BREAST CANCER
Breast Conserative Therapy |
1
EBM
|
1. Breast conserving therapy versus
mastectomy in early stage breast cancer: a meta-analysis
of 10-year survival.
Morris AD, Morris RD, et al; Cancer J Sci Am 1997;
3: 6-12.
BACKGROUND: The randomized trials comparing breast-conserving
therapy (BCT), i.e., surgery and radiation to the
breast, with mastectomy in early-stage breast cancer
use a variety of protocols. Meta-analysis may assist
in understanding the impact of these differences
on survival. PURPOSE: To evaluate the possible variations
of the relative efficacy of BCT and mastectomy in
terms of overall survival according to tumor size,
nodal status, and use of adjuvant radiation therapy.
METHODS: The most recent published results and,
where available, updated patient-level data from
randomized controlled trials of BCT and mastectomy
for early-stage breast cancer were combined in a
meta-analysis using a random effects model. Pooled
survival rates and odds ratios were generated according
to subgroups of nodal status and tumor size. Five-
and 10-year odds ratios were also determined according
to adjuvant radiation protocol. RESULTS: The pooled
odds ratio comparing 10-year survival for BCT and
mastectomy was 0.91. The odds ratios comparing the
two treatment regimens were not significant after
grouping according to tumor size and nodal status.
When more than 50% of node-positive patients in
both the mastectomy and BCT arms received adjuvant
radiation, both arms had similar survival rates.
When less than 50% of node-positive patients in
both arms received adjuvant nodal radiation, the
odds ratio was 0.69, and patients receiving BCT
had a survival advantage. CONCLUSIONS: Patients
allocated to BCT have survival rates at least as
high as patients allocated to mastectomy. When all
protocols were combined, nodal status and tumor
size did not significantly alter the relative survival
rates. However, under some conditions, particularly
for node-positive patients, BCT may confer a relative
survival advantage over mastectomy. In particular,
mastectomy without adjuvant radiation appears to
be inferior to BCT for node-positive patients.
2. Effects of radiotherapy and surgery in early
breast cancer: An overview of randomized trials.
EBCTCG, N Eng J Med 1995, 333: 1444-1455.
BACKGROUND. Randomized trials of radiotherapy and
surgery for early breast cancer may have been too
small to detect differences in long-term survival
and recurrence reliably. We therefore performed
a systematic overview (meta-analysis) of the results
of such trials. METHODS. Information was sought
on each subject from investigators who conducted
trials that began before 1985 and that compared
local therapies for early breast cancer. Data on
mortality were available from 36 trials comparing
radiotherapy plus surgery with the same type of
surgery alone, 10 comparing more extensive surgery
with less extensive surgery, and 18 comparing more
extensive surgery with less extensive surgery plus
radiotherapy. Information on mortality was available
for 28,405 women (97.4 percent of the 29,175 women
in the trials). RESULTS. The addition of radiotherapy
to surgery resulted in a rate of local recurrence
that was three times lower than the rate with surgery
alone, but there was no significant difference in
10-year survival; among a total of 17,273 women
enrolled in such trials, mortality was 40.3 percent
with radiotherapy and 41.4 percent without radiotherapy
(P = 0.3). Radiotherapy was associated with a reduced
risk of death due to breast cancer (odds ratio,
0.94; 95 percent confidence interval, 0.88 to 1.00;
P = 0.03), which indicates that, after 10 years,
there would be about 0 to 5 fewer deaths due to
breast cancer per 100 women. However, there was
an increased risk of death from other causes (odds
ratio, 1.24; 95 percent confidence interval, 1.09
to 1.42; P = 0.002). This, together with the age-specific
death rates, implies, after 10 years, a few extra
deaths not due to breast cancer per 100 older women
or per 1000 younger women. During the first decade
or two after diagnosis, the excess in the rate of
such deaths that was associated with radiotherapy
was much greater women who were over 60 years of
age at randomization (15.3 percent vs. 11.1 percent
[339 vs. 249 deaths]) than among those under 50
(2.5 percent vs. 2.0 percent [62 vs. 49 deaths]).
Breast-conserving surgery involved some risk of
recurrence in the remaining tissue, but no significant
differences in overall survival at 10 years were
found in the studies of mastectomy versus breast-conserving
surgery plus radiotherapy (4891 women), more extensive
surgery versus less extensive surgery (4818 women),
or axillary clearance versus radiotherapy as adjuncts
to mastectomy (4370 women). CONCLUSIONS. Some of
the local therapies for breast cancer had substantially
different effects on the rates of local recurrence--such
as the reduced recurrence with the addition of radiotherapy
to surgery--but there were no definite differences
in overall survival at 10 years.
3. Twenty-year follow-up of a randomized trial
comparing total mastectomy, lumpectomy, and lumpectomy
plus irradiation for the treatment of invasive breast
cancer. Fisher B, et al. NSABP; N Engl J Med.
2002;347:1233-41
BACKGROUND: In 1976, we initiated a randomized
trial to determine whether lumpectomy with or without
radiation therapy was as effective as total mastectomy
for the treatment of invasive breast cancer. METHODS:
A total of 1851 women for whom follow-up data were
available and nodal status was known underwent randomly
assigned treatment consisting of total mastectomy,
lumpectomy alone, or lumpectomy and breast irradiation.
Kaplan-Meier and cumulative-incidence estimates
of the outcome were obtained. RESULTS: The cumulative
incidence of recurrent tumor in the ipsilateral
breast was 14.3 percent in the women who underwent
lumpectomy and breast irradiation, as compared with
39.2 percent in the women who underwent lumpectomy
without irradiation (P<0.001). No significant
differences were observed among the three groups
of women with respect to disease-free survival,
distant-disease-free survival, or overall survival.
The hazard ratio for death among the women, who
underwent lumpectomy alone, as compared with those
who underwent total mastectomy, was 1.05 (95 percent
confidence interval, 0.90 to 1.23; P=0.51). The
hazard ratio for death among the women who underwent
lumpectomy followed by breast irradiation, as compared
with those who underwent total mastectomy, was 0.97
(95 percent confidence interval, 0.83 to 1.14; P=0.74).
Among the lumpectomy-treated women whose surgical
specimens had tumor-free margins, the hazard ratio
for death among the women who underwent postoperative
breast irradiation, as compared with those who did
not, was 0.91 (95 percent confidence interval, 0.77
to 1.06; P=0.23). Radiation therapy was associated
with a marginally significant decrease in deaths
due to breast cancer. This decrease was partially
offset by an increase in deaths from other causes.
CONCLUSIONS: Lumpectomy followed by breast irradiation
continues to be appropriate therapy for women with
breast cancer, provided that the margins of resected
specimens are free of tumor and an acceptable cosmetic
result can be obtained.
4. Recurrence rates after treatment of breast
cancer with standard radiotherapy with or without
additional radiation. Bartelink H, et al. NEJM
2001; 345:1378-87.
BACKGROUND: Radiotherapy prevents local recurrence
of breast cancer after breast-conserving surgery.
We evaluated the effect of a supplementary dose
of radiation to the tumor bed on the rates of local
recurrence among patients who received radiotherapy
after breast-conserving surgery for early breast
cancer. METHODS: After lumpectomy and axillary dissection,
patients with stage I or II breast cancer received
50 Gy of radiation to the whole breast in 2-Gy fractions
over a five-week period. Patients with a microscopically
complete excision were randomly assigned to receive
either no further local treatment (2657 patients)
or an additional localized dose of 16 Gy, usually
given in eight fractions by means of an external
electron beam (2661 patients). RESULTS: During a
median follow-up period of 5.1 years, local recurrences
were observed in 182 of the 2657 patients in the
standard-treatment group and 109 of the 2661 patients
in the additional-radiation group. The five-year
actuarial rates of local recurrence were 7.3 percent
(95 percent confidence interval, 6.8 to 7.6 percent)
and 4.3 percent (95 percent confidence interval,
3.8 to 4.7 percent), respectively (P<0.001),
yielding a hazard ratio for local recurrence of
0.59 (99 percent confidence interval, 0.43 to 0.81)
associated with an additional dose. Patients 40
years old or younger benefited most; at five years,
their rate of local recurrence was 19.5 percent
with standard treatment and 10.2 percent with additional
radiation (hazard ratio, 0.46 [99 percent confidence
interval, 0.23 to 0.89]; P=0.002). At five years
in the age group 41 to 50 years old, no differences
were found in rates of metastasis or overall survival
(which were 87 and 91 percent, respectively). CONCLUSIONS:
In patients with early breast cancer who undergo
breast-conserving surgery and receive 50 Gy of radiation
to the whole breast, an additional dose of 16 Gy
of radiation to the tumor bed reduces the risk of
local recurrence, especially in patients younger
than 50 years of age.
5. Pathologic margin involvement and the risk
of recurrence in patients treated with breast-conserving
therapy. Gage I, Schnitt SJ, et al. Cancer 1996;78:1921-8
BACKGROUND: The relationship between the microscopic
margins of resection and ipsilateral breast recurrence
(IBR) after breast-conserving therapy for carcinomas
with or without an extensive intraductal component
(EIC) has not been adequately defined. METHODS:
Of 1,790 women with unilateral clinical Stage I
or II breast carcinoma treated with radiation therapy
as part of breast-conserving therapy, 343 had invasive
ductal histology evaluable for an extensive intraductal
component (EIC), had inked margins that were evaluable
for an review of their pathology slides, and received
> or = 60 Gray to the tumor bed; these 343 women
constitute the study population. The median follow-up
was 109 months. All available slides were reviewed
by one of the study pathologists. Final inked margins
of excision were classified as negative > 1 mm
(no invasive or in situ ductal carcinoma within
1 mm of the inked margin); negative-1 mm, or close
carcinoma < or = 1 mm from the inked margin but
not at the margin); or positive (carcinoma at the
inked margin). A focally positive margin was defined
as invasive or in situ ductal carcinoma at the margin
in three or fewer low-power fields. The first site
of recurrent disease was classified as either ipsilateral
breast recurrence (IBR) or distant metastasis/regional
lymph node failure. RESULTS: Crude rates for the
first site of recurrence were calculated first for
all 340 patients evaluable at 5 years, then separately
for the 272 patients with EIC-negative cancers and
the 68 patients with EIC-positive cancers. The 5-year
rate of IBR for all patients with negative margins
was 2%; and for all patients with positive margins,
the rate was 16%. Among patients with negative margins,
the 5-year rate of IBR was 2% for all patients with
close margins (negative < or = 1 mm) and 3% for
those with negative > 1 mm margins. For patients
with close margins, the rates were 2% and 0% for
EIC-negative and EIC-positive tumors, respectively;
the corresponding rates for patients with negative
margins > 1 mm were 1% and 14%. The 5-year rate
of IBR for patients with focally positive margins
was 9% (9% for EIC-negative and 7% for EIC-positive
patients). The 5-year crude rate of IBR for patients
with greater than focally positive margins was 28%
(19% for EIC-negative and 42% for EIC-positive patients).
CONCLUSIONS: Patients with negative margins of excision
have a low rate of recurrence in the treated breast,
whether the margin is > 1 mm or < or = 1 mm
and whether the carcinoma is EIC-negative or EIC-positive.
Among patients with positive margins, those with
focally positive margins have a considerably lower
risk of local recurrence than those with more than
focally positive margins, and could be considered
for breast-conserving therapy.
| Breast
Conservation Surgery is the gold standard for
early breast cancer. Modified radical mastectomy
remains the standard of treatment when disease
is multi-centric or compliance to postoperative
radiotherapy is doubtful. |
BREAST CANCER
Adjuvant Systemic Therapy |
2
EBM
|
6. Tamoxifen for early breast cancer.
Cochrane Database Syst Rev 2001;(1):CD000486
Early Breast Cancer Trialists' Collaborative Group.
In this report, the Early Breast Cancer Trialists'
Collaborative Group present their third 5-yearly
systematic overview (meta-analysis) of treatment
with tamoxifen. SELECTION CRITERIA: All randomised
trials that began before 1990 and compared adjuvant
tamoxifen for any duration versus no such treatment
for women with early breast cancer. Information
was obtained and analysed centrally on each of 37,000
women in 55 such trials, comprising about 87% of
the worldwide evidence. RESULTS: Nearly 8000 of
the women had a low, or zero, level of the oestrogen-receptor
protein (ER) measured in their primary tumour. Among
them, the overall effects of tamoxifen appeared
to be small, and subsequent analyses of recurrence
and total mortality are restricted to the remaining
women (18,000 with ER-positive tumours, plus nearly
12,000 more with untested tumours, of which an estimated
8000 would have been ER-positive). For trials of
1 year, 2 years, and about 5 years of adjuvant tamoxifen,
the proportional recurrence reductions produced
among these 30,000 women during about 10 years of
follow-up were 21% (SD 3), 29% (SD 2), and 47% (SD
3), respectively, with a highly significant trend
towards greater effect with longer treatment (2p<0.00001).
The corresponding proportional mortality reductions
were 12% (SD 3), 17% (SD 3), and 26% (SD 4), respectively,
and again the test for trend was significant (2p=0.003).
The absolute improvement in recurrence was greater
during the first 5 years, whereas the improvement
in survival grew steadily larger throughout the
first 10 years. The proportional mortality reductions
were similar for women with node-positive and node-negative
disease, but the absolute mortality reductions were
greater in node-positive women. In the trials of
about 5 years of adjuvant tamoxifen the absolute
improvements in 10-year survival were 10.9% (SD
2.5) for node-positive (61.4% vs 50.5% survival,
2p<0.00001) and 5.6% (SD 1.3) for node-negative
(78.9% vs 73.3% survival, 2p<0.00001). These
benefits appeared to be largely irrespective of
age, menopausal status, daily tamoxifen dose (which
was generally 20 mg), and of whether chemotherapy
had been given to both groups. In terms of other
outcomes among all women studied (ie, including
those with "ER-poor" tumours), the proportional
reductions in contralateral breast cancer were 13%
(SD 13), 26% (SD 9), and 47% (SD 9) in the trials
of 1, 2, or about 5 years of adjuvant tamoxifen.
The incidence of endometrial cancer was approximately
doubled in trials of 1 or 2 years of tamoxifen and
approximately quadrupled in trials of 5 years of
tamoxifen (although the number of cases was small
and these ratios were not significantly different
from each other). The absolute decrease in contralateral
breast cancer was about twice as large as the absolute
increase in the incidence of endometrial cancer.
Tamoxifen had no apparent effect on the incidence
of colorectal cancer or, after exclusion of deaths
from breast or endometrial cancer, on any of the
other main categories of cause of death (total nearly
2000 such deaths; overall relative risk 0.99 [SD
0.05]). CONCLUSIONS: For women with tumours that
have been reliably shown to be ER-negative, adjuvant
tamoxifen remains a matter for research. However,
some years of adjuvant tamoxifen treatment substantially
improves the 10-year survival of women with ER-positive
tumours and of women whose tumours are of unknown
ER status, with the proportional reductions in breast
cancer recurrence and in mortality appearing to
be largely unaffected by other patient characteristics
or treatments.
7. Ovarian ablation for early breast cancer
Cochrane Database Syst Rev 2000;(3):CD000485
Early Breast Cancer Trialists' Collaborative Group.
In this report, the Early Breast Cancer Trialists'
Collaborative Group present their third 5-yearly
systematic overview (meta-analysis), now with 15
years' follow-up. SELECTION CRITERIA: All properly
randomised trials that began recruiting before 1990
which compared the ablation or suppression of ovarian
function, sometimes with the addition of prednisone,
versus no such adjuvant treatment for women with
operable breast cancer. In practice, all the trials
that can be reviewed here began before 1980, and
all involved surgical or therapeutic ablation. Data
were obtained for 12 of the 13 studies that assessed
ovarian ablation by irradiation or surgery, all
of which began before 1980, but not for the four
studies that assessed ovarian suppression by drugs,
all of which began after 1985. Menopausal status
was not consistently defined across trials; therefore,
the main analyses are limited to women aged under
50 (rather than "premenopausal") when
randomised. Oestrogen receptors were measured only
in the trials of ablation plus cytotoxic chemotherapy
versus the same chemotherapy alone. MAIN RESULTS:
Among 2102 women aged under 50 when randomised,
most of whom would have been premenopausal at diagnosis,
1130 deaths and an additional 153 recurrences were
reported. 15-year survival was highly significantly
improved among those allocated ovarian ablation
(52.4 vs 46.1%, 6.3 [SD 2.3] fewer deaths per 100
women, logrank 2p=0.001), as was recurrence-free
survival (45.0 vs 39.0%, 2p=0.0007). The numbers
of events were too small for any subgroup analyses
to be reliable. The benefit was, however, significant
both for those with ("node positive")
and for those without ("node negative")
axillary spread when diagnosed. In the trials of
ablation plus cytotoxic chemotherapy versus the
same chemotherapy alone, the benefit appeared smaller
(even for women with oestrogen receptors detected
on the primary tumour) than in the trials in the
absence of chemotherapy (where the observed survival
improvements were about six per 100 node-negative
women and 12 per 100 node-positive women). Among
1354 women aged 50 or over when randomised, most
of whom would have been perimenopausal or postmenopausal,
there was only a non-significant improvement in
survival and recurrence-free survival. CONCLUSIONS:
In women aged under 50 with early breast cancer,
ablation of functioning ovaries significantly improves
long-term survival, at least in the absence of chemotherapy.
Further randomised evidence is needed on the additional
effects of ovarian ablation in the presence of other
adjuvant treatments, and to assess the relevance
of hormone-receptor measurements.
8. Anastrozole alone or in combination with
tamoxifen versus tamoxifen alone for adjuvant treatment
of postmenopausal women with early breast cancer:
first results of the ATAC randomised trial.
The ATAC Trialists' Group. Lancet; 2002 22;2131-9
BACKGROUND: In the adjuvant setting, tamoxifen
is the established treatment for postmenopausal
women with hormone-sensitive breast cancer. However,
it is associated with several side effects including
endometrial cancer and thromboembolic disorders.
We aimed to compare the safety and efficacy outcomes
of tamoxifen with those of anastrozole alone and
the combination of anastrozole plus tamoxifen for
5 years. METHODS: Participants were postmenopausal
patients with invasive operable breast cancer who
had completed primary therapy and were eligible
to receive adjuvant hormonal therapy. The primary
endpoints were disease-free survival and occurrence
of adverse events. Analysis for efficacy
was by intention to treat. FINDINGS: 9366 patients
were recruited, of whom 3125 were randomly assigned
anastrozole, 3116 tamoxifen, and 3125 combination.
Median follow-up was 33.3 months. 7839 (84%) patients
were known to be hormone-receptor-positive. Disease-free
survival at 3 years was 89.4% on anastrozole and
87.4% on tamoxifen (hazard ratio 0.83 [95% CI 0.71-0.96],
p=0.013). Results with the combination were not
significantly different from those with tamoxifen
alone (87.2%, 1.02 [0.89-1.18], p=0.8). The improvement
in disease-free survival with anastrozole was seen
in the subgroup of hormone-receptor-positive patients,
but not the receptor-negative patients. Incidence
of contralateral breast cancer was significantly
lower with anastrozole than with tamoxifen (odds
ratio 0.42 [0.22-0.79], p=0.007). Anastrozole was
significantly better tolerated than tamoxifen with
respect to endometrial cancer (p=0.02), vaginal
bleeding and discharge (p<0.0001 for both), cerebrovascular
events (p=0.0006), venous thromboembolic events
(p=0.0006), and hot flushes (p<0.0001). Tamoxifen
was significantly better tolerated than anastrozole
with respect to musculoskeletal disorders and fractures
(p<0.0001 for both). INTERPRETATION: Anastrozole
is an effective and well-tolerated endocrine option
for the treatment of postmenopausal patients with
hormone-sensitive early breast cancer. Longer follow-up
is required before a final benefit:risk assessment
can be made.
9. Multi-agent chemotherapy for early breast
cancer.
Cochrane Database Syst Rev 2002;(1):CD000487
Early Breast Cancer Trialists' Collaborative Group.
In this report, the Early Breast Cancer Trialists'
Collaborative Group present their updated systematic
overview (meta-analysis) of treatment with polychemotherapy.
All randomised trials that began before 1990 and
involved treatment groups that differed only with
respect to the chemotherapy regimens were compared.
Analyses involved about 18,000 women in 47 trials
of prolonged polychemotherapy versus no chemotherapy,
about 6000 in 11 trials of longer versus shorter
polychemotherapy, and about 6000 in 11 trials of
anthracycline-containing regimens versus CMF (cyclophosphamide,
methotrexate, and fluorouracil). RESULTS: For recurrence,
polychemotherapy produced substantial and highly
significant proportional reductions both among women
aged under 50 at randomisation (35% [SD 4] reduction;
2p <0.00001) and among those aged 50-69 (20%
[SD 3] reduction; 2p <0.00001); few women aged
70 or over had been studied. For mortality, the
reductions were also significant both among women
aged under 50 (27% [SD 5] reduction; 2p <0.00001)
and among those aged 50-69 (11% [SD 3] reduction;
2p=0.0001). The recurrence reductions emerged chiefly
during the first 5 years of follow-up, whereas the
difference in survival grew throughout the first
10 years. After standardisation for age and time
since randomisation, the proportional reductions
in risk were similar for women with node-negative
and node-positive disease. Applying the proportional
mortality reduction observed in all women aged under
50 at randomisation would typically change a 10-year
survival of 71% for those with node-negative disease
to 78% (an absolute benefit of 7%), and of 42% for
those with node-positive disease to 53% (an absolute
benefit of 11%). The smaller proportional mortality
reduction observed in all women aged 50-69 at randomisation
would translate into smaller absolute benefits,
changing a 10-year survival of 67% for those with
node-negative disease to 69% (an absolute gain of
2%) and of 46% for those with node-positive disease
to 49% (an absolute gain of 3%). The age-specific
benefits of polychemotherapy appeared to be largely
irrespective of menopausal status at presentation,
oestrogen receptor status of the primary tumour,
and of whether adjuvant tamoxifen had been given.
In terms of other outcomes, there was a reduction
of about one-fifth (2p=0.05) in contralateral breast
cancer, which has already been included in the analyses
of recurrence, and no apparent adverse effect on
deaths from causes other than breast cancer (death
rate ratio 0.89 [SD 0.09]). The directly randomised
comparisons of longer versus shorter durations of
polychemotherapy did not indicate any survival advantage
with the use of more than about 3-6 months of polychemotherapy.
By contrast, directly randomised comparisons did
suggest that, compared with CMF alone, the anthracycline-containing
regimens studied produced somewhat greater effects
on recurrence (2p=0.006) and mortality (69% vs 72%
5-year survival; log-rank 2p=0.02). But this comparison
is one of many that could have been selected for
emphasis, the 99% CI reaches zero, and the results
of several of the relevant trials are not yet available.
CONCLUSIONS: Some months of adjuvant polychemotherapy
(eg, with CMF or an anthracycline-containing regimen)
typically produces an absolute improvement of about
7-11% in 10-year survival for women aged under 50
at presentation with early breast cancer, and of
about 2-3% for those aged 50-69 (unless their prognosis
is likely to be extremely good even without such
treatment). Treatment decisions involve consideration
not only of improvements in cancer recurrence and
survival but also of adverse side-effects of treatment,
and this report makes no recommendations as to who
should or should not be treated.
10. Phase III Trial comparing two doses of Epirubicin
combined with cyclophosphamide with Cyclophosphamide,
Methotrexate, and Fluorouracil in node-positive
breast cancer.
Piccart MJ, et el: J Clin Oncol, 19(12), 2001: 3103-3110.
PURPOSE: To compare a full-dose epirubicin-cyclophosphamide
(HEC) regimen with classical cyclophosphamide, methotrexate,
and fluorouracil (CMF) therapy and with a moderate-dose
epirubicin-cyclophosphamide regimen (EC) in the
adjuvant therapy of node-positive breast cancer.
PATIENTS AND METHODS: Node-positive breast cancer
patients who were aged 70 years or younger were
randomly allocated to one of the following treatments:
CMF for six cycles (oral cyclophosphamide); EC for
eight cycles (epirubicin 60 mg/m(2), cyclophosphamide
500 mg/m(2); day 1 every 3 weeks); and HEC for eight
cycles (epirubicin 100 mg/m(2), cyclophosphamide
830 mg/m(2); day 1 every 3 weeks). RESULTS: Two
hundred fifty-five, 267, and 255 eligible patients
were treated with CMF, EC, and HEC, respectively.
Patient characteristics were well balanced among
the three arms. One and three cases of congestive
heart failure were reported in the EC and HEC arms,
respectively. Three cases of acute myeloid leukemia
were reported in the HEC arm. After 4 years of median
follow-up, no statistically significant differences
were observed between HEC and CMF (event-free survival
[EFS]: hazards ratio [HR] = 0.96, 95% confidence
interval [CI], 0.70 to 1.31, P =.80; distant-EFS:
HR = 0.97, 95% CI, 0.70 to 1.34, P =.87; overall
survival [OS]: HR = 0.97, 95% CI, 0.65 to 1.44,
P =.87). HEC is more effective than EC (EFS: HR
= 0.73, 95% CI, 0.54 to 0.99, P =.04; distant-EFS:
HR = 0.75, 95% CI, 0.55 to 1.02, P =.06; OS HR =
0.69, 95% CI, 0.47 to 1.00, P =.05). CONCLUSION:
This three-arm study does not show an advantage
in favor of an adequately dosed epirubicin-based
regimen over classical CMF in the adjuvant therapy
of node-positive pre- and postmenopausal women with
breast cancer. Moreover, this study confirms that
there is a dose-response curve for epirubicin in
breast cancer adjuvant therapy.
11. ESMO Minimum Clinical Recommendations for
diagnosis, adjuvant treatment and follow-up of primary
breast cancer. Annals of Oncology 12: 1047-48,
2001. (No abstract available)
12. National Institute of Health. Consensus
Development Conference Statement: Adjuvant Therapy
for Breast Cancer. Nov 1-3 2000, J Natl Cancer
Inst Monogr 2001: 30: 5-15.
OBJECTIVE: Our goal was to provide health-care providers,
patients, and the general public with an assessment
of currently available data regarding the use of
adjuvant therapy for breast cancer. PARTICIPANTS:
The participants included a non-Federal, non-advocate,
14-member panel representing the fields of oncology,
radiology, surgery, pathology, statistics, public
health, and health policy as well as patient representatives.
In addition, 30 experts in medical oncology, radiation
oncology, biostatistics, epidemiology, surgical
oncology, and clinical trials presented data to
the panel and to a conference audience of 1000.
EVIDENCE: The literature was searched with the use
of MEDLINE for January 1995 through July 2000, and
an extensive bibliography of 2230 references was
provided to the panel. Experts prepared abstracts
for their conference presentations with relevant
citations from the literature. Evidence from randomized
clinical trials and evidence from prospective studies
were given precedence over clinical anecdotal experience.
CONSENSUS PROCESS: The panel, answering predefined
questions, developed its conclusions based on the
evidence presented in open forum and the scientific
literature. The panel composed a draft statement,
which was read in its entirety and circulated to
the experts and the audience for comment. Thereafter,
the panel resolved conflicting recommendations and
released a revised statement at the end of the conference.
The panel finalized the revisions within a few weeks
after the conference. The draft statement was made
available on the World Wide Web immediately after
its release at the conference and was updated with
the panel's final revisions. The statement is available
at http://consensus.nih.gov. CONCLUSIONS: The panel
concludes that decisions regarding adjuvant hormonal
therapy should be based on the presence of hormone
receptor protein in tumor tissues. Adjuvant hormonal
therapy should be offered only to women whose tumors
express hormone receptor protein. Because adjuvant
polychemotherapy improves survival, it should be
recommended to the majority of women with localized
breast cancer regardless of lymph node, menopausal,
or hormone receptor status. The inclusion of anthracyclines
in adjuvant chemotherapy regimens produces a small
but statistically significant improvement in survival
over non-anthracycline-containing regimens. Available
data are currently inconclusive regarding the use
of taxanes in adjuvant treatment of lymph node-positive
breast cancer. The use of adjuvant dose-intensive
chemotherapy regimens in high-risk breast cancer
and of taxanes in lymph node-negative breast cancer
should be restricted to randomized trials. Ongoing
studies evaluating these treatment strategies should
be supported to determine if such strategies have
a role in adjuvant treatment. Studies to date have
included few patients older than 70 years. There
is a critical need for trials to evaluate the role
of adjuvant chemotherapy in these women. There is
evidence that women with a high risk of locoregional
tumor recurrence after mastectomy benefit from postoperative
radiotherapy. This high-risk group includes women
with four or more positive lymph nodes or an advanced
primary cancer. Currently, the role of postmastectomy
radiotherapy for patients with one to three positive
lymph nodes remains uncertain and should be tested
in a randomized controlled trial. Individual patients
differ in the importance they place on the risks
and benefits of adjuvant treatments. Quality of
life needs to be evaluated in selected randomized
clinical trials to examine the impact of the major
acute and long-term side effects of adjuvant treatments,
particularly premature menopause, weight gain, mild
memory loss, and fatigue. Methods to support shared
decision-making between patients and their physicians
have been successful in trials; they need to be
tailored for diverse populations and should be tested
for broader dissemination.
| Adjuvant
chemotherapy reduces death due to breast cancer
by 25% (RR) in premenopausal women. Effect is
halved in postmenopausal women. Adjuvant tamoxifen
reduces death in hormone sensitive breast cancer
by 26% (RR) irrespective of menopausal status.
|
BREAST CANCER -
Adjuvant loco-regional radiotherapy |
3
EBM
|
13. DBCG 82B Danish Breast Cancer Cooperative
Group randomized trial: Postmastectomy radiotherapy
in high-risk premenopausal breast cancer patients
given adjuvant chemotherapy. Overgaard M et
al. N Engl J Med 1997; 337:949-55
Irradiation after mastectomy can reduce locoregional
recurrences in women with breast cancer, but whether
it prolongs survival remains controversial. We conducted
a randomized trial of radiotherapy after mastectomy
in high-risk premenopausal women, all of whom also
received adjuvant systemic chemotherapy with cyclophosphamide,
methotrexate, and fluorouracil (CMF). METHODS: A
total of 1708 women who had undergone mastectomy
for pathological stage II or III breast cancer were
randomly assigned to receive eight cycles of CMF
plus irradiation of the chest wall and regional
lymph nodes (852 women) or nine cycles of CMF alone
(856 women). The median length of follow-up was
114 months. The end points were locoregional recurrence,
distant metastases, disease-free survival, and overall
survival. RESULTS: The frequency of locoregional
recurrence alone or with distant metastases was
9 percent among the women who received radiotherapy
plus CMF and 32 percent among those who received
CMF alone (P<0.001). The probability of survival
free of disease after 10 years was 48 percent among
the women assigned to radiotherapy plus CMF and
34 percent among those treated only with CMF (P<0.001).
Overall survival at 10 years was 54 percent among
those given radiotherapy and CMF and 45 percent
among those who received CMF alone (P<0.001).
Multivariate analysis demonstrated that irradiation
after mastectomy significantly improved disease-free
survival and overall survival, irrespective of tumor
size, the number of positive nodes, or the histopathological
grade. CONCLUSIONS: The addition of postoperative
irradiation to mastectomy and adjuvant chemotherapy
reduces locoregional recurrences and prolongs survival
in high-risk premenopausal women with breast cancer.
14. DBCG 82C Danish Breast Cancer Cooperative
Group randomized trial: Postmastectomy radiotherapy
in high-risk postmenopausal breast cancer patients
given adjuvant tamoxifen. Overgaard M, et al.
Lancet 1999;353:1641-8
Postmastectomy radiotherapy is associated with a
lower locoregional recurrence rate and improved
disease-free and overall survival when combined
with chemotherapy in premenopausal high-risk breast-cancer
patients. However, whether the same benefits apply
also in postmenopausal women treated with adjuvant
tamoxifen for similar high-risk cancer is unclear.
In a randomised trial among postmenopausal women
who had undergone mastectomy, we compared adjuvant
tamoxifen alone with tamoxifen plus postoperative
radiotherapy. METHODS: Between 1982 and 1990, postmenopausal
women with high-risk breast cancer (stage II or
III) were randomly assigned adjuvant tamoxifen (30
mg daily for 1 year) alone (689) or with postoperative
radiotherapy to the chest wall and regional lymph
nodes (686). Median follow-up was 123 months. The
endpoints were first site of recurrence (locoregional
recurrence, distant metastases, or both), and disease-free
and overall survival. FINDINGS: Locoregional recurrence
occurred in 52 (8%) of the radiotherapy plus tamoxifen
group and 242 (35%) of the tamoxifen only group
(p<0.001). In total there were 321 (47%) and
411 (60%) recurrences, respectively. Disease-free
survival was 36% in the radiotherapy plus tamoxifen
group and 24% in the tamoxifen alone group (p<0.001).
Overall survival was also higher in the radiotherapy
group (385 vs 434 deaths; survival 45 vs 36% at
10 years, p=0.03). INTERPRETATION: Postoperative
radiotherapy decreased the risk of locoregional
recurrence and was associated with improved survival
in high-risk postmenopausal breast-cancer patients
after mastectomy and limited axillary dissection,
with 1 year of adjuvant tamoxifen treatment. Improved
survival in high-risk breast cancer can best be
achieved by a strategy of both locoregional and
systemic tumour control.
15. Radiotherapy for early breast cancer
Cochrane Database Syst Rev 2002;(2):CD003647
Early Breast Cancer Trialists' Collaborative Group.
OBJECTIVES: In this report the Early Breast Cancer
Trialists' Collaborative Group present their systematic
overview of treatment with radiotherapy. SELECTION
CRITERIA: A meta-analysis was done of 10-year and
20-year results from 40 unconfounded randomised
trials of radiotherapy for early breast cancer.
Radiotherapy fields generally included not only
chest wall (or breast) but also axillary, supraclavicular,
and internal mammary nodes. DATA COLLECTION AND
ANALYSIS: Data collection involved central review
of individual patient data on recurrence and cause-specific
mortality from 20,000 women. MAIN RESULTS: A reduction
of approximately two-thirds in local recurrence
was seen in all trials, largely independent of the
type of patient or type of radiotherapy (8.8% vs
27.2% local recurrence by year 10). Hence, to assess
effects on breast cancer mortality of substantially
better local control, results from all trials were
combined. Breast cancer mortality was reduced (2p=0.0001)
but other, particularly vascular, mortality was
increased (2p=0.0003), and overall 20-year survival
was 37.1% with radiotherapy versus 35.9% control
(2p=0.06). There was little effect on early deaths,
but log rank analyses of later deaths indicate that,
on average after year 2, radiotherapy reduced annual
mortality rates from breast cancer by 13.2% (SE
2.5) but increased those from other causes by 21.2%
(SE 5.4). Nodal status, age, and decade of follow-up
strongly affected the ratio of breast cancer mortality
to other mortality, and hence affected the ratio
of absolute benefit to absolute hazard from these
proportional changes in mortality. REVIEWER'S CONCLUSIONS:
Radiotherapy regimens able to produce the two-thirds
reduction in local recurrence seen in these trials,
but without long-term hazard, would be expected
to produce an absolute increase in 20-year survival
of about 2-4% (except for women at particularly
low risk of local recurrence). The average hazard
seen in these trials would, however, reduce this
20-year survival benefit in young women and reverse
it in older women.
| Post-operative
RT is mandatory following breast conservation
surgery and saves lives when administered post-mastectomy
in women with T > 5cm and / or N > 3 |
BREAST CANCER - LABC
Multimodal therapy / Neoadjuvant CT |
4
EBM
|
Evidence from the NSABP B-18 randomized trial and
other retrospective studies have shown that neoadjuvant
chemotherapy effectively reduces the primary tumor
size in nearly 80% cases. Tumour regression increases
the feasibility of BCT in large operable and locally
advanced cancers. However, anterior chemotherapy
has not resulted in any improvement in disease-free
or overall survival. A good response to chemotherapy
does indicate a better prognosis. No large randomised
evidence is available to assess effect of neoadjuvant
chemotherapy in locally advanced breast cancer.
16. Effect of preoperative chemotherapy on the
outcome of women with operable breast cancer.
Fisher B, et al. NSABP J Clin Oncol, 16:1998:2672-85
PURPOSE: To determine, in women with primary operable
breast cancer, if preoperative doxorubicin (Adriamycin)
and cyclophosphamide (Cytoxan; AC) therapy yields
a better outcome than postoperative AC therapy,
if a relationship exists between outcome and tumor
response to preoperative chemotherapy, and if such
therapy results in the performance of more lumpectomies.
PATIENTS AND METHODS: Women (1,523) enrolled onto
National Surgical Adjuvant Breast and Bowel Project
(NSABP) B-18 were randomly assigned to preoperative
or postoperative AC therapy. Clinical tumor response
to preoperative therapy was graded as complete (cCR),
partial (cPR), or no response (cNR). Tumors with
a cCR were further categorized as either pathologic
complete response (pCR) or invasive cells (pINV).
Disease-free survival (DFS), distant disease-free
survival (DDFS), and survival were estimated through
5 years and compared between treatment groups. In
the preoperative arm, proportional-hazards models
were used to investigate the relationship between
outcome and tumor response. RESULTS: There was no
significant difference in DFS, DDFS, or survival
(P = .99, .70, and .83, respectively) among patients
in either group. More patients treated preoperatively
than postoperatively underwent lumpectomy and radiation
therapy (67.8% v 59.8%, respectively). Rates of
ipsilateral breast tumor recurrence (IBTR) after
lumpectomy were similar in both groups (7.9% and
5.8%, respectively; P = .23). Outcome was better
in women whose tumors showed a pCR than in those
with a pINV, cPR, or cNR (relapse-free survival
[RFS] rates, 85.7%, 76.9%, 68.1%, and 63.9%, respectively;
P < .0001), even when baseline prognostic variables
were controlled. CONCLUSION: Preoperative chemotherapy
is as effective as postoperative chemotherapy, permits
more lumpectomies, is appropriate for the treatment
of certain patients with stages I and II disease,
and can be used to study breast cancer biology.
Tumor response to preoperative chemotherapy correlates
with outcome and could be a surrogate for evaluating
the effect of chemotherapy on micrometastases; however,
knowledge of such a response provided little prognostic
information beyond that which resulted from postoperative
therapy.
17. The efficacy of neoadjuvant chemotherapy
compared to postoperative therapy in the treatment
of locally advanced breast cancer. Cunningham
JD et al. Cancer Invest 1998;16:80-6.
The current approach to the treatment of locally
advanced breast cancer is sequential chemotherapy,
surgery and/or radiation, and consolidation chemotherapy.
Although significant tumor response is seen with
this regimen, there are few studies that compare
this approach to postoperative chemotherapy. The
purpose of this study was to compare the disease-free
and overall survival of patients with locally advanced
breast cancer treated with neoadjuvant chemotherapy
and surgery to patients treated with surgery followed
by adjuvant chemotherapy. Ninety-four patients with
stage IIB, IIIA, and IIIB breast cancer were treated
with a standardized chemotherapy regimen. The first
group, 60 patients who were followed prospectively,
was treated with neoadjuvant chemotherapy (NCT)
consisting of vincristine, prednisone, cytoxan,
methotrexate, and 5-FU (CVFMP) followed by surgery
and consolidation chemotherapy with adriamycin.
The second group, 34 patients evaluated retrospectively,
had surgery followed by postoperative chemotherapy
(PCT) with CVFMP followed by adriamycin. Overall
median follow-up was 38 months. In the NCT group,
45/60 (75%) patients had a clinical response to
induction therapy and the median reduction in tumor
size was 50%. The rates of local recurrence, distant
recurrence, and death from disease were similar
in the two groups. The time to local recurrence
was similar for the two groups. However, the median
time to distant recurrence was shorter in the NCT
group (19 month vs. 31 months, p = NS). Overall
median survival among the NCT patients was shorter
than for the PCT group (30 vs. 47 months, p = NS).
The current study suggests that postoperative therapy
is comparable to a neoadjuvant regimen in patients
with locally advanced breast cancer with regard
to local recurrence, distant recurrence, and overall
survival.
18. Relationship of clinical and pathologic
response to neoadjuvant chemotherapy and outcome
of locally advanced breast cancer.
Gajdos C, Tartter PI, et al. J Surg Oncol 2002;
80: 4-11.
BACKGROUND AND OBJECTIVES: Neoadjuvant chemotherapy
in locally advanced breast cancers produces histologically
evaluable changes and frequently reduces the size
of the primary tumor. Local clinical response to
neoadjuvant chemotherapy may correlate with response
of distant metastases. Therefore, clinical or pathological
factors, which predict or assess response to treatment,
may predict outcome after consideration for initial
extent of disease. METHODS: To identify pretreatment
characteristics of locally advanced breast cancers
which predict clinical and pathologic response to
neoadjuvant chemotherapy as well as survival and
to assess the utility of postoperative histologic
changes, we retrospectively studied one hundred
forty-four patients with locally advanced breast
cancer treated with neoadjuvant chemotherapy between
January 1975 and July 1996. Patients were identified
through pathology records of the Mount Sinai Medical
Center and via one of the author's clinical databases.
Pathologic and clinical responses to neoadjuvant
chemotherapy were correlated with survival. Stepwise
logistic regression was used to identify variables
most significantly related to clinical response
and pathologic axillary lymph node involvement.
RESULTS: Complete clinical response with no palpable
tumor was noted in 7/86 patients (8%) and complete
pathologic response was achieved in 18/138 patients
(13%). Both clinical (P = 0.038) and pathologic
response (P = 0.011) were related to tumor size
at the time of diagnosis: smaller tumors were more
likely to respond to chemotherapy than larger tumors.
Histologic evidence of chemotherapeutic effect,
i.e., cytoplasmic vacuolization, change in the number
of mitoses and localized fibrosis in lymph nodes
did not correlate with clinical or pathologically
measured response. Clinical and pathologic response
was not associated with age, histology, differentiation,
or type of chemotherapy. No residual tumor was found
in the axillary nodes of 27% (37) of the patients.
Age and complete pathologic response were the only
variables significantly related to pathologic nodal
status. Eighty-four percent of the 61 patients under
50 years of age had nodal involvement compared to
65% of older patients (P = 0.014). Fifty percent
of complete pathologic responders had positive axillary
lymph nodes compared to 76% of patients who did
not have a complete pathologic response (P = 0.020).
Distant disease-free (P = 0.039) and overall survival
(P = 0.035) were related to the number of involved
axillary lymph nodes. After consideration for pathologic
lymph node status, no other variable was significantly
related to distant disease-free or overall survival
in multivariate analysis. No variable was significantly
related to local disease-free survival. Age, clinical
tumor size, clinical lymph node status, clinical
response, type of chemotherapy, histology, differentiation,
chemotherapy effects on primary tumor and lymph
nodes, decline in the number of mitoses, and degree
of fibrosis in nodes were not predictive of distant
recurrence or overall survival. CONCLUSIONS: This
study of patients treated with neoadjuvant chemotherapy
for locally advanced breast cancers found little
evidence that measurable clinical or pathologic
changes attributable to chemotherapy predicted survival.
Axillary lymph node status, associated with young
age, was the most important prognostic indicator
in these patients.
| Neoadjuvant
chemotherapy does not improve survival in breast
cancer but it facilitates breast conservation |
BREAST CANCER -
Follow-up after primary treatment |
5
EBM
|
19. Intensive diagnostic follow-up after treatment
of primary breast cancer: a randomised trial.
Rosselli Del Turco M, Palli D, Cariddi A: . JAMA.
1994; 271: 1593-97.National Research Council Project
on Breast Cancer follow-up.
OBJECTIVE. To evaluate the effectiveness of early
detection of intrathoracic and bone metastases in
reducing mortality in breast cancer patients. DESIGN.
Randomized clinical trial allocating breast cancer
patients to two alternative follow-up protocols
(intensive vs clinical) for at least 5 years. SETTING.
Twelve breast clinics (referral centers) in different
areas in Italy. PATIENTS. A total of 1243 consecutive
patients (either premenopausal or postmenopausal)
surgically treated for unilateral invasive breast
carcinoma with no evidence of metastases. The two
study groups were well balanced in terms of clinical
and prognostic characteristics. INTERVENTION. Patients
in both treatment groups had physical examination
and mammography, while patients of the intensive
follow-up group had, in addition, chest roentgenography
and bone scan every 6 months. MAIN OUTCOME MEASURES.
Vital status at 5 years was the main outcome; information
was available for all except five patients (0.4%).
Relapse-free survival was also analyzed. RESULTS.
Overall, 393 recurrences (104 local and 289 distant)
were observed during the study. Increased detection
of isolated intrathoracic and bone metastases was
evident in the intensive follow-up group compared
with the clinical follow-up group (112 vs 71 cases),
while no difference was observed for other sites
and for local and/or regional recurrences. The 5-year
relapse-free survival rate was significantly higher
for the clinical follow-up group, with patients
in the intensive follow-up group showing earlier
detection of recurrences. No difference in 5-year
overall mortality (18.6% vs 19.5%) was observed
between the two follow-up groups. CONCLUSIONS. Periodic
chest roentgenography and bone scan allow earlier
detection of distant metastases, but anticipated
diagnosis appears to be the only effect of intensive
follow-up, and no impact on prognosis is evident
after 5 years. Periodic intensive follow-up with
chest roentgenography and bone scan should not be
recommended as a routine policy.
20. Impact of follow-up testing on survival
& health-related quality of life in breast cancer
patients. A multi-center randomised controlled
trial. The GIVIO Investigators:
JAMA 1994; 271: 1587-92
OBJECTIVE. To assess prospectively the impact on
survival and health-related quality of life of two
follow-up protocols in patients with early breast
cancer. DESIGN. Randomized controlled clinical trial.
SETTING. Multicenter study involving 26 general
hospitals in Italy. PATIENTS: A consecutive sample
of 1320 women younger than 70 years with stage I,
II, and III unilateral primary breast cancer. INTERVENTION:
Patients were randomly assigned to an intensive
surveillance, which included physician visits and
performance of bone scan, liver echography, chest
roentgenography, and laboratory tests at predefined
intervals (n = 655), or to a control regimen (n
= 665), in which patients were seen by their physicians
at the same frequency but only clinically indicated
tests were performed. Both groups received a yearly
mammogram aimed at detecting contralateral breast
cancer. MAIN OUTCOME MEASURES. Primary end points
were overall survival and health-related quality
of life. RESULTS. Compliance to the two follow-up
protocols was more than 80%. At a median follow-up
of 71 months, no difference was apparent in overall
survival with 132 deaths (20%) in the intensive
group and 122 deaths (18%) in the control group.
No significant differences were apparent in time
to detection of recurrence between the two groups.
Measurements of health-related quality of life (ie,
overall health and quality-of-life perception, emotional
well-being, body image, social functioning, symptoms,
and satisfaction with care) at 6, 12, 24, and 60
months of follow-up did not show differences by
type of care received. CONCLUSIONS. Results of this
trial support the view that a protocol of frequent
laboratory tests and roentgenography after primary
treatment for breast cancer does not improve survival
or influence health-related quality of life. Routine
use of these tests should be discouraged.
| No
intensive investigations to be done to detect
metastasis during routine follow-up of women
after completion of primary treatment. Investigate
only when symptomatic. |
BREAST CANCER -
Recurrent breast cancer |
6
EBM
|
21. First isolated loco-regional recurrence
following mastectomy for breast cancer: Results
of a Phase III multi-center study comparing systemic
treatment with observation after excision and radiation.
M. Borner, M. Bacchi, Goldirsh et al. J Clin Oncol
1994;12: 2071-77.
PURPOSE: We performed a randomized phase III multicenter
study to compare systemic treatment versus no treatment
after complete excision and radiotherapy for isolated
first locoregional recurrence in patients with breast
cancer. PATIENTS AND METHODS: One hundred sixty-seven
good-risk patients with an estrogen receptor (ER+)
positive recurrence or, in case of unknown receptor
status, a disease-free interval (DFI) of greater
than 12 months and < or = three recurrent tumor
nodules each < or = 3 cm in diameter were entered
onto the study. They were randomized to observation
subsequent to local treatment or to receive tamoxifen
(TAM) until disease progression. Seventy-nine percent
of the patients were postmenopausal. RESULTS: The
median observation period for the entire study population
was 6.3 years. The median disease-free survival
(DFS) duration was 26 months for observation and
82 months for TAM patients (P = .007). This was
mainly due to the reduction of further local recurrences,
whereas the occurrence of early distant metastases
was delayed. A multivariate analysis identified
DFI and treatment with TAM as significant prognostic
factors for DFS. The 5-year overall survival (OS)
rates were 76% and 74%, respectively (P = .77).
DFI was also a prognostic factor for OS. CONCLUSION:
Systemic therapy with TAM after isolated locoregional
recurrence of breast cancer significantly increased
5-year DFS rates from 36% to 59% compared with observation
alone and prolonged median DFS by more than 4.5
years in patients with ER+ tumors or in the case
of unknown ER status with a DFI of greater than
12 months and minimal tumor burden. Treatment with
TAM currently has no significant impact on OS, but
the median survival duration of the study population
has not yet been reached.
22. Superior efficacy of letrozole versus tamoxifen
as first-line therapy for postmenopausal women with
advanced breast cancer: results of a phase III study
of the International Letrozole Breast Cancer Group.
Mouridsen H, et al, J Clin Oncol: 2001;19:2596-606
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, and tolerability.
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.
23. Radiotherapy for the palliation of painful
bone metastasis.
McQuay HJ, Collins SL, Carroll D et al.
Cochrane Database Syst Rev 2000;(2):CD001793
BACKGROUND: Radiotherapy is used commonly to provide
pain relief for painful bone metastases, and there
is a perception that of the three-quarters of patients
who achieve pain relief, half of these stay free
from pain. However, the precise contribution from
radiotherapy may be unclear because of difficulties
in assessing the numbers of people achieving relief,
the extent of relief and its duration, and the influence
of other contemporaneous interventions, such as
analgesics. OBJECTIVES: To assess pain relief from:
1. localised bone metastases achieved by radiotherapy,
comparing the efficacy of different fractionation
schedules 2. more generalised metastatic disease
achieved by radiotherapy or radioisotopes. SEARCH
STRATEGY: Studies were identified by searching Medline
(1966 to August 1998), Embase (1980 to 1998), the
Cochrane Library (1998 Issue 3) and the Oxford Pain
Relief Database (1950 to 1994). SELECTION CRITERIA:
The inclusion criteria used were: full journal publication,
patients with pain due to bone metastases, and random
allocation to a radiotherapeutic intervention (either
external irradiation or administration of radioisotopes).
DATA COLLECTION AND ANALYSIS: The number of patients
achieving complete pain relief and at least 50%
at one month were compared with an assumed natural
history of 1 in 100 patients achieving pain relief
without treatment to obtain the number-needed-to-treat
(NNT). Summed pain relief or pain intensity difference
over four to six hours was extracted, converted
into dichotomous information yielding the number
of patients with at least 50% pain relief, and used
to calculate the relative benefit and the NNT for
one patient to achieve at least 50% pain relief.
MAIN RESULTS: Twenty trials reported on 43 different
radiotherapy fractionation schedules and eight studies
of radioisotopes. Radiotherapy produced complete
pain relief at one month in 395/1580 (25%) patients,
and at least 50% relief in 788/1933 (41%) patients
at some time during the trials. There were no differences
in the proportions of patients achieving these outcomes
between single or multiple fraction schedules. The
number-needed-to-treat (NNT) to achieve complete
relief at one month (compared with an assumed natural
history of 1 in 100 patients whose pain resolved
without treatment) was 4.2 (95% CI 3.7-4.7). No
pooled estimates of speed of onset of relief, or
of its duration, could be obtained. In the largest
trial (759 patients) 52% of those who had complete
relief had achieved it within four weeks, and the
median duration of complete relief was 12 weeks.
For more generalised disease, radioisotopes produced
similar analgesic results to external irradiation.
Adverse effect reporting was poor. There were no
obvious differences between the various fractionation
schedules in the incidence of nausea and vomiting,
diarrhoea or pathological fractures. REVIEWER'S
CONCLUSIONS: Radiotherapy is clearly effective at
reducing pain from painful bone metastases. There
was no evidence of any difference in efficacy between
different fractionation schedules, nor indeed of
a dose-response with total dose of radiation. For
treatment of generalised bone pain both hemibody
irradiation and radioisotopes can reduce the number
of painful new sites.
24. Bisphosphonates for the relief of pain secondary
to bone metastases.
Wong R, Wiffen PJ.Cochrane Database Syst Rev. 2002;(2):CD002068.
BACKGROUND: Bisphosphonates form part of standard
therapy for hypercalcemia and the prevention of
skeletal events in some cancers. However, the role
of bisphosphonates in pain relief for bony metastases
remains uncertain. OBJECTIVES: To determine the
effectiveness of bisphosphonates for the relief
of pain from bone metastases. SEARCH STRATEGY: MEDLINE
(1966-1999), EMBASE (1980-1999), CancerLit (1966-1999),
the Cochrane library (Issue 1, 2000) and the Oxford
Pain Database were searched using the strategy devised
by the Cochrane Pain, Palliative and Supportive
Care Group with additional terms 'diphosphonate',
'bisphosphonate', 'multiple myeloma' and 'bone neoplasms'.
(Last search: January 2000). SELECTION CRITERIA:
Randomized trials of bisphosphonates compared with
open, blinded, or different doses/types of bisphosphonates
in cancer patients were included where pain and/or
analgesic consumption were outcome measures. Studies
where pain was reported only by observers were excluded.
DATA COLLECTION AND ANALYSIS: Article eligibility,
quality assessment and data extraction were undertaken
by both reviewers. The proportions of patients with
pain relief at 4, 8 and 12 weeks were assessed.
The proportion of patients with analgesic reduction,
the mean pain score, mean analgesic consumption,
adverse drug reactions, and quality of life data
were compared as secondary outcomes. MAIN RESULTS:
Thirty randomized controlled studies (21 blinded,
four open and five active control) with a total
of 3682 subjects were included. For each outcome,
there were few studies with available data. For
the proportion of patients with pain relief (eight
studies) pooled data showed benefits for the treatment
group, with an NNT at 4 weeks of 11[95% CI 6-36]
and at 12 weeks of 7 [95% CI 5-12]. In terms of
adverse drug reactions, the NNH was 16 [95% CI 12-27]
for discontinuation of therapy. Nausea and vomiting
were reported in 24 studies with a non-significant
trend for greater risk in the treatment group. One
study showed a small improvement in quality of life
for the treatment group at 4 weeks. The small number
of studies in each subgroup with relevant data limited
our ability to explore the most effective bisphosphonates
and their relative effectiveness for different primary
neoplasms. REVIEWER'S CONCLUSIONS: There is evidence
to support the effectiveness of bisphosphonates
in providing some pain relief for bone metastases.
There is insufficient evidence to recommend bisphosphonates
for immediate effect; as first line therapy; to
define the most effective bisphosphonates or their
relative effectiveness for different primary neoplasms.
Bisphosphonates should be considered where analgesics
and/or radiotherapy are inadequate for the management
of painful bone metastases.
| Isolated
locoregional recurrences should be treated with
locoregional therapy as appropriate.Hormone
therapy improves DFS in ER+ve locoregional recurrences.Radiotherapy
provides excellent palliation in bone,brain
and choroidal metastasis.Bisphosphonates are
useful in lytic bone metastasis |
BREAST CANCER -
Screening for breast cancer |
7
EBM
|
25. Efficacy of screening mammography. A meta-analysis.
Kerlikowske K, Grady D, et al. JAMA 1995 Jan 11;273(2):149-54
OBJECTIVE. To determine the efficacy of screening
mammography by age, number of mammographic views
per screen, screening interval, and duration of
follow-up. DESIGN. Literature review and meta-analysis.
DATA IDENTIFICATION AND ANALYSIS. Literature search
of English-language studies reported from January
1966 to October 31, 1993, using MEDLINE, manual
literature review, and consultation with experts.
A total of 13 studies were selected, and their results
were combined using meta-analytic techniques based
on the assumption of fixed effects. MAIN RESULTS.
The overall summary relative risk (RR) estimate
for breast cancer mortality for women aged 50 to
74 years undergoing screening mammography compared
with those who did not was 0.74 (95% confidence
interval [CI], 0.66 to 0.83). The magnitude of the
benefit in this age group was similar regardless
of number of mammographic views per screen, screening
interval, or duration of follow-up. In contrast,
none of the summary RR estimates for women aged
40 to 49 years was significantly less than 1.0,
irrespective of screening intervention or duration
of follow-up. The overall summary RR estimate in
women aged 40 to 49 years was 0.93 (95% CI, 0.76
to 1.13); the summary RR estimate for those studies
that used two-view mammography was 0.87 (95% CI,
0.68 to 1.12) compared with 1.02 (95% CI, 0.73 to
1.44) for those studies that used one-view mammography,
and for those studies with 7 to 9 years of follow-up,
the summary RR estimate was 1.02 (95% CI, 0.82 to
1.27) compared with 0.83 (95% CI, 0.65 to 1.06)
for those studies with 10 to 12 years of follow-up.
CONCLUSION. Screening mammography significantly
reduces breast cancer mortality in women aged 50
to 74 years after 7 to 9 years of follow-up, regardless
of screening interval or number of mammographic
views per screen. There is no reduction in breast
cancer mortality in women aged 40 to 49 years after
7 to 9 years of follow-up. Screening mammography
may be effective in reducing breast cancer mortality
in women aged 40 to 49 years after 10 to 12 years
of follow-up, but the same benefit could probably
be achieved by beginning screening at menopause
or 50 years of age.
26. Breast Screening: the case for physical
examination without mammography. Mittra I.
Lancet; 1994, 343 : 342-344.
Many studies have shown that screening for breast
cancer can reduce mortality from the disease. Mammography
has come to be regarded as the screening method
of choice, but evidence suggests that physical examination
(PE) is at least as effective in reducing mortality.
Mammography detects many non-infiltrating and small,
non-palpable tumours, but we do not know whether
these would ever cause symptoms or threaten the
woman's life. It is doubtful whether the time gained
by early mammographic detection confers any survival
benefit over PE detection. PE has substantial advantages
over mammography in terms of human and economic
costs. The question we should be asking is not how
to refine mammographic screening but whether we
need it at all.
27. Randomized trial of breast self-examination
in Shanghai: Final results. Thomas DB, Gao DL,
Ray RM, et al: J Natl Cancer Inst; 2002;94:1445-57.
BACKGROUND: Among women who practice breast self-examination
(BSE), breast cancers may be detected when they
are at an earlier stage and are smaller than in
women who do not practice BSE. However, the efficacy
of breast self-examination for decreasing breast
cancer mortality is unproven. This study was conducted
to determine whether an intensive program of BSE
instruction will reduce the number of women dying
of breast cancer. METHODS: From October 1989 through
October 1991, 266,064 women associated with 519
factories in Shanghai were randomly assigned to
a BSE instruction group (132,979 women) or a control
group (133,085 women). Initial instruction in BSE
was followed by reinforcement sessions 1 and 3 years
later, by BSE practice under medical supervision
at least every 6 months for 5 years, and by ongoing
reminders to practice BSE monthly. The women were
followed through December 2000 for mortality from
breast cancer. Cumulative risk ratios of dying from
breast cancer were estimated using Cox proportional
hazards models. All statistical tests were two-sided.
RESULTS: There were 135 (0.10%) breast cancer deaths
in the instruction group and 131 (0.10%) in the
control group. The cumulative breast cancer mortality
rates through 10 to 11 years of follow-up were similar
(cumulative risk ratio for women in the instruction
group relative to that in the control group = 1.04,
95% confidence interval = 0.82 to 1.33; P =.72).
However, more benign breast lesions were diagnosed
in the instruction group than in the control group.
CONCLUSIONS: Intensive instruction in BSE did not
reduce mortality from breast cancer. Programs to
encourage BSE in the absence of mammography would
be unlikely to reduce mortality from breast cancer.
Women who choose to practice BSE should be informed
that its efficacy is unproven and that it may increase
their chances of having a benign breast biopsy.
|
Screening mammography alone is effective
in saving lives in postmenopausal women. There
is direct evidence that physical examination
is as effective as mammogram in a single randomised
trial. In premenopausal women, screening by
mammography and or physical examination is
debatable.
|
BREAST CANCER -
Familial Breast Cancer |
8
EBM
|
28. Risks of cancer in BRCA1-mutation carriers.
Ford D, et al: Breast Cancer Linkage Consortium.
Lancet 1994;343:692-5
Germline mutations in a gene on chromosome 17q known
as BRCA1 are responsible for a large proportion
of inherited predispositions to breast and ovarian
cancer. In 33 families with evidence of linkage
to BRCA1, we estimated the risks of breast and ovarian
cancer from the occurrence of second cancers in
individuals with breast cancer, and examined the
risks of other cancers in BRCA1 carriers. 26 contralateral
primary breast cancers occurring more than 3 years
after a first breast cancer were observed before
age 70, giving an estimated cumulative risk of breast
cancer in gene carriers of 87% by age 70.23 primary
ovarian cancers occurred in women with a previous
breast cancer, resulting in an estimated cumulative
risk of ovarian cancer of 44% by age 70.87 cancers
other than breast or ovarian cancer were observed
in individuals with breast or ovarian cancer and
their first-degree relatives compared with 69.3
expected, based on national incidence rates. Significant
excesses were observed for colon cancer (estimated
relative risk [RR] to gene carriers 4.11 [95% CI
2.36-7.15]) and prostate cancer (3.33 [1.78-6.20]).
No significant excesses (or deficits) were noted
for cancers of other sites. Our study provides estimates
of breast and ovarian cancer risks, which are useful
for counseling BRCA1-mutation carriers. It also
shows that carriers are at increased risk of colon
and prostate cancer, which may be of clinical significance
in certain families if the risks are associated
with specific mutations.
29. The risk of cancer associated with specific
mutations of BRCA1 and BRCA2 among Ashkenazi Jews.
Struewing JP, et al N Engl J Med 1997;336:1401-8
BACKGROUND: Carriers of germ-line mutations in
BRCA1 and BRCA2 from families at high risk for cancer
have been estimated to have an 85 percent risk of
breast cancer. Since the combined frequency of BRCA1
and BRCA2 mutations exceeds 2 percent among Ashkenazi
Jews, we were able to estimate the risk of cancer
in a large group of Jewish men and women from the
Washington, D.C., area. METHODS: We collected blood
samples from 5318 Jewish subjects who had filled
out epidemiologic questionnaires. Carriers of the
185delAG and 5382insC mutations in BRCA1 and the
6174delT mutation in BRCA2 were identified with
assays based on the polymerase chain reaction. We
estimated the risks of breast and other cancers
by comparing the cancer histories of relatives of
carriers of the mutations and noncarriers. RESULTS:
One hundred twenty carriers of a BRCA1 or BRCA2
mutation were identified. By the age of 70, the
estimated risk of breast cancer among carriers was
56 percent (95 percent confidence interval, 40 to
73 percent); of ovarian cancer, 16 percent (95 percent
confidence interval, 6 to 28 percent); and of prostate
cancer, 16 percent (95 percent confidence interval,
4 to 30 percent). There were no significant differences
in the risk of breast cancer between carriers of
BRCA1 mutations and carriers of BRCA2 mutations,
and the incidence of colon cancer among the relatives
of carriers was not elevated. CONCLUSIONS: Over
2 percent of Ashkenazi Jews carry mutations in BRCA1
or BRCA2 that confer increased risks of breast,
ovarian, and prostate cancer. The risks of breast
cancer may be overestimated, but they fall well
below previous estimates based on subjects from
high-risk families.
| Genetic
testing provides information in a research setting
but its use in routine practice needs much evaluation,
social debate & counseling.A negative genetic
testing does not completely eliminate breast
cancer risk, and a positive test cannot be remedied
easily or prevented from being transmitted vertically.
|
Tata Memorial Hospital, Dr.
E Borges Road, Parel, Mumbai - 400 012 India. 