ADVANCED BREAST CANCER
What's new about management of patients with advanced breast cancer?
PIOGLITAZONE MAY INHIBIT EARLY ATHEROSCLEROTIC LESIONS IN TYPE 2 DIABETES
Pioglitazone decreases intima-media thickness (IMT) of the common carotid artery,
Japanese investigators report, and thereby may inhibit the early atherosclerotic
process in type 2 diabetes.
A systematic review of chemotherapy trials in several tumour types was performed
by The Swedish Council of Technology Assessment in Health Care (SBU). The procedures
for the evaluation of the scientific literature are described separately (Acta
Oncol 2001; 40: 155-65). This synthesis of the literature on chemotherapy for
breast cancer is based on 233 randomised studies, 9 meta-analysis of randomised
studies, a population-based cohort study and 18 overviews/retrospective analyses
including a total of 155,243 patients. The conclusions reached can be summarised
into the following points:
Adjuvant Treatment -- There is solid scientific support from
randomised studies that adjuvant polychemotherapy at 10 years will result in an
absolute mortality reduction for patients younger than 50 years by 12% for node
positive (34% relative mortality reduction corresponding to an estimated median
survival prolongation of several years) and 6% for node negative patients. For
women aged 50 to 69 years, the corresponding figures for node positive and node
negative patients are 6% and 2%, respectively (approximately 11% relative mortality
reduction). Anthracycline-containing combinations result in an absolute survival
benefit at five years of 3%, compared with non-anthracycline based polychemotherapy.
There are indications that the taxane paclitaxel may further improve the survival
compared with anthracyclines. However, the limited data preclude conclusions for
the routine care. The addition of tamoxifen to chemotherapy further enhances the
survival benefit for receptor positive subgroups. The roles of more dose-intensive
regimens, including high-dose therapy with stem cell support, are presently studied
in randomised investigations. The data presented so far are conflicting but they
do not in general support high-dose therapy. Quality of life, based on analyses
of randomised studies, demonstrate that adjuvant polychemotherapy has an initial
detrimental effect, but long-term follow-up of treated patients demonstrates no
impairment of quality of life compared with untreated patients. Polychemotherapy
in standard doses should be offered to premenopausal node positive patients, and
the corresponding postmenopausal group with a receptor-negative breast cancer
and to node negative patients with high risk factors. Polychemotherapy should
be combined with tamoxifen to all patients with receptor-positive tumours. Due
to a need of more knowledge in this field, patients should be included in investigational
protocols. Locally advanced breast cancer-- Based on current knowledge, treatment
of patients with locally advanced breast cancer should include neoadjuvant/preoperative
polychemotherapy since there is evidence from controlled studies that such therapy
will statistically significantly increase the number of patients who can be offered
breast-conserving surgery. Indirect comparisons also demonstrate survival improvements,
but the scientific support is equivocal.
Metastatic Breast Cancer -- The median survival for patients
with metastatic disease treated with conventional chemotherapy doses and regimens
is 12 to 24 months. Retrospective cohort studies indicate that the use of non-anthracycline
containing chemotherapy compared with no chemotherapy might add a survival gain
of six to nine months. However, this estimation is based on equivocal data. Based
on overview data, polychemotherapy results in a statistically significant survival
gain compared with single-agent therapy. Based on repeated randomised studies,
the addition of anthracyclines increases the response rate and statistically significantly
improves the survival compared with non-anthracycline containing chemotherapy,
except for CMF combined with prednisone/prednisolone, which will statistically
significantly improve the survival compared with some anthracycline combinations.
Second line therapy using vinorelbine or docetaxel is statistically significantly
better than other regimens with a time to progression and survival benefit in
the order of one to three months based on few randomised studies. The role, if
any, of third line therapy is yet to be demonstrated. In the metastatic setting,
conventional chemotherapy improves the quality of life. In standard care, first
line therapy should contain an anthracycline and second line therapy using vinorelbine
or docetaxel could be offered to selected patients failing first line therapy.
Based on numerous randomised studies, breast cancer demonstrates a positive dose-response
relationship both in the adjuvant situation and for metastatic disease. However,
in the conventional dose-range there seems to be a plateau in the dose-response
curve, with no further survival gains.
Effects of High-Dose Chemotherapy and SCT on Quality of Life
Carlson LE, Koski T, Gluck S. Bone Marrow Transplant 2001;27:989-998
This study determined the effects of high-dose chemotherapy (HDCT) with autologous
blood stem cell transplantation (ASCT) on quality of life (QL) in women with metastatic
breast cancer prior to, and during treatment, and up to 1-year post-ASCT. Thirty-three
women diagnosed with metastatic breast cancer participated in a phase 1 clinical
trial of a new combination of cyclophosphamide (CTX) and mitoxantrone (MXT), with
dose escalation of paclitaxel. Longitudinal QL data were collected using the functional
living index-cancer (FLIC) and symptom scales at seven time periods: pre-induction
chemotherapy (CT), post-induction CT, post-high dose CT (HDCT), and at 3, 6, 9
and 12 months post-ASCT. FLIC scores indicated that the worst problems for patients
were feelings of hardship on themselves and their families, followed by psychological
functioning and physical functioning problems. The time around diagnosis of the
metastatic disease and following HDCT were the worst times for all levels of quality
of life, but anxiety and depression symptoms continued to increase in severity
across the entire follow-up period. The symptoms that were most problematic were
worry about the future, loss of sexual interest, anxiety about the treatment,
general worrying, and joint pain. These data highlight the problems that women
with metastatic breast cancer encounter at different stages of the disease and
treatment process, and can be used to tailor psychosocial interventions appropriate
for treating the relevant issues at different points in time.
Sequential Administration of Docetaxel and Doxorubicin/Cyclophosphamide
Khayat D, Chollet P, Antoine EC, et al. J Clin Oncol 2001;19:3367-3375
Purpose: To evaluate the feasibility and efficacy of a sequential
administration of four cycles of docetaxel (100 mg/m(2) every 3 weeks) followed
by four cycles of doxorubicin and cyclophosphamide (AC; 60/600 mg/m(2) every 3
weeks), with subsequent consolidation with docetaxel or AC, as first-line chemotherapy
in patients with metastatic breast cancer (MBC).
Patients and Methods: Forty-eight patients received 443 cycles
of chemotherapy (median, 11 cycles/patient; range, 1 to 13 cycles). A total of
267 cycles of docetaxel (60.3%) and 176 of AC (39.7%) were given. Consolidation
therapy was given to 33 patients (29 with docetaxel).
Results: Grade 4 neutropenia was the most frequent toxicity (83%
of patients). This was not cumulative and was rarely complicated by febrile neutropenia
or severe infection. The nonhematologic safety profile was favorable: there were
no grade 4 adverse events, and grade 3 episodes were infrequent. Docetaxel-specific
toxicities were generally not severe. With a median cumulative doxorubicin dose
of 397 mg/m(2) (range, 150 to 543 mg/m(2)), two incidences of unrelated congestive
heart failure after further treatment with anthracyclines and two of asymptomatic
left ventricular ejection fraction decrease were observed. Among the 42 assessable
patients, five (12%) had complete and 25 (60%) had partial responses, for an overall
response rate of 71% (95% confidence interval, 55% to 84%). Median duration of
response was 53 weeks (range, 12 to 72 weeks), and median time to progression
was 46 weeks (range, 3 of 72 weeks). With a median follow-up of 40.4 months, median
survival was 32 months (range, 2 to 55 months). Conclusion: This docetaxel-based sequential schedule is safe
and effective in first-line therapy for MBC, without incurring cumulative toxicity,
and provides a feasible chemotherapeutic option in this clinical setting.
Weekly Trastuzumab and Paclitaxel for Metastatic Breast Cancer
Purpose: This phase II study evaluated weekly trastuzumab and
paclitaxel therapy in women with HER2-normal and HER2-overexpressing metastatic
breast cancer. Efficacy was correlated with immunohistochemical and fluorescent
in situ hybridization (FISH) assay results.
Patients and Methods: Eligible patients had bidimensionally measurable
metastatic breast cancer. Up to three prior chemotherapy regimens, including prior
anthracycline and taxane therapy, were allowed. Trastuzumab 4 mg/kg and paclitaxel
90 mg/m2 were administered on week 1, with trastuzumab 2 mg/kg and paclitaxel
90 mg/m2 administered on subsequent weeks. HER2 status was evaluated using four
different immunohistochemical assays and FISH.
Results: Patients received a median of 25 weekly infusions (range,
one to 85 infusions). Median delivered paclitaxel dose-intensity was 82 mg/m2/wk
(range, 52 to 90 mg/m2/wk). The intent-to-treat response rate for all 95 patients
enrolled was 56.8% (95% confidence interval, 47% to 67%). A response rate of 61.4%
(4.5% complete response, 56.8% partial response) was observed in 88 fully assessable
patients. In patients with HER2-overexpressing tumors, overall response rates
ranged from 67% to 81% compared with 41% to 46% in patients with HER2-normal expression
(ranges reflect the different assay methods used to assess HER2 status). Differences
in response rates between patients with HER2-overexpressing tumors and those with
normal HER2 expression were statistically significant for all assay methods, with
CB11 and TAB250 antibodies and FISH having the strongest significance. Therapy
was generally well tolerated, although three patients had serious cardiac complications.
Conclusion: Weekly trastuzumab and paclitaxel therapy is active
in women with metastatic breast cancer. Therapy was relatively well tolerated;
however, attention to cardiac function is necessary.
Clinical Activity of Trastuzumab and Vinorelbine in HER2+ Tumors
Burstein HJ, Kuter I, Campos SM, et al. J Clin Oncol 2001;19:2722-2730
Purpose: To determine the response rate and toxicity profile
of trastuzumab administered concurrently with weekly vinorelbine in women with
HER2-overexpressing advanced breast cancer.
Patients and Methods: Forty women with HER2-positive (+3 by immunohistochemistry,
n = 30; +2 or positive, n = 10) breast cancer were enrolled onto a study of trastuzumab
(4 mg/kg x 1, 2 mg/kg weekly thereafter) and vinorelbine (25 mg/m2 weekly, with
dose adjusted each week for neutrophil count). Eighty-two percent of women had
received prior chemotherapy as part of adjuvant (30%), metastatic (25%), or both
(28%) treatment, including substantial portions of patients who had previously
received either anthracyclines (20%), taxanes (15%), or both types (38%) of chemotherapy.
Results: Responses were observed in 30 of 40 patients (overall
response rate, 75%, conditional corrected 95% confidence interval, 57% to 89%).
The response rate was 84% in patients treated with trastuzumab and vinorelbine
as first-line therapy for metastatic disease, and 80% among HER2 +3 positive patients.
High response rates were also seen in women treated with second- or third-line
therapy, and among patients previously treated with anthracyclines and/or taxanes.
Combination therapy was feasible; patients received concurrent trastuzumab and
vinorelbine in 93% of treatment weeks. Neutropenia was the only grade 4 toxicity.
No patients had symptomatic heart failure. Grade 2 cardiac toxicity was observed
in three patients. Prior cumulative doxorubicin dose in excess of 240 mg/m2 and
borderline pre-existing cardiac function were associated with grade 2 cardiac
Conclusion: Trastuzumab in combination with vinorelbine is highly
active in women with HER2-overexpressing advanced breast cancer and is well tolerated.
Paclitaxel and Gemcitabine as Salvage Treatment?
Murad AM, Guimaraes RC, Aragao BC, et al. Am J Clin Oncol 2001;24:264-268
The purpose of this study was to evaluate gemcitabine plus paclitaxel in heavily
pretreated patients with metastatic breast cancer (MBC). Patients with MBC with
second or third relapse to anthracycline-containing regimens received a 3-hour
infusion of paclitaxel 175 mg/m2 on day 1, and gemcitabine 1.0 g/m2 on days 1,
8, and 15, every 28 days. Because of unacceptable thrombocytopenia seen in the
first 5 patients, the gemcitabine schedule was changed to days 1 and 8 (G-1,8)
for the remainder of the study, every 21 days. Twenty-nine patients (median age,
46 years; range, 32-68 years) received 137 cycles (median: 4 per patient). The
regimen was well tolerated. World Health Organization grades III and IV thrombocytopenia
were observed in 5 (18.5%) of the first 27 cycles (G-1,8,15), and in 6 (5.4%)
of the 110 subsequent cycles (G-1,8)--p = 0.04 for the difference between schedules.
Five patients had grade I and two had grade III neuropathy. Eight patients had
grade III neutropenia, two had grade IV neutropenia associated with fever (G-1,8,15),
and eight had grades I and II myalgia and fatigue. There were 16 (55%) objective
responses (95% CI 36-73%); 5 (17%) complete responses, 11 (38%) partial responses
(95% CI 3-30% and 19-56%, respectively), and 6 (20.5%) patients with stable disease.
Median response duration was 8 months (range, 4-26 months). Median overall survival
was 12 months (range, 4-28+ months), and 1-year and 2-year survival rates were
45% and 30%, respectively. This phase II study demonstrated a manageable toxicity
profile with the gemcitabine day 1, 8 schedule in combination with paclitaxel
and significant and promising activity in heavily pretreated patients with MBC.
A confirmatory phase III trial is warranted.
Pemetrexed Disodium for Recurrent or Metastatic Breast Cancer?
Miles DW, Smith IE, Coleman RE, Calvert AH, Lind MJ. Eur J Cancer 2001;37:1366-1371
A phase II study was conducted to evaluate the activity of pemetrexed in patients
with locally recurrent or metastatic breast cancer. 38 patients, median age 52
years (range 36-71 years), were given pemetrexed (LY231514) 600 mg/m(2) as a 10-min
intravenous (i.v.) infusion every 3 weeks. Median time from diagnosis to study
entry was 48 months (range 14.7-310 months). 33 of 38 patients had prior chemotherapy;
16 adjuvant, 12 metastatic and 5 in both settings. Sites of disease included skin
and soft tissue (19/38) nodes (18/38), lung (17/38), liver (13/38) and bone (3/38).
An overall response rate of 28% (95% confidence interval (CI): 14.2-45.2%) in
10/36 evaluable patients (1 complete response (CR), 9 partial responses (PR)),
included reductions in hepatic and pulmonary metastases. 5 of 10 responders had
received taxoid or anthracycline therapy for metastatic disease; 3 of these 5
had also received adjuvant chemotherapy. Median duration of response was 8 months
(range 1.6-14+ months), and median survival was 13 months (95% CI 9.56-17.38 months).
167 courses were given (median five per patient; range 1-9), with 37 reductions
and 33 delays. Reasons for reduction included neutropenia (11%) and mucositis
(5%), with delays due to raised LFTs (21%), neutropenia (12%) and other non-treatment
related events. The major haematological toxicities (Common Toxicity Criteria)
(CTC) were grade 3/4 neutropenia (47%) and thrombocytopenia (15.7%) of patients.
There was one report of a grade 3 infection. Non-haematological toxicities (all
grades 2/3) included elevated transaminases (92%), vomiting (34%), nausea (34%)
and mucositis (32%). One episode of grade 4 diarrhoea was reported. Other toxicities
included a skin rash, grade 2 (42%), 3 (5%) and 4 (13%), which was ameliorated
by the use of prophylactic dexamethasone. These results suggest that pemetrexed
has significant antitumour activity in advanced breast cancer with responses in
patients who had previously received anthracyclines and taxoids.
Phase I Trial of Pegylated Liposomal Doxorubicin and Docetaxel Sparano
JA, Malik U, Rajdev L, et al. J Clin Oncol 2001;19:3117-3125
Purpose: To develop a combination of pegylated liposomal doxorubicin
(Doxil) and docetaxel (Taxotere) that can be safely used for the treatment of
advanced breast cancer.
Patients and Methods: Forty-one patients with locally advanced
(n = 10) or metastatic (n = 31) breast cancer received Doxil (30-, 40-, or 45-mg/m(2)
intravenous [IV] infusion over 30 to 60 minutes), followed 1 hour later by docetaxel
(60 or 75 mg/m(2) by IV infusion over 1 hour) in cohorts of three to six patients.
Dose-limiting toxicity (DLT) was defined as febrile neutropenia, prolonged neutropenia,
or grade 3 to 4 nonhematologic toxicity that occurred during cycle 1.
Results: In conjunction with docetaxel 75 mg/m(2) every 4 weeks,
the MTD of Doxil was 30 mg/m(2) and required granulocyte colony-stimulating factor
(G-CSF) to prevent febrile neutropenia. Without G-CSF, the MTD was docetaxel 60
mg/m(2) and Doxil 30 mg/m(2) every 3 weeks; only 1 (7%) out of 15 patients treated
at this dose level had cycle 1 DLT. Infusion reactions were common with Doxil
with the recommended infusion schedule during the first cycle (55%) but were reduced
with a modified schedule (7%). There was no clinically significant cardiac toxicity.
Objective response occurred in eight of nine assessable patients with stage III
disease and in 16 (52%) of 31 patients (95% confidence interval, 34% to 70%) with
stage IV disease.
Conclusion: The recommended dose and schedule of this combination
for further evaluation is Doxil 30 mg/m(2) and docetaxel 60 mg/m(2) given every
3 weeks without G-CSF. When used with G-CSF, it is Doxil 30 mg/m(2) and docetaxel
75 mg/m(2) every 4 weeks.
Letrozole vs Megestrol Acetate for Advanced Breast Cancer
Buzdar A, Douma J, Davidson NJ, et al. Clin Oncol 2001;19:3357-3366
Purpose: To compare two doses of letrozole (0.5 mg and 2.5 mg
every day) and megestrol acetate (40 mg qid) as endocrine therapy in postmenopausal
women with advanced breast cancer previously treated with antiestrogens.
Patients and Methods: This double-blind, randomized, multicenter,
multinational study enrolled 602 patients, all of whom were included in the primary
analysis in the protocol. Patients had advanced or metastatic breast cancer with
evidence of disease progression while receiving continuous adjuvant antiestrogen
therapy, had experienced relapse within 12 months of stopping adjuvant antiestrogen
therapy given for at least 6 months, or had experienced disease progression while
receiving antiestrogen therapy for advanced disease. Tumors were required to be
estrogen receptor- and/or progesterone receptor-positive or of unknown status.
Confirmed objective response rate was the primary efficacy variable. Karnofsky
Performance Status and European Organization for Research and Treatment of Cancer
quality-of-life assessments were collected for 1 year.
Results: There were no statistically significant differences
among the three treatment groups for overall objective tumor response. Patients
treated with letrozole 0.5 mg had improvements in disease progression (P =.044)
and a decreased risk of treatment failure (P =.018), compared with patients treated
with megestrol acetate. Letrozole 0.5 mg showed a trend (P =.053) for survival
benefit when compared with megestrol acetate. Megestrol acetate was more likely
to produce weight gain, dyspnea, and vaginal bleeding, and the letrozole groups
were more likely to experience headache, hair thinning, and diarrhea.
Conclusion: Given a favorable tolerability profile, once-daily
dosing, and evidence of clinically relevant benefit, letrozole is equivalent to
megestrol acetate and should be considered for use as an alternative treatment
of advanced breast cancer in postmenopausal women after treatment failure with
antiestrogens. Letrozole vs Tamoxifen as First-Line Therapy for Metastatic Cancer
Mouridsen H, Gershanovich M, Sun Y, et al. J Clin Oncol 2001;19:2596-2606
Purpose: To compare the efficacy and tolerability of tamoxifen
with that of letrozole, an oral aromatase inhibitor, with tamoxifen as first-line
therapy in postmenopausal women with advanced breast cancer.
Patients and Methods: Nine hundred seven patients were randomly
assigned letrozole 2.5 mg once daily (453 patients) or tamoxifen 20 mg once daily
(454 patients). Patients had estrogen receptor- and/or progesterone receptor-positive
tumors, or both receptors were unknown. Recurrence during adjuvant antiestrogen
therapy or within the following 12 months or prior endocrine therapy for advanced
disease precluded enrollment. One prior chemotherapy regimen for metastatic disease
was allowed. The primary end point was time to progression (TTP). Secondary end
points included overall objective response rate (ORR), its duration, rate and
duration of clinical benefit, time to treatment failure (TTF), overall survival,
Results: TTP was significantly longer for letrozole than for
tamoxifen (median, 41 v 26 weeks). Treatment with letrozole reduced the risk of
progression by 30% (hazards ratio, 0.70; 95% confidence interval, 0.60 to 0.82,
P =.0001). TTP was significantly longer for letrozole irrespective of dominant
site of disease, receptor status, or prior adjuvant antiestrogen therapy. Similarly,
TTF was significantly longer for letrozole (median, 40 v 25 weeks). ORR was higher
for letrozole (30% v 20%; P =.0006), as was the rate of clinical benefit (49%
v 38%; P =.001). Survival data are currently immature and not reported here. Both
treatments were well tolerated.
Conclusion: Letrozole was significantly superior to tamoxifen
in TTP, TTF, ORR, and clinical benefit rate. Our results support its use as first-line
endocrine therapy in postmenopausal women with advanced breast cancer.
Pioglitazone May Inhibit Early Atherosclerotic
Lesions in Type 2 Diabetes
WESTPORT, CT (Reuters Health) Jul 25 - Pioglitazone decreases intima-media thickness
(IMT) of the common carotid artery, Japanese investigators report, and thereby
may inhibit the early atherosclerotic process in type 2 diabetes.
The results of two recent studies showed that agonists of peroxisome proliferator-activated
receptor gamma (PPAR-gamma), including the thiazolidinediones, promote the uptake
of lipids by macrophages. It has been suggested that PPAR-gamma agonists may promote
progression of atherosclerosis. This prompted Dr. Hiroyuki Koshiyama and colleagues
of Hyogo Prefectural Amagasaki Hospital in Hyogo to further investigate this possibility.
Fifty-three subjects with type 2 diabetes were treated with pioglitazone 30 mg
daily for 6 months, the investigators report in a rapid communication of the Journal
of Clinical Endocrinology and Metabolism for July. A control group included 40
subjects treated with glibenclamide, 9 treated with gliclazide and 4 treated with
At baseline, IMT measurements made by high-resolution B-mode ultrasonography were
similar in the two groups. After 6 months, however, mean IMT among pioglitazone-treated
subjects had decreased significantly by 0.084 mm, while among control subjects
the IMT increased by 0.022 mm (p < 0.001).
The decrease in IMT that followed thiazolidinedione administration could reflect
an "inhibitory effect on atherosclerotic lesions, such as reduction in vascular
smooth muscle cells," Dr. Koshiyama's group writes. However, "other
effects, such as a decrease in interstitial/intracellular water or in the vascular
wall cell volume, could not be totally excluded."