection of patients likely to benefit
from high dose chemotherapy. In two series of patients with documented chemosensitivity, who were
treated with high dose chemotherapy,54,55 the prognostic factors associated with progression free survival
were a CR to induction chemotherapy, few disease
sites, the absence of soft tissue or liver metastases, and
a long disease free interval. Evidently, these factors
offer little benefit in the selection of patients. There is
a need for a better definition, either clinical or biological, of the chemosensitivity parameter that may be of
major importance in the selection of patients likely to
benefit from high dose chemotherapy.
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