A DISSENTING VIEW ON
PRIORITIES IN ADJUVANT THERAPY
FOR BREAST CANCER
May 16, 1998
prepared by
Michael J. Halliwell, Ph.D.
California State University
Long Beach CA 90840
Home address:
2930 Colorado Ave. # D-18
Santa Monica, CA 90404-3647
Home phone: 310-829-2821
Home fax: 310-828-9174
UNSETTLING ASPECTS OF A "SETTLED" CONSENSUS
Sometimes
cancer
a
treatment
prevailing
is
so
well
consensus
on
established
an
aspect
that
it
of
breast
requires
no
footnoting in an otherwise well documented review of the state of
our knowledge.
Thus Dr. Hortobagyi's introduces CONTROVERSIES IN
THE MANAGEMENT OF EARLY-STAGE BREAST CANCER by stating:
It has been established that . . . four to six cycles of a
single combination are as effective as longer durations of
treatment. Id. at 129.
With the benefit of adjuvant chemotherapy thus circumscribed,
there is no mention of any potential gains from the more extensive
use of cytotoxic drugs in the defining goals for Session E6, which
urge oncologists to move in the opposite direction:
At the conclusion of this session, the participant should be
able to. . . .determine what subgroups of patients with early
breast cancer do not require adjuvant systemic therapies.
However, there are very few invasive breast cancers which are
so unlikely to relapse that the popular regimens of chemotherapy
(such as CMF) carry a greater mortality risk.
This is especially
true for premenopausal women who are in generally good health and
whose breast cancers account for most of the years of life lost to
this disease.
The
recent
publication
patients
(which
shows
that
in
Lancet
of
a
study
tamoxifen
is
very
of
37,000
effective
in
postponing breast cancer relapses in premenopausal women) means
that once any surge in micrometastatic growth has been halted, it
is safe to spread out chemotherapy to the point where it can be
tolerated indefinitely by normal tissues.
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GAINS FROM LONGER CHEMOTHERAPY ARE LARGER FOR LESS ADVANCED TUMORS
In these comparisons, Ontario study results are from Table 4
at 1221 of Levine et al (1990), and SECSG study results are from
Tables 2 and 3 at 276-277 of Velez-Garcia et al (1984).
ONTARIO STUDY: 36 MONTH RELAPSE-FREE SURVIVAL IN WOMEN UNDER 50
36 WEEK REGIMEN
Patients RFS
12 WEEK REGIMEN
Patients RFS
Long-Short
Prob.
Any Nodes
89
72%
89
54%
+ 18%
.002
1-3 Nodes
55
84%
56
59%
+ 25%
.002
SECSG STUDY: 42 MONTH RELAPSE-FREE SURVIVAL IN PREMENOPAUSAL WOMEN
12 MONTH REGIMEN
Patients RFS
6 MONTH REGIMEN
Patients RFS
Long-Short
Prob.
1-3 Nodes
42
93%
58
78%
+ 15%
.047
1 Node
18
100%
29
76%
+ 24%
.034
In the Milan II study, intention-to-treat analysis is used
even though there are three times as many dropouts in the 12-month
arm, and in the longer-treatment group 21% fewer of the patients
completing therapy received at least 85% of the prescribed dosage
(Tancini et al, 1979 at 286; Bonadonna et al, 1985b at 98). Table
6 at 440 Bonadonna et al (1981) and Table 3 at 98 of Bonadonna et
al (1985) produce a relationship free of most of this dosage bias:
MILAN STUDY: 48 MONTH RELAPSE-FREE SURVIVAL IN PREMENOPAUSAL WOMEN
12 MONTH REGIMEN
> 85% Dose Patients RFS
6 MONTH REGIMEN
Patients RFS
Long-Short
Prob.
Any Nodes
30
80.0%
66
66.7%
+13.3%
.046
1-3 Nodes
18
88.9%
39
69.3%
+19.6%
.030
These advantages can be extended with tamoxifen or raloxifene.
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EXTENDED CHEMOTHERAPY HELPS HOST DEFENSES DELAY TUMOR RECURRENCES
Demichelli et al (1996) analyze Milan Tumor Institute data:
A total of 1173 patients treated between 1964 and 1980 with
mastectomy alone and no adjuvant therapy were studied. The
hazard function for first failure presented an early peak at
about 18 months after surgery, a second peak at about 60
months and then a tapered plateau-like tail extending up to
15 years.
Relapse can take place at the local-regional
level when the body tumor burden is low and
the capacity of host defenses has yet reached
the breaking point.
However, there is a very
noticeable "dam burst" effect in the case of
distant metastases, as their Figure 4 shows.
Senn and Barett-Mahler (1987) discuss how a short regimen of
chemotherapy affects breast cancer recurrence in a Swiss study:
While node-negative women experienced an impressive RelapseFree Survival gain during the first 3-4 years, this advantage
was vanishing thereafter at 5 and more years of median
follow-up (figure 3a). The strange accumulation of relapses
among our chemotherapy patients at 4-5 years favors the idea
of testing "late adjuvant reinduction regimens" (Speer et al,
1984) in present day trials such as International Breast
Cancer Study Group Trial VI (Goldhirsch and Gelber, 1987).
Id. at 244.
When the Vienna study used much longer chemotherapy, Jakesz
et al (1987) found that the relapse curve was greatly pushed back:
Our results are comparable with those from Osako at the same
observation period (Senn et al (1986).
Interestingly this
trial reported at 4-5 years of median follow-up an
accumulation of late relapses among the chemoimmunotherapy
group. Whether or not our concept of delivering chemotherapy
over 3 years is the reason why we did not observe these late
re-currences has to remain speculative. There is, however,
theoretical reason to believe that late periodic adjuvant
consolidation cycles could be of some benefit (Speer et al
(1984). Id. at 230.
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OPPORTUNITIES AND RISKS ASSOCIATED WITH PREMENOPAUSAL MAMMOGRAPHY
The increasing utilization of mammographic screening by women
in their 40's will catch many breast cancers at an earlier stage,
where longer chemotherapy is most advantageous.
However, when a
breast
into
tumor
is
shifted
by
earlier
detection
the
node-
negative category, there is a serious risk if this causes one to
withhold
adjuvant
documented
a
chemotherapy.
shortening
of
Simpson-Herren
lifespans
in
murine
et
al
tumor
(1976)
implant
experiments, which are linked with "outbursts of metastatic growth
following surgical excision of a primary tumor." Id. at 1753.
In the Stockholm trial, Frisell et al
(1991) report a small medium-term increase
in breast cancer deaths in 40-49 year-old
screened patients, but a sharp increase in
the years just after tumor removal:
Of the women under 50, 16 died of
breast cancer in the screened population and 8 in the control population. The relative risk was 1.09
(95 percent confidence interval:
0.4-3.0) and no reduction in mortality was found (Table 5). The cumulative number of deaths in this age
group is seen in Fig. 6. Id. at 52.
These earlier deaths may be caused by a growth surge of
metastases in the lungs (whose castoff clumps pass through the
heart only once before entering the general circulation).
With
respect to a similar phenomenon, Simpson-Herren et al (1976) note
"the residual tumor foci, stimulated to more rapid growth, should
be appropriate targets for adjuvant chemotherapy." Id. at 1749.
4
REFERENCES
Bonadonna G, Valagussa P, Rossi A, et al (1981): Multimodal
Therapy with CMF in Resectable Breast Cancer with Positive
Axillary Nodes -- The Milan Institute Experience. Pp. 435-444 in
Adjuvant Therapy of Cancer III (Salmon SE and Jones SE, eds.)
Orlando, Grune & Stratton.
Bonadonna G, Valagussa P, Rossi A, et al (1985): Ten-Year
Experience with CMF-Based Adjuvant Chemotherapy in Resectable
Breast Cancer. Breast Cancer Res Treat 5: 95-115.
Demicheli R, Abbattista A, Miceli R, Valagussa P, and Bonadonna G
(1996): Time Distribution of the Recurrence Risk for Breast Cancer
Patients Undergoing Mastectomy: Further Support about the Concept
of Tumor Dormancy. Breast Cancer Res Treat 41:177-185.
Frisell J, Eklund G, Hellstrom L, Lindbrink E, Rutqvist LE, and
Somell A (1991): Randomized Study of Mammography Screening
-- Preliminary Report on Mortality in the Stockholm Trial. Breast
Cancer Res Treat 18: 49-56.
Goldhirsch A and Gelber RD (1987): Adjuvant Therapy for Breast
Cancer: The Ludwig Breast Cancer Trials 1987. Pp 297-309 in
Adjuvant Therapy of Cancer V (Salmon SE, ed.) Orlando, Grune &
Stratton.
Jakesz R, Kolb R, Reiner G, et al (1987): Adjuvant Chemotherapy in
Node-Negative Breast Cancer Patients. Pp 223-231 in Adjuvant
Therapy of Cancer V (Salmon SE, ed.) Orlando, Grune & Stratton.
Levine MN, Gent M, Hryniuk WM, et al (1990): A Randomized Trial
Comparing 12 Weeks Versus 36 Weeks of Adjuvant Chemotherapy in
Stage II Breast Cancer. J Clin Oncol 8: 1217-1225.
Senn HJ and Barett-Mahler AR (1987): Update of Swiss Adjuvant
Trials with LMF and CMF in Operable Breast Cancer. Pp. 243-252 in
Adjuvant Therapy of Cancer V (Salmon SE, ed.) Orlando, Grune &
Stratton.
Senn HJ, Jungi WF, Amgwerd R, et al (1986): Swiss Adjuvant Trial
(OSAKO 06/74) with Chlorambucil, Methotrexate, and 5-Fluorouracil
Plus BCG in Node-Negative Breast Cancer Patients: Nine-Year
Results. NCI Monographs 1: 129-134.
Simpson-Herren L, Sanford AH, and Holmquist JP (1976): Effects of
Surgery on the Cell Kinetics of Residual Tumor. Cancer Treat Rep
60: 1749-1760.
Speer JF, Petrovsky VE, Retsky MW, and Wardwell RH (1984): A
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Stochastic Numerical Model of Breast Cancer Growth that Simulates
Clinical Data. Cancer Res 44: 4124-4130.
Tancini G, Bajetta E, Marchini S, Valagussa P, Bonadonna G, and
Veronesi U (1979): Preliminary 3-Year Results of 12 versus 6
Cycles of Surgical Adjuvant CMF in Premenopausal Breast Cancer.
Cancer Clin Trials 2: 285-292.
Velez-Garcia E, Moore M, Vogel C, et al (1984): Adjuvant
Chemotherapy with or without Radiation Therapy in Women with
Breast Cancer and Positive Axillary Nodes: The Southeastern Cancer
Study Group (SECSG) Experience. Pp. 273-282 in Adjuvant Therapy of
Cancer IV (Jones SE and Salmon SE, eds.) Orlando, Grune &
Stratton.
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