Table of Contents
1
UI - 11735647
AU - Waterhouse D N; Tardi P G; Mayer L D; Bally M B
TI -
A comparison of liposomal formulations of doxorubicin with drug
administered in free form: changing toxicity profiles.
SO - Drug Saf 2001;24(12):903-20
AD - Department of Pathology and Laboratory Medicine, University of British
Columbia, Vancouver, Canada. dsaxon@bccancer.bc.ca
The anthracycline antibiotic doxorubicin has wide activity against a
number of human neoplasms and is used extensively both as a single agent
and in combination regimens. In addition to the use of free,
unencapsulated doxorubicin, there are two US Food and Drug
Administration approved liposomal formulations of doxorubicin currently
available, with several additional liposomal formulations being
researched either in the laboratory or in clinical trials. The two
approved liposomal formulations of doxorubicin have significantly
different lipid compositions and loading techniques, which lead to both
unique pharmacokinetic and toxicity profiles, distinct from those of the
unencapsulated form. This article discusses the toxicities associated
with the free form of doxorubicin, as well as those associated with the
two most common liposomal formulations, namely Doxil and Myocet. One of
the key toxicity issues linked to the use of free doxorubicin is that of
both an acute and a chronic form of cardiomyopathy. This is circumvented
by the use of liposomal formulations, as these systems tend to sequester
the drug away from organs such as the heart, with greater accumulation
in liver, spleen and tumours. However, as will be discussed, the
liposomal formulations of doxorubicin are not without their own related
toxicities, and, in the case of Doxil, may be associated with the unique
toxicity of palmar-plantar erythrodysaesthesia. Overall, the use of
liposomal doxorubicin allows for a greater lifetime cumulative dose of
doxorubicin to be administered, however acute maximal tolerated doses
differ significantly, with that of Myocet being essentially equivalent
to free doxorubicin, while higher doses of Doxil may be safely
administered. This review highlights the differences in both toxicity
and pharmacokinetic properties between free doxorubicin and the
different liposomal formulations, as have been determined in
pre-clinical and clinical testing against a number of different human
neoplasms. The need for further testing of the liposomal formulations
prior to the replacement of free doxorubicin with liposomal doxorubicin
in any established combination therapy regimens, as well as in
combination with the newer therapeutics such as monoclonal antibodies is
also discussed.
2
UI - 11759828
AU - Konecny G; Fritz M; Untch M; Lebeau A; Felber M; Lude S; Beryt M; Hepp
TI -
H; Slamon D; Pegram M
HER-2/neu overexpression and in vitro chemosensitivity to CMF and FEC in
primary breast cancer.
SO - Breast Cancer Res Treat 2001 Sep;69(1):53-63
AD - Department of Medicine, UCLA School of Medicine, 90095-1678, USA.
gkonecny@ucla.edu
Available clinical and experimental data on the effect of HER-2/neu
overexpression on chemosensitivity are controversial. It was the purpose
of this in vitro study to define the association between HER-2/neu
overexpression and the sensitivity to the chemotherapeutic drug
combinations of cyclophosphamide, methotrexate and 5-fluorouracil (CMF)
and 5-fluorouracil, epirubicin and cyclophosphamide (FEC) of breast
cancer cells derived from 140 chemotherapy-naive patients at the time of
primary surgery. Both drug combinations were tested at six different
concentrations ranging from 6.25-200% peak plasma concentration (PPC).
Immunohistochemical detection of HER-2/neu overexpression was performed
with the HER-2/neu antibodies, CB11, TAB250 and AO485, in the same tumor
specimens. Immunoreactions were determined as negative (0/1+), weakly
positive (2+) and strongly positive (3+). However, the antibodies varied
in their degrees of sensitivity. Breast cancer samples with strong (3+)
HER-2/neu overexpression demonstrated 90% growth inhibition (IC90) at
significantly lower PPC values, using the CB11 (p = 0.048), TAB250 (p =
0.007) and AO485 (p < or =0.01) antibodies, and showed 50% growth
inhibition (IC50) at significantly lower PPC values, using the CB11
antibody (p = 0.01) compared to their counterparts with lower levels of
HER-2/neu expression. When analyzing the group of patients with
intermediate and strong HER-2/neu overexpression (2+ and 3+), an
association between HER-2/neu overexpression and increased
chemosensitivity was seen with the TAB250 (p = 0.044) and AO485 (p =
0.032) antibodies, but not with the CB11 antibody (p =0.8) at the IC90
level. Differences in chemosensitivity between samples with strong
HER-2/neu overexpression and those with lower levels were then analyzed
separately for CMF and FEC. Both regimens achieved 90% tumor growth
inhibition at lower PPC values in samples with strong HER-2/neu
overexpression (3+) compared to their counterparts with lower expression
levels (AO485 p = 0.011 for CMF, and p = 0.09 for FEC). Cumulative
concentration-response plots of tumors responding in vitro with 90%
tumor cell inhibition showed a stronger dose dependence for both CMF and
FEC among tumor samples with strong HER-2/neu overexpression compared to
those with lower levels of expression. In conclusion, the data show that
HER-2/neu overexpression was not associated with in vitro drug
resistance to CMF or FEC. In contrast, tumors with strong HER-2/neu
overexpression demonstrated increased dose-dependent in vitro
sensitivity to both the FEC and CMF regimens.
3
UI - 11759829
AU - Powell B L; Bydder S; Grieu F; Gnanasampanthan G; Elsaleh H; Seshadri R;
TI -
Berns E M; Iacopetta B
Prognostic value of TP53 gene mutation in adjuvant treated breast cancer
patients.
SO - Breast Cancer Res Treat 2001 Sep;69(1):65-8
AD - Department of Surgery, University of Western Australia, Nedlands,
Australia.
We investigated the prognostic significance of mutation to the TP53
tumor suppressor gene in a series of 908 breast cancer patients treated
with or without adjuvant therapies. The frequency of TP53 mutation
detected by single strand conformation polymorphism (SSCP) was 19.4%
(176/908) in the overall tumor series. In multivariate analysis, TP53
mutation was independently associated with worse survival in the overall
(HR = 2.1, 95% CI [1.5-3.1], P<0.0001), non-adjuvant treated (HR=2.2,
95% CI [1.2-4.2], P=0.017) and adjuvant treated (HR= 2.0, 95% CI
[1.3-3.1], P = 0.0009) patients.
4
UI - 11759820
AU - Fiorentino C; Berruti A; Bottini A; Bodini M; Brizzi MP; Brunelli A;
TI -
Marini U; Allevi G; Aguggini S; Tira A; Alquati P; Olivetti L; Dogliotti
L
Accuracy of mammography and echography versus clinical palpation in the
assessment of response to primary chemotherapy in breast cancer patients
with operable disease.
SO - Breast Cancer Res Treat 2001 Sep;69(2):143-51
AD - Dipartimento di Radiologia, Azienda Ospedaliera Istituti Ospitalieri
Cremona, Italy.
The response to primary chemotherapy is an important prognostic factor
in patients with non metastatic breast cancer. In this study we compared
the assessment of response performed by clinical palpation to that
performed by echography and mammography in 141 out of 157 consecutive
breast cancer patients (T2-4, N0-1, M0) submitted to primary
chemotherapy. A low relationship was recorded between tumor size
assessed clinically and that evaluated by either mammography: Spearman R
= 0.38 or echography: R = 0.24, while a greater correlation was found
between the tumor dimension obtained by the two imaging techniques (R =
0.62). According to the WHO criteria, the grade of response of breast
cancer to primary chemotherapy, showed by mammography and echography,
was less marked than the grade of response seen at clinical examination.
Residual tumor size assessed clinically depicted a stronger correlation
with pathological findings (R = 0.68) than the residual disease assessed
by echography (R = 0.29) and mammography (R = 0.33). Post-chemotherapy
histology evaluation revealed pathological complete response in three
cases (2.1%). Two of these cases were judged as complete responders by
clinical palpation but only one was recognized by mammography, and none
by echography. Clinical response, but not the response obtained by the
two imaging techniques, was a significant predictor for longer disease
free survival (p = 0.04). To conclude, physical examination measurements
remain the method of choice in evaluating preoperatively the disease
response in trials of primary chemotherapy. Prediction of pathological
outcome is not improved by echography and mammography.
5
UI - 11801870
AU - Bentrem DJ; Jordan VC
TI -
Role of antiestrogens and aromatase inhibitors in breast cancer
treatment.
SO - Curr Opin Obstet Gynecol 2002 Feb;14(1):5-12
AD - Department of Surgery, Robert H. Lurie Comprehensive Cancer Center,
Northwestern University Medical School, Chicago, Illinois 60611, USA.
This review explores the recent experience with, and the basis for, the
use of selective estrogen receptor modulators to treat and prevent
breast cancer. As new agents are unveiled, they will continue to be
tested against tamoxifen. A number of new selective estrogen receptor
modulators are in clinical development in an attempt to decrease the
unwanted effects of tamoxifen. Raloxifene holds the promise of treating
osteoporosis with the beneficial side effect of breast cancer
prevention. Additionally, two different classes of hormonal agents, the
aromatase inhibitors and estrogen receptor down-regulators, which have
no estrogen-like properties at any site, appear to be promising new
treatments for advanced breast cancer.
6
UI - 11900209
AU - Jonat W
TI -
Goserelin (Zoladex)--its role in early breast cancer in pre- and
perimenopausal women.
SO - Br J Cancer 2001 Nov;85 Suppl 2():1-5
AD - Gynaecology and Obstetrics Clinic, University of Kiel, Germany.
Current standard adjuvant therapies for premenopausal women with early
breast cancer include ovarian ablation by surgery or irradiation,
chemotherapy and tamoxifen. The value of ovarian ablation in prolonging
the survival of premenopausal patients with early breast cancer was
clearly established by the analyses performed by the Early Breast Cancer
Trialists' Collaborative Group in 1996. More recently, the value of
ovarian suppression using the luteinizing hormone releasing hormone
analogue goserelin as adjuvant therapy in pre-/perimenopausal women with
early breast cancer has been confirmed in a series of studies involving
over 8000 patients. The results from these studies provide evidence that
goserelin, alone or in combination with tamoxifen, is at least as
effective as cytotoxic chemotherapy in patients with hormone
receptor-positive tumours and is effective when used after adjuvant
chemotherapy. The use of goserelin in the management of early breast
cancer presents an option which can avoid the side-effects experienced
with cytotoxic chemotherapy and may offer unique benefits to
premenopausal patients. The consolidation of these emerging results
should help in defining the optimal role for goserelin in
pre-/perimenopausal patients with early breast cancer.
7
UI - 11900210
AU - Robertson J F
TI -
ICI 182,780 (Fulvestrant)--the first oestrogen receptor
down-regulator--current clinical data.
SO - Br J Cancer 2001 Nov;85 Suppl 2():11-4
AD - Department of Surgery, City Hospital Nottingham, UK.
ICI 182,780 (Fulvestrant) is the first in a new class of novel,
steroidal, 'pure' antioestrogens--the oestrogen receptor (ER)
down-regulators. Its unique mode of action and the absence of partial
agonist activity make it a candidate for the treatment of advanced
breast cancer in both pre- and postmenopausal women. Tamoxifen has been
available for use over the past 25 years. However, its partial agonist
activity has been associated with detrimental effects, particularly on
the endometrium, and may be associated with the development of tamoxifen
resistance. Other antioestrogen agents have previously been unable to
demonstrate clinically relevant activity following the development of
resistance to tamoxifen. In contrast, the unique mechanism of action of
ICI 182,780 results in significant clinical activity in patients failing
on tamoxifen therapy. Indeed, phase III clinical trials have
demonstrated that ICI 182,780 is at least as effective as the aromatase
inhibitor anastrozole in the treatment of postmenopausal patients with
advanced disease who have progressed during threatment with prior
enocrine therapy. As such, ICI 182,780 will provide a valuable addition
to the armamentarium for the treatment of advanced breast cancer.
8
UI - 11900211
AU - Baum M
TI -
A vision for the future?
SO - Br J Cancer 2001 Nov;85 Suppl 2():15-8
AD - Department of Psycho-oncology, University College London Medical School,
UK.
Systemic adjuvant therapy is recommended immediately following surgical
removal of the primary tumour in the majority of patients with early
breast cancer, to prevent the recurrence of distant metastases.
Significant progress has been made in the development and evaluation of
endocrine therapies for systemic adjuvant therapy. In pre- and
perimenopausal women, ovarian ablation has proven to be a valuable
treatment option, though not always desirable for young patients. Thus,
reversible medical ovarian suppression with a luteinizing hormone
releasing hormone agonist, such as goserelin (Zoladex), may provide an
attractive alternative for such patients. International trials have
indicated that goserelin provides an important addition to the choice of
adjuvant therapies now available to pre- and perimenopausal patients.
For postmenopausal patients, it is hoped that the ATAC (Arimidex,
tamoxifen, alone or in combination) trial will reveal whether or not the
benefits of anastrozole (Arimidex) observed in advanced disease, where
it has proven to be well tolerated and at least as effective as
tamoxifen in recent trials, will translate to the early setting to
provide further management options for these patients. On the horizon is
yet another exciting endocrine agent, ICI 182,780 (Fulvestrant), which
has also been shown to be as effective as anastrozole in advanced
disease. In terms of the future, these agents are likely to provide
additional valuable treatment choices for early breast cancer across the
patient spectrum.
9
UI - 11900212
AU - Buzdar A U
TI -
Anastrozole (Arimidex)--an aromatase inhibitor for the adjuvant setting?
SO - Br J Cancer 2001 Nov;85 Suppl 2():6-10
AD - Department of Breast Medical Oncology, MD Anderson Cancer Center,
University of Texas, Houston 77030, USA.
Anastrozole (Arimidex) is a third-generation aromatase inhibitor which
has been shown to possess superior efficacy and tolerability over
established endocrine agents in advanced breast cancer. Inhibition of
aromatase prevents the conversion of androgen substrates to oestrogen,
its sole source in postmenopausal women, thereby leading to regression
of hormone-sensitive breast carcinomas. Clinical pharmacology data
indicate that anastrozole is a potent aromatase inhibitor, providing
near-maximal suppression of serum and intratumoural oestrogens to below
detectable levels. Anastrozole may offer greater selectivity compared
with other aromatase inhibitors, being without any intrinsic endocrine
effects and with no apparent effect on the synthesis of adrenal
steroids. It is well tolerated and has a convenient once-daily dosing
regimen, ensuring maximum patient compliance. A major clinical programme
has demonstrated that anastrozole is superior to the standard endocrine
therapy, tamoxifen, for the first-line treatment of postmenopausal women
with hormone-sensitive advanced breast cancer. Its superior efficacy in
advanced disease, together with its improved tolerability and convenient
dosage, make it a suitable agent to be assessed for the treatment of
early breast cancer in postmenopausal women. This was investigated in
the largest single adjuvant breast cancer study ever to be carried out,
the ATAC (Arimidex, tamoxifen, alone or in combination) trial, which has
now completed recruitment, with the first efficacy and safety data
awaited.
10
UI - 11875727
AU - Spielmann M; Tubiana-Hulin M; Namer M; Mansouri H; Bougnoux P;
TI -
Tubiana-Mathieu N; Lotz V; Eymard JC
Sequential or alternating administration of docetaxel (Taxotere)
combined with FEC in metastatic breast cancer: a randomised phase II
trial.
SO - Br J Cancer 2002 Mar 4;86(5):692-7
AD - Institut Gustave Roussy, 39-53 rue Camille Desmoulins, 94805 Villejuif,
France. spielman@igr.fr
The aim of this study, using a Fleming single-stage design, was to
explore the efficacy and safety of Taxotere 100 x mg x m(-2) docetaxel
and FEC 75 cyclophosphamide 500 mg x m(-2), fluorouracil 500 x mg x
m(-2) and epirubicin 75 mg x m(-2), in alternating and sequential
schedules for the first-line treatment of metastatic breast cancer. One
hundred and thirty-six women were randomly allocated, to one of three
treatment regimens: DTX 100 plus FEC 75, alternated for eight courses
(ALT); four courses of DTX 100 followed by four courses of FEC 75 (SEQ
T); or four courses of FEC 75 followed by four courses of DTX 100 (SEQ
F). One hundred and thirty-one women were evaluable for tumour response.
Although the treatment outcome was equivalent in the two sequential arms
and the alternating regimen (P=0.110, not significant), the response
rate was less encouraging in the SEQ F arm (52.3%) than in the other two
arms (71.1% for ALT and 70.5% for SEQ T), in which docetaxel was
administered first. Time to progression was similar in the ALT, SEQ T
and SEQ F arms (9.5, 9.3 and 10.4 months respectively). Grade 3-4
neutropenia was observed in nearly all patients; febrile neutropenia
occurred in 9% (ALT), 16% (SEQ T) and 2% (SEQ F) of patients. Few
patients (< or =9%) developed grade 3-4 non-haematological toxicities.
Relative dose intensity was 97-99% for all regimens. All treatment
regimens were active and well tolerated. Copyright 2002 Cancer Research
UK
11
UI - 11875740
AU - Hague S; Manek S; Oehler MK; MacKenzie IZ; Bicknell R; Rees MC
TI -
Tamoxifen induction of angiogenic factor expression in endometrium.
SO - Br J Cancer 2002 Mar 4;86(5):761-7
AD - Nuffield Department of Obstetrics and Gynaecology, Women's Centre, John
Radcliffe Hospital, Oxford OX3 9DU, UK.
Tamoxifen is the current therapy of choice for patients with oestrogen
receptor positive breast cancer, and it is currently under evaluation as
a prophylactic for women at high risk of developing the disease.
However, tamoxifen is also known to induce proliferative changes in the
endometrium increasing the risk of developing endometrial hyperplasia,
polyps and carcinoma. Angiogenesis is an intimate part of this process.
For this reason, we have examined the expression of several well
characterized angiogenic factors, namely, acidic and basic fibroblast
growth factor, thymidine phosphorylase, vascular endothelial growth
factor and adrenomedullin in both normal and tamoxifen exposed pre- and
postmenopausal endometrium. Vascular density and endothelial
proliferation index were also quantified. We found increased expression
of acidic and basic fibroblast growth factor and adrenomedullin after
treatment with tamoxifen mainly in premenopausal tissue. Vascular
density was significantly increased in pre- but not post-menopausal
endometrium (P=0.0018) following tamoxifen treatment. These results
support the notion that angiogenesis is integral to the response to
tamoxifen exposure, and is a potential target with which to block these
side effects of tamoxifen. Copyright 2002 Cancer Research UK
12
UI - 11908256
AU - Lavrenkov K; Man S; Geffen DB; Cohen Y
TI -
Experience of hormonal therapy with anastrozole for previously treated
metastatic breast cancer.
SO - Isr Med Assoc J 2002 Mar;4(3):176-7
AD - Department of Oncology, Soroka University Medical Center, Beer Sheva,
Israel. constant@bgumail.bgu.ac.il
BACKGROUND: Recent years have brought significant progress to the
development of hormonal therapies for the treatment of breast cancer.
Several new agents have been approved for the treatment of breast cancer
in the metastatic setting, among which is the new non-steroidal
aromatase inhibitor, anastrozole, introduced for clinical use in Israel
duration of patients treated with anastrozole for metastatic breast
cancer, who had previously received at least one line of hormonal
therapy. METHODS: Anastrozole was administered to 37 patients with
metastatic breast cancer. The median age was 64 years. Estrogen receptor
was positive in 20 patients, negative in 10 and unknown in 7. All
patients were previously treated with tamoxifen in the adjuvant setting
or as first-line hormonal therapy for metastatic disease. Anastrozole
was given orally, 1 mg/day. Response was evaluated 2 months after the
initiation of treatment and reevaluated every 2 months. Therapy was
given until disease progression. Ten ER-negative patients were excluded
from the final analysis. RESULTS: Twenty-seven patients were eligible
for response and toxicity analysis. The median follow-up was 20 months.
One patient (3.7%) achieved complete response and remains free of
disease 28 months after start of therapy. No partial responses were
seen. Twenty patients (74%) had stable disease. Two year actuarial
survival was 57%. Median survival was 26.5 months after starting therapy
and median progression-free survival was 11 months. The toxicity was
mild: one patient (3.7%) complained of weight gain and one patient
(3.7%) had mild fatigue. CONCLUSION: Although the response rate was low,
hormonal therapy with anastrozole seems to be beneficial in terms of
disease stabilization, freedom from progression, and overall survival
without serious toxicity.
13
UI - 11915733
AU - Miyamoto H; Yoshida S; Imatomi M; Saitoh T; Nakata A
TI -
[Successful treatment of advanced recurent breast cancer using DMpC
therapy as maintenance therapy]
SO - Gan To Kagaku Ryoho 2002 Mar;29(3):427-9
AD - Dept. of Surgery, OE Kyohdoh Hospital.
felt swelling and numbness of her left lower jaw. As a result of bone
biopsy and scintigraphy, multiple bone metastasis was diagnosed. After 6
cycles of CMF therapy, the swelling and numbness of the left lower jaw
were reduced, but atelectasis of the left lung upper lobe appeared.
After 10 cycles of paclitaxel therapy, atelectasis and bone metastasis
were reduced. Daily oral chemoendocrine combination therapy, DMpC
therapy (5'-DFUR 800 mg/day + CPA 100 mg/day + MPA 800 mg/day) was
continued for 12 months. No recurrent signs and serious side effects
were observed during DMpC therapy.
14
UI - 11902499
AU - Leyland-Jones B
TI -
Trastuzumab: hopes and realities.
SO - Lancet Oncol 2002 Mar;3(3):137-44
AD - Department of Oncology, McGill University, Montreal, Quebec Canada.
leylandj@med.mcgill.ca
Despite improvements in care of patients with breast cancer, up to half
develop refractory or resistant disease. There is therefore a need for
new, modified anticancer therapies with greater effectiveness,
tolerability to patients, and tumour specificity. Trastuzumab
(Herceptin) is the first clinically available oncogene-targeted
therapeutic agent for treatment of solid tumours. Clinical trials in
patients positive for HER2 (human epidermal-growth-factor receptor 2)
show that trastuzumab is effective and well tolerated; as a single-agent
second-line or third-line treatment, the drug produced durable tumour
responses. First-line trastuzumab in combination with chemotherapy,
particularly paclitaxel, significantly improved time to disease
progression, duration of response, and time to treatment failure.
Combination therapy resulted in a 25% improvement in overall survival
compared with chemotherapy alone. Patients with HER2 gene amplification,
high overexpression of HER2 (3+ on immunohisto-chemistry), or both
features, obtained the greatest clinical benefit. Trastuzumab is the
first monoclonal antibody with efficacy in breast cancer and the first
gene-product-targeted therapy to produce a significant survival
advantage in this disease. Trastuzumab is likely to find its ultimate
role in the adjuvant setting. Its development provides a model for the
integration of other gene-targeted therapies into breast-cancer
management to improve survival and quality of life.
15
UI - 11905631
AU - Senior K
TI -
Supercomputer-designed drug protects against chemotherapy toxicity.
SO - Lancet Oncol 2000 Dec;1():198
16
UI - 10760830
AU - Schmoor C; Bastert G; Dunst J; Bojar H; Christmann D; Unbehaun V;
TI -
Tummers G; Bauer W; Sauerbrei W; Schumacher M
Randomized trial on the effect of radiotherapy in addition to 6 cycles
CMF in node-positive breast-cancer patients. The German Breast-Cancer
Study Group.
SO - Int J Cancer 2000 May 1;86(3):408-15
AD - Institute of Medical Biometry and Medical Informatics, University of
Freiburg, Freiburg, Germany. cs@imbi.uni-freiburg.de
In 1984 the GBSG started a multicenter randomized trial to compare the
effectiveness of 6 cycles of cyclophosphamide, methotrexate and
fluorouracil (CMF) with or without radiotherapy (RT) as adjuvant
treatment in node-positive breast-cancer patients treated by mastectomy.
During 5 years, 199 patients were randomized. After a median follow-up
of about 9 years, the treatment groups 6 x CMF and 6 x CMF + RT were
compared regarding time to recurrence and death. As the first event of
failure, we observed locoregional recurrence in 22 patients, distant
metastases in 66 patients, a secondary malignancy in 9 patients and
death without previous event in 5 patients. For event-free survival
(EFS), no significant difference was observed [relative risk (RR) 6 x
CMF + RT vs. 6 x CMF 0.82, 95% confidence interval (CI) 0.55-1.21].
Event-specific analysis showed a significant decreased risk after
radiotherapy for locoregional recurrence. The risk for distant
metastases was estimated as slightly decreased and the risk for
secondary malignancy and for death without previous event was estimated
as increased in treatment group 6 x CMF + RT in comparison with
treatment group 6 x CMF, but these effects were not significant. For
overall survival (OS) and breast-cancer-specific survival (BCS), no
significant treatment effect could be demonstrated. There is a
beneficial effect of radiotherapy on locoregional recurrence. For EFS
and BCS, a tendency in favour of radiotherapy is observed, but this is
not significant; for OS, no difference can be demonstrated, but the
power of the study is too low to detect small treatment effects.
Copyright 2000 Wiley-Liss, Inc.
17
UI - 11900215
AU - Bajetta E; Procopio G; Ferrari L; Martinetti A; Zilembo N; Catena L; Alu
TI -
M; Della TS; Alberti D; Buzzoni R
A randomized, multicenter prospective trial assessing long-acting
release octreotide pamoate plus tamoxifen as a first line therapy for
advanced breast carcinoma.
SO - Cancer 2002 Jan 15;94(2):299-304
AD - Medical Oncology Unit B, Istituto Nazionale per lo Studio e la Cura dei
Tumori, Milan, Italy. bajetta@institutotumori.mi.it
BACKGROUND: Long-acting release octreotide pamoate (OP-LAR) is a
synthetic octapeptide that can be administered monthly and whose
activity is similar to that of endogenous somatostatin. In vitro and in
vivo data suggest that OP-LAR may act as a growth inhibitor or a
modulator of growth stimulatory peptides. The potential mechanisms of
action of somatostatin analogues in breast carcinoma include the
suppression of insulin-like growth factor-1 (a putative tumor growth
factor) and the binding to the somatostatin receptors expressed by
breast carcinoma cells in order to induce apoptosis. METHODS: This Phase
III, multicenter, randomized, double-blind, placebo-controlled trial
involved 203 patients (13% premenopausal and 87% postmenopausal) with
locally recurrent (but unsuitable for local treatment) or metastatic
breast carcinoma, 199 of whom were actually treated (99 patients with
OP-LAR and 100 patients with placebo). All patients received TAM and
were estrogen and/or progesteron receptor positive (receptor positivity
was an eligibility criterion), and all had measurable or evaluable
disease. Any patients who had received previous chemotherapy not given
in an adjuvant or neoadjuvant setting were excluded. RESULTS: At the
time of the interim analysis, the tumor response rates (RR) were 20.2%
(9 complete responses [CR] and 11 partial responses [PR]) in the OP-LAR
arm and 21% (11 CRs and 10 PRs) in the placebo arm, and the median time
to progression (TTP) was 25.0 and 26.9 weeks (P = 0.62), respectively.
The adverse events experienced by 10% or more of the patients and
attributed to octreotide were gastrointestinal in nature: diarrhea
(53%), nausea (16%), and abdominal pain (11%). CONCLUSIONS: Because of
the similar RR and TTP in both arms, the trial was stopped at the
interim analysis. The current data confirm there is no indication for
adding somatostatin analogues to TAM in advanced breast carcinoma.
18
UI - 11899785
AU - Hartman AR; Fleming GF; Dillon JJ
TI -
Meta-analysis of adjuvant cyclophosphamide/methotrexate/5-fluorouracil
chemotherapy in postmenopausal women with estrogen receptor-positive,
node-positive breast cancer.
SO - Clin Breast Cancer 2001 Jul;2(2):138-43; discussion 144
AD - Department of Oncology, Stanford University Medical Center, Palo Alto,
CA, USA.
Conflicting results have been published regarding the efficacy of
adjuvant cyclophosphamide/methotrexate/5-fluorouracil (CMF)-type
chemotherapy in postmenopausal, estrogen receptor (ER)-positive women.
The Oxford overview suggests real but limited benefit of any
chemotherapy in this group of patients but avoids analyzing smaller
subsets. We wished to better quantitate the benefit of adding CMF to
tamoxifen in postmenopausal ER-positive women with tumor involvement of
axillary lymph nodes. Six randomized studies comparing CMF plus
tamoxifen to tomoxifen alone in postmenopausal, ER-positive,
node-positive women have been published since 1992. They include 2368
patients. We performed a meta-analysis of 6 endpoints: survival,
disease-free survival, locoregional recurrence, distant recurrence,
contralateral breast recurrence, and thromboembolic complications. There
was a statistically significant increase in disease-free survival from
the addition of CMF-type chemotherapy to tamoxifen in this population;
the absolute risk of relapse was reduced by 5.5% at 5 years. Effects of
locoregional recurrence were greater than those on overall recurrence.
No significant survival benefit was observed.
19
UI - 11899378
AU - D'Orazio AI
TI -
Paclitaxel in the adjuvant setting: results so far are inconclusive.
SO - Clin Breast Cancer 2001 Apr;2(1):27-9
20
UI - 11899379
AU - D'Orazio AI
TI -
Is HER2/neu overexpression a predictor of anthracycline utility?
SO - Clin Breast Cancer 2001 Apr;2(1):30-2
21
UI - 11899382
AU - Spielmann M; Martin M; Namer M; duBois A; Unger C; Dodwell DJ
TI -
Activity of pemetrexed (ALIMTA, multitargeted antifolate, LY231514) in
metastatic breast cancer patients previously treated with an
anthracycline and a taxane: an interim analysis.
SO - Clin Breast Cancer 2001 Apr;2(1):47-51
As many breast cancer patients receive adjuvant chemotherapy using
anthracyclines or anthracenediones and taxanes, more therapeutic options
are needed for subsequent lines of therapy. Pemetrexed (ALIMTA,
multitargeted antifolate, LY231514) is a novel antifolate that inhibits
several enzymes in the de novo pathways of pyrimidine and purine
biosynthesis. This paper reports on a subset analysis of a phase II
clinical trial of pemetrexed in heavily pretreated metastatic breast
cancer (MBC) patients. Patients were required to have received prior
first-line anthracycline therapy for metastatic disease. Prior adjuvant
chemotherapy and prior taxanes were allowed. A substantial subset of the
study population (31 of 72 patients, 43%) had also received a taxane in
the metastatic setting. All patients were treated with pemetrexed, 600
mg/m2 by intravenous infusion, once every 21 days. In the study subset,
23 of 31 (74%) patients were anthracyclines failures (progression > 30
days following treatment), and eight (26%) patients were anthracyclines
refractory (progression during or < or = 30 days of treatment). The
median age was 55 years (range, 30-75 years) and the median World Health
Organization performance status was 0. Metastases were present in the
liver (61%), lung (29%), bone (6%), and soft tissue (19%). The overall
response rate for this subset was 26%, with one complete response, seven
partial responses, and 13 (42%) patients with stable disease. The median
duration of response was 5.4 months and median survival was 12.8 months.
Pemetrexed was well tolerated by patients in the study. This post hoc
analysis suggests promising activity in MBC patients previously treated
with both anthracyclines and taxanes. An ongoing trial is prospectively
evaluating activity in this same population.
22
UI - 11899351
AU - Smorenburg CH; Bontenbal M; Verweij J
TI -
Capecitabine in breast cancer: current status.
SO - Clin Breast Cancer 2001 Jan;1(4):288-93; discussion 294
AD - Rotterdam Cancer Institute (Daniel den Hoed Kliniek), University
Hospital Rotterdam, Rotterdam, The Netherlands. smorenburg@vvdh.azr.nl
Anthracyclines, together with taxanes, are at present the most active
agents in metastatic breast cancer, while single-agent, bolus
5-fluorouracil (5-FU) is not very active in this setting. In view of
encouraging results and tolerable toxicity of continuous infusion of
5-FU in gastrointestinal cancer, innovative oral 5-FU agents such as
capecitabine have been developed. Capecitabine is a prodrug that is
converted into the active compound 5-FU preferentially at the tumor
site. An intermittent dosing schedule of capecitabine twice daily at a
dose of 2510 mg/m2/day on days 1-14 in a 3-week cycle appeared to be
feasible and resulted in a high dose intensity. A large phase II study
investigating capecitabine in 135 advanced breast cancer patients,
pretreated with anthracyclines and taxanes, observed three complete and
24 partial responses (response rate, 20%), with a mean duration of 8.0
months. Preliminary results of a study comparing capecitabine with
paclitaxel in 42 breast cancer patients failing anthracyclines indicate
that the efficacy of capecitabine is comparable to that of paclitaxel,
with response rates of 36% and 21%, respectively. Another study reported
a response rate of 25% for capecitabine as first-line therapy for
advanced breast cancer in women aged > or = 55 years, which tended to be
better than combination chemotherapy with
cyclophosphamide/methotrexate/5-FU. In all studies, capecitabine side
effects were mainly mild, and treatment-related grade 3/4 toxicity
consisted of diarrhea (8%-11%), nausea (4%-11%), hand-foot syndrome
(10%-18%), neutropenia (3%-20%), and bilirubin elevation (6%).
Capecitabine is clearly an active agent for the treatment of breast
cancer. It is currently registered in various countries for use in
third-line treatment of metastatic disease. Its further role will have
to be defined from data of randomized phase III studies.
23
UI - 11899352
AU - Geisler J; Lonning PE
TI -
Resistance to endocrine therapy of breast cancer: recent advances and
tomorrow's challenges.
SO - Clin Breast Cancer 2001 Jan;1(4):297-308; discussion 309
AD - Department of Oncology, Haukeland University Hospital, Bergen, Norway.
The role of endocrine therapy in early as well as advanced breast cancer
cannot be overrated. Long-term tamoxifen exposure (5 years) in the
adjuvant setting has been shown to be effective not only in improving
relapse-free and overall survival but also in reducing the incidence of
contralateral cancers. Promising results have been achieved in breast
cancer prevention with use of antiestrogens. Novel aromatase inhibitors
and inactivators have been found superior to conventional treatment in
metastatic disease and are currently being evaluated in the adjuvant
setting to improve relapse-free and overall survival. If potential
health hazards from estrogen deprivation with regard to cardiovascular
disease as well as bone metabolism can be addressed, adjuvant endocrine
therapy may include such drugs in the future. However, while endocrine
therapy of breast cancer has become more and more important in the
clinic, the major problems in hormonal therapy are primary and acquired
resistance to endocrine manipulations. The causes for endocrine
resistance and possible ways to delay or avoid this phenomenon are only
allusively understood. Elucidation of the mechanisms underlying
endocrine resistance in vivo represents the key to improve our treatment
strategies. Due to intense use of in vitro models and animal systems,
many potential mechanisms of endocrine resistance have been described;
however, our understanding of the problem of drug resistance in vivo
remains limited. Hopefully, ongoing programs on translational research
in the neoadjuvant, adjuvant, and palliative settings will provide
information that will improve our understanding of the biology of
endocrine resistance in vivo and, thus, provide us with a better
rationale to improve early as well as late endocrine therapy in breast
cancer patients. The present publication summarizes the state of the art
with respect to endocrine resistance.
24
UI - 11899388
AU - Sparano JA
TI -
Taxanes for breast cancer: an evidence-based review of randomized phase
II and phase III trials.
SO - Clin Breast Cancer 2000 Apr;1(1):32-40; discussion 41-2
AD - Albert Einstein Comprehensive Cancer Center, Montefiore Medical
Center-Weiler, Division South, Room 52, Bronx, New York 10461, USA.
sparano@jimmy.harvard.edu
The taxanes paclitaxel and docetaxel have an important role in the
treatment of breast cancer, and numerous randomized trials have
evaluated their efficacy for this indication. A systematic,
evidence-based review was performed, which included all randomized,
controlled trials evaluating taxanes for the treatment of early-or
advanced-stage breast cancer that were identified in CANCERLIT and
MEDLINE searches. The primary objectives of this review were to
determine the dose and schedule for each taxane that was associated with
the most favorable therapeutic index, and to determine whether (and
under what circumstances) the taxanes improved survival. The search
revealed 18 randomized phase II (n = 1) or phase III (n = 17) trials.
For metastatic breast cancer, the dose and schedule associated with the
most favorable therapeutic index for paclitaxel was 175 mg/m2 given as a
3-hour infusion every 3 weeks, and docetaxel was 60-100 mg/m2 given as a
1-hour infusion every 3 weeks. Survival was improved under the following
circumstances: (1) when 4 cycles of paclitaxel (175 mg/m2 every 3 weeks)
was given following 4 cycles of conventional
doxorubicin-cyclophosphamide for axillary node-positive operable breast
cancer, (2) when trastuzumab was added to paclitaxel as first-line
therapy for metastatic breast cancer that overexpressed HER2/neu, and
(3) when docetaxel was given as second-line therapy for
anthracycline-resistant disease. Although a survival benefit was found
for taxanes as a component of first-line therapy in two of six trials,
the interpretation of both positive trials was confounded by a lack of
crossover to taxane therapy in those who were initially randomized to
receive standard therapy. The taxanes improve survival in patients with
early-stage breast cancer and selected patients with metastatic breast
cancer. Further research is necessary in order to identify the efficacy
of docetaxel relative to paclitaxel, the optimal dose of docetaxel, the
role of weekly taxane therapy, the role of trastuzumab plus taxanes in
early-stage disease, and whether taxanes are more effective when given
concomitantly or sequentially in patients with early-stage disease.
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