chemotherapy by hedongchenchen


Abbreviations: chemo

Definition: (kee-mo-THER-a-pee) Slang: chemo. Treatment with
drugs that have a specific toxic effect upon the cancer, usually
interfering with cell reproduction (mitosis).

Most are given intravenously but oral (by mouth) drugs may be

The drugs may be antimitotic, antimetabolite, or antineoplastic.

Systemic Therapy for Breast Cancer

Approaching the treatment of breast cancer... must know basics...

For simplification, we will consider systemic therapy to be independent of type of
local therapy. Disease free survival (DFS) will be defined independent of a salvagable
breast recurrence that might be seen with breast conservation therapy.

Premenopausal patients are approached differently than postmenopausal patients. In
general, compared to postmenopausal patients, premenopausal patients are more
likely to have high grade, ER/PR negative tumors, may tolerate chemotherapy better,
and are producing endogenous estrogen from their functioning ovaries. Therefore,
premenopausal patients tend to be more likely to benefit from chemotherapy and less
likely to benefit from hormone therapies than postmenopausal women.

Determing the best approach to systemic therapy, one must consider the risk
(likelihood of failure with no therapy), the likelihood of benefit with additional
therapy, the impact of a failure, and the morbidity of treatment. Approaches include
observation, hormone therapy (usually tamoxifen), chemotherapy, or chemotherapy
plus tamoxifen. In most women, tamoxifen is very well tolerated. Though supportive
care during chemotherapy has improved and chemotherapy can be given with
relatively few long term risks, it still requires 4-6 months of moderately toxic therapy.
Therefore, many patients and physicians prefer tamoxifen to chemotherapy if
outcomes are comparable. Relatively few studies have addressed the impact of
chemotherapy + tamoxifen vs. either chemotherapy or tamoxifen alone.

Over 100 randomized trials have been reported testing the impact of adjuvant
chemotherapy. These have been summarized in a number of overview or
"metanalysis" studies. These papers often report a "reduction in annual odds" of
recurrence and/or death. One should realize, however, that the absolute reduction in
events is actually much less for two reasons. First, the reduction is "annualized" so
that the absolute benefit is lower than the annualized benefit. Second, the reduction is
a relative reduction in risk. So if an intervention decreases the risk of failure by 30%,
a previous risk of 30% is reduced to 21% and a 10% risk is reduced to only a 7% risk.
To illustrate this (discounting the "annualized" effect), see the following table:

                   Baseline Risk 10 % reduction 30 % reduction
                      10 %            1%             3%
                      30 %            3%             9%
                      50 %            5%            15 %

Typical risks are in the range of 10-50 %, with a relative risk reduction of 20-35 % in
DFS and 10-25 % in survival for treatment vs. no treatment. Therefore, the absolute
benefit is much smaller, in the range of 1-15 %. The differences between treatment
with chemotherapy vs. treatment with hormone therapy is usually even less.

A recent metanalysis of 10 year results comparing combination adjuvant
chemotherapy vs. no chemotherapy included 11,000 patients in 31 randomized trials
(Lancet 1992;339:1,71). Most patients were pathologically node positive. Overall,
chemotherapy was associated with an annual reduction in odds of recurrence (28 %)
and death (17 %). This was more pronounced in premenopausal patients (actually age
< 50) compared to postmenopausal patients (age > 50) in terms of both recurrence
(36% vs. 24%) and death (24% vs. 13%). In other words, chemotherapy appeard to
decrease the relative likelihood of recurrence by about 1/3 in premenopausal women,
and by 1/4 in postmenopausal women. Because of prolonged survival with breast
cancer and competing risks for death, the survival benefit was less. As expected,
benefits were even less for older (age > 60) patients.

In node positive patients, at 10 years both DFS (44% vs. 36%) and OS (51% vs. 45%)
were improved with chemotherapy. Though the above overview had mostly node
positive patients, the same relative risk benefit is thought to apply to node negative
patients, relative to the risk of failure. Since node negative patients are a very diverse
group of patients, the likelihood of benefit can be estimated on the basis of likelihood
of failure. For example, a < 1 cm tumor has an approximate 10% chance of
recurrence. A 30% relative improvement is only 3 % absolute benefit. On the other
hand, a 5 cm tumor has a 50% chance of recurrence. A 30% relative improvement
results in a 15% absolute benefit.

Dose-intensive chemotherapy trials with bone marrow and stem cell rescue have
recently become a politically active topic. Randomized trials are underway. In my
opinion, unless a benefit is proven in a well designed randomized trial, such dose-
intensive chemotherapy should only be given on IRB aproved studies designed to
determine if the potential benefit of such therapy outweighs the hazards.

Tamoxifen has also been compared to no treatment in a large metanalysis of 30,000
patients participating in 20 trials (Lancet 1992;339:1,71). Contrary to reports of
chemotherapy, older patients (age > 50) appeared to have more benefit than younger
patients with the use of tamoxifen, with a reduction in annual odds of both recurrence
(29% vs. 12%) and death (20% vs. 6%). Most of this benefit was seen in Estrogen
Receptor (ER) positive patients, though ER negative patients also probably derive a
modest benefit.
As discussed above with regard to chemotherapy, the absolute benefit with tamoxifen
can be estimated by combining this relative risk reduction with the risk of failure in
the absence of further therapy. Unlike chemotherapy, tamoxifen has few side
effects/risks in most women (<1 % risk of endometrial cancer which is usually
discovered early, small risk thromboembolic disease, hot flashes), and has some other
health benefits (improved bone density and blood lipids levels).

To summarize, patients can generally be stratified according to risk for distant relapse,
age (or menopausal status), and ER status. Chemotherapy with or without tamoxifen
is usually the treatment of choice for premenopausal women at high risk for distant
relapse, regardless of ER status. Tamoxifen is usually recommended to ER positive
postmenopausal women, and can be given to lower risk patients due to the relatively
mild toxicity profile. Chemotherapy may be given to ER negative postmenopausal
women, though increased consideration should be given to toxicities. Therefore,
observation or tamoxifen may be reasonable alternatives. Data comparing
chemotherapy + tamoxifen to tamoxifen alone in ER positive women is lacking.

     Submitted by Dennis Carter, M.D., PGY4, Duke University Medical Center

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