nlmpubs.nlm.nih.gov/2014.05.nlmpubs.nlm.nih.gov.tar/nlmpubs.nlm.nih.gov/alerts/tamoxif.txt

Text File | 1995-11-29 | 18KB | 371 lines

Clinical Alert: Adjuvant Therapy of Breast Cancer - Tamoxifen Update.
National Cancer Institute (NCI)
November 30, 1995

Abstract:
The National Cancer Institute wants to bring new information
regarding the optimal duration of adjuvant tamoxifen therapy to
the attention of clinicians.  Recent results from the National
Surgical Adjuvant Breast and Bowel Project (NSABP) Protocol B-14,
that evaluated 5 years versus 10 years of adjuvant tamoxifen for
early stage breast cancer, indicate no advantage for continuation
of tamoxifen beyond 5 years in women with node-negative, estrogen
receptor-positive breast cancers.  In view of the proven benefits
of 5 years of adjuvant tamoxifen, this treatment should continue
to be administered whenever appropriate to women with early stage
breast cancer.  However, the new data suggest that more than 5
years of adjuvant treatment is not warranted in routine clinical
practice in this patient population.

The full-text of the announcement is available via the
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The full text of this alert has been mailed to all libraries
that are members of the National Network of Libraries of
Medicine.

Full Text:
The following is the text of a clinical announcement released
by the National Cancer Institute on November 30, 1995.

***********************************************************

The National Cancer Institute wants to bring new information
regarding the optimal duration of adjuvant tamoxifen therapy to
the attention of clinicians.  Recent results from the National
Surgical Adjuvant Breast and Bowel Project (NSABP) Protocol B-14,
that evaluated 5 years versus 10 years of adjuvant tamoxifen for
early stage breast cancer, indicate no advantage for continuation
of tamoxifen beyond 5 years in women with node-negative, estrogen
receptor-positive breast cancers.  In view of the proven benefits
of 5 years of adjuvant tamoxifen, this treatment should continue
to be administered whenever appropriate to women with early stage
breast cancer.  However, the new data suggest that more than 5
years of adjuvant treatment is not warranted in routine clinical
practice in this patient population.

***********************************************************

The adjuvant administration of tamoxifen has significantly
improved disease free survival and overall survival in women with
early stage breast cancer.  In 1981, the National Surgical
Adjuvant Breast and Bowel Project (NSABP) initiated Protocol B-14
in order to determine the efficacy of tamoxifen in women with
primary breast cancer with histologically negative nodes and
estrogen receptor- positive tumors.  Two thousand eight-hundred
and ninety-two patients were randomized to receive either
tamoxifen or  placebo.  The results initially published in 1989
(1) indicated a significant prolongation of disease-free survival
in favor of the group receiving tamoxifen treatment. Updated
results from this study provided by NSABP indicate that the
tamoxifen treated patients have a 10-year disease-free survival
of 68% compared with 57% for the placebo-treated group
(p<0.0001).  There is a concomitant improvement in overall
survival in favor of tamoxifen, 78% vs. 75% (p=0.037).  This
beneficial effect of tamoxifen was also noted in other randomized
trials (2,3) and has been confirmed by a worldwide meta-analysis
of tamoxifen trials performed by the Early Breast Cancer
Trialists' Collaborative Group (4).

Although there was an unequivocal prolongation in
disease-free survival and survival in favor of tamoxifen, the
optimum length of administration of this agent has not been
determined.  A secondary goal of NSABP B-14 was to compare the
effectiveness of 5 years of tamoxifen to 10 years of tamoxifen
treatment.  Those patients who received 5 years of tamoxifen and
were free of disease at the end of this period were re-randomized
to either an additional 5 years of tamoxifen or 5 years of
placebo.

Results from this re-randomized component of the trial
comparing 5 years to 10 years of tamoxifen indicate that there is
no additional advantage forthcoming from prolonging the
administration of tamoxifen to 10 years.  Results from a smaller
trial, the Scottish Tamoxifen Trial, also comparing 5 years of
tamoxifen to more prolonged treatment, have recently been
published in abstract form (5).  They are consistent with the
conclusion of the NSABP B-14 study.

Complete manuscripts describing details of treatment benefits
and side effects from the re-randomized components of both the
NSABP and Scottish tamoxifen trials are in preparation.  However,
because adjuvant tamoxifen is widely used in this country and
abroad, rapid disclosure of these data is appropriate. This
communication briefly summarizes important features of the NSABP
trial and the Scottish trial.  Some of the figures may change
with the availability of more complete data and longer follow-up.

NSABP B-14

Following either mastectomy or lumpectomy plus breast
irradiation for primary breast cancer, women with histologically
negative axillary lymph nodes and estrogen receptor-positive
tumors were eligible for NSABP Protocol B-14.  The study design
of B-14 had two components; the first and principal component was
initiated in 1981 and consisted of a direct comparison between 5
years of tamoxifen to placebo.

1st Randomization: 1981-88

In the first randomization, 2892 patients were randomized to
tamoxifen or placebo.  A total of 1439 patients were randomized
to tamoxifen (20 mg/d x 5 years) and 1453 patients were
randomized to placebo (x 5 years).

This randomization was closed in January 1988 after 2892
patients had been entered.  Between January 1988 and October 1988
an additional 1235 patients who fulfilled the same eligibility
criteria were registered on this study, all of whom were to
receive 5 years of tamoxifen.  This patient cohort was added in
order to increase the number of tamoxifen-treated patients
available for the secondary randomization.

In order to determine whether tamoxifen should be
administered for 5 or 10 years following the operation, those
patients who received tamoxifen for 5 years (in both the
randomized and registered groups) and were disease-free at the
end of this 5 year period were offered a second double-blinded
randomization to an additional 5 years of tamoxifen or to a
placebo.

2nd Randomization: 1987- 1993

In the second randomization, 1166 patients who had received
tamoxifen for 5 years were randomized to tamoxifen or placebo.  A
total of 591 patients were randomized to an additional 5 years of
tamoxifen (20 mg/d x 5 years) and 575 patients were randomized to
placebo (x 5 years).

B-14 Results:

Results from the initial randomization to tamoxifen versus
placebo for 5 years were  reported in 1989 (1).  They indicate a
disease-free survival and overall survival advantage for
tamoxifen.  Nearly 66% of those eligible, 1172 patients, agreed
to the second randomization. Of these, 1166 are eligible for
analysis (591 on tamoxifen and 575 on placebo).  Starting from
the time of the second randomization, the average duration of
follow-up is 43 months.   Patient pre-treatment characteristics
(age, tumor size, type of surgery, ER and PR receptor levels) are
well balanced per treatment arm.

Using actuarial estimates at 4 years of follow-up since the
re- randomization, the data indicate that 92% of the group that
received 5 years of tamoxifen are alive and disease-free compared
to 86% of the group scheduled to receive 10 years of tamoxifen.
This difference at an interim analysis does not represent
statistically significant evidence of a detrimental effect, but
it does make it very unlikely that continuation of tamoxifen
would produce an actual clinical benefit.  As a result of this
finding, the trial was stopped by NSABP in concordance with the
recommendation of its Data Safety Monitoring Committee.  There is
no significant difference in overall survival with 96% of the
group receiving 5 years of tamoxifen and 94% of the patients
receiving 10 years of tamoxifen still alive 4 years after re-
randomization.  The occurrence of second primary tumors diagnosed
after re-randomization included 11 contralateral breast cancers,
5 in the five-year tamoxifen group, 6 in the ten-year group; 8
endometrial cancers, 2 versus 6, and 21 other primaries, 9 versus
12, respectively.

An investigator from St. Luc's Hospital, Montreal submitted
falsified data for several NSABP protocols, including NSABP B-14.
Among the 1172 patients enrolled in the second randomization, 66
(5.6%) were entered from St. Luc's.  When all St. Luc's patients
were omitted from the analysis, or when all ineligible patients
were omitted, all conclusions remain the same.

B-14 Conclusions:

These results make it very unlikely that continuation of
tamoxifen beyond 5 years will result in a disease-free survival
or overall survival benefit in women with node-negative, estrogen
receptor- positive breast cancers.

THE SCOTTISH TAMOXIFEN TRIAL

Following mastectomy for primary breast cancer, women were
randomly allocated to receive adjuvant tamoxifen 20 mg daily for
5 years, or to a control group in which tamoxifen was to be given
only on relapse of disease.  Like B-14, pre- and postmenopausal
women with negative axillary lymph nodes were eligible, but
unlike B-14, postmenopausal women with positive axillary nodes
were also eligible. In this study, estrogen receptor values were
not required.  Accrual to the first randomization began in 1978.
Subsequently, a second randomization was added in February 1985
that was limited to those women treated on-study with tamoxifen
for 5 years who had no recurrence of breast cancer.  Thus, only
patients who had entered the initial randomization after March
1980 were eligible for the second randomization. Eligible
patients were randomized to continue tamoxifen indefinitely or to
stop treatment at 5 years.

1st randomization (1978-84)

In the 1st randomization, 1312 patients were randomized to
tamoxifen or no treatment for relapse.  Of these, 661 were
randomized to tamoxifen (20 mg/d x 5 years) and 651 were
randomized to no treatment.

2nd randomization (1985-89)

In the 2nd randomization to continue or stop tamoxifen, 173
patients were allocated to continue tamoxifen (20 mg/d)
indefinitely and 169 were allocated to stop tamoxifen.

Scottish Trial Results:

The results of the first randomization were reported in 1987
(2) and showed a significant disease-free survival and overall
survival benefit for adjuvant tamoxifen.  Three hundred and
forty-two patients consented to the second randomization,
representing 87% of those available for inclusion.  Median
follow-up for living patients from the date of re-randomization
is 6.2 years.  Pre-treatment patient characteristics for the
re-randomized groups such as age, menopausal status, nodal
status, post-mastectomy radiation therapy, and estrogen receptor
status were well balanced between the two groups.

At 6.2 years of median follow-up since the re-randomization,
the data indicate that 70% of the group that received 5 years of
tamoxifen are alive and disease-free compared to 62% of the group
that continued treatment beyond 5 years.  This represents a
non-statistically significant trend in favor of stopping
tamoxifen at 5 years. The occurrence of second primary tumors
diagnosed after re-randomization included 8 contralateral breast
cancers, 3 in the group that stopped tamoxifen at 5 years and 5
in the group continuing tamoxifen indefinitely; 5 endometrial
cancers, 0 versus 5, and 18 other primaries, 9 versus 9,
respectively.

Scottish Trial Conclusions:

In view of its relatively limited size, this trial is not
able to exclude the possibility that continuation of tamoxifen
beyond 5 years might be beneficial.  However, the data do suggest
that, if there is a disease-free survival or overall survival
benefit to be derived, it would likely be small.  As a result of
these findings, no changes have as yet been made regarding the
trial policy.

SUMMARY:

Tamoxifen for Breast Cancer Treatment

Adjuvant treatment with tamoxifen results in improved
survival for women with early stage breast cancer. The results of
NSABP Protocol B- 14 represent an important advance in our
understanding of the appropriate duration of tamoxifen treatment.
To our knowledge, it is the only available trial with a
substantial sample size to directly compare 5 years of tamoxifen
treatment to 10 years of tamoxifen treatment.  The B-14  data,
taken together with the results of the Scottish trial, provide no
evidence of benefit for continuing tamoxifen beyond 5 years.  The
troublesome possibility that continuation of tamoxifen beyond 5
years might actually be detrimental cannot be unequivocally
resolved by these data.  However, both  trials suggest a greater
likelihood of relapse in women who take tamoxifen for durations
greater than 5 years when compared to women who receive 5 years
of therapy.

The NSABP B-14 trial and the Scottish trial highlight the
importance to cancer medicine of performing carefully controlled,
randomized clinical trials.  Obviously, there was no way to
anticipate the results of these studies in advance. It is
noteworthy that some laboratory investigators hypothesized that
prolonged exposure to tamoxifen could induce tumor-dependence (6)
or resistance (7).

Although the NSABP and Scottish trials provide evidence that
continuation beyond 5 years is not beneficial, the optimal
duration of adjuvant tamoxifen treatment still remains to be
determined. Indirect evidence from combined analysis of tamoxifen
trials suggests that the benefit from 2 to 5 years of treatment
is greater than that derived from durations less than 2 years
(4). There are currently several trials directly comparing 2
years versus longer durations (3-5 years), but results from these
are either not available or not definitive. There are ongoing
trials that are also comparing 5 years of treatment versus longer
durations.  While we eagerly anticipate the results of such
trials,  all available evidence indicates that 5 years of
tamoxifen is a reasonable standard for the adjuvant setting.

Tamoxifen for Breast Cancer Prevention

It is also important to note that NSABP B-14 has served as
the basis for the current NCI-sponsored Breast Cancer Prevention
Trial (BCPT) in which women who do not have breast cancer but who
are at increased risk are randomly allocated to tamoxifen or
placebo for 5 years.  These new results do not affect the
rationale for the BCPT, which is primarily based on the 47%
reduction of contralateral breast cancers observed after 5 years
of adjuvant tamoxifen therapy.  The B- 14 data indicate that 5
years of tamoxifen significantly reduces the incidence of new
primary breast cancers in the contralateral breast (52 versus 29
events), and that 10 years of tamoxifen provides no additional
benefit over and above this reduction.  Because this new
information from the B-14 trial does not change the overall risk-
benefit profile for 5 years of tamoxifen, NCI supports the
continued evaluation of 5 years of tamoxifen as a breast cancer
preventive regimen in the context of a randomized clinical trial.

Acknowledgment

The NCI wishes to express its appreciation to the NSABP for
providing their data to us and for collaborating on the
preparation of this announcement. We also want to thank Dr. Helen
J. Stewart and the Scottish Cancer Trials Breast Group for
sharing their data with us.

References:

1. Fisher B, Costantino J, Redmond C, et al: A randomized
clinical trial evaluating tamoxifen in the treatment of patients
with node- negative breast cancer who have
estrogen-receptor-positive tumors. N Engl J Med 1989;320:
479-84.

2. Scottish Cancer Trials Office (MRC): Adjuvant tamoxifen in
the management of operable breast cancer: The Scottish trial.
Lancet 1987;2:171-74.

3. Nolvadex Adjuvant Trial Organization: Controlled trial of
tamoxifen as a single agent in management of early breast cancer;
analysis at six years. Lancet 1985;1:836-39.

4. Early Breast Cancer Trialists' Collaborative Group:
Systemic treatment of early breast cancer by hormonal, cytotoxic,
or immune therapy: 133 randomized trials involving 31,000
recurrences and 24,000 deaths among 75,000 women. Lancet
1992;339:1-15, 71-85.

5. Stewart H.J. for the Scottish Breast Group: Adjuvant
tamoxifen duration in a randomized trial. The Breast 1995;
4(3):256 (abstract 102).

6. Gottardis MM, Jordan VC: Development of
tamoxifen-stimulated growth of MCF-7 tumors in athymic mice after
long-term antiestrogen administration. Cancer Res
1988;48:5183-5187.

7. Sluyser M: Nuclear hormone receptor variants: Their role
in malignancy and progression to hormone resistance in cancer.
Acta Endocrinol 1991;126 (suppl 1):48-53.

The full text of this alert has been mailed to all libraries
that are members of the National Network of Libraries of
Medicine.