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Innovation and clinical specialities: oncology
Figure 1: Advanced breast cancer
treatment while for a woman at low risk the benefit will be small yet
she will be exposed to the same toxicity. For example, a 20%
reduction with chemotherapy for a patient with a baseline 50% risk
of recurrence will result in an absolute reduction to 10% (from 50%
to 40%) where as a woman with a 10% recurrence risk reduces
her risk of recurrence to 8%, only a 2 % absolute reduction. Some
women would not choose chemotherapy for a 2% risk reduction
and others might. The decision to take systemic therapy therefore
is therefore very much dependent on the woman and her
understanding of these risks. 99
Adjuvant endocrine therapy is effective in ER and/ or PR positive
tumors. The most commonly used endocrine therapy is the
Selective Estrogen Receptor Modulator (SERM) Tamoxifen, used
in premenopausal women. Other SERM agents like Toremifene
and Raloxifene are equally effective. There is strong evidence to
support the superiority of a 5 year Tamoxifen therapy over shorter
durations. Tamoxifen in addition helps to maintain bone mineral
density in post menopausal women and reduces the risk of
developing cancer in the contralateral breast. The side effects of
Tamoxifen include hot flashes, risk of thrombo-embolic disease,
endometrial carcinoma and cataracts.
For post-menopausal women, third generation selective
aromatase inhibitors have been shown in recent trials to be more
effective than Tamoxifen and have become the standard of care.
Examples include non steroidal type (anastrozole and letrozole)
and the steroidal type exemestane. Patients using aromatase
inhibitors have less gynecological symptoms such as endometrial
cancer, vaginal bleeding, and vaginal discharges. Fewer
cerebrovascular events and venous thromboembolic events were
also observed with patients receiving aromatase inhibitors.
However, musculoskeletal effects (arthritis, arthralgia, and/or
myalgia) and bone toxicity (bone fractures) are associated with
aromatase inhibitors.
The combination of endocrine therapy and cytotoxic
chemotherapy provides benefits greater than the benefits from
either therapy alone. They are therefore usually offered sequentially,
with chemotherapy given right after surgery, local radiation therapy
is then given, and endocrine therapy commenced. Premenopausal
women are given Tamoxifen for five years. The optimal duration of
the aromatase inhibitors has not yet been determined and
postmenopausal women remain on them indefinitely.
Ovarian ablation (e.g., surgical oophorectomy or radiation
ablation) or suppression (e.g., use of the gonadotropin- releasing
hormone or luteinizing hormone-releasing hormone analogues) is
another effective way to reduce estrogen in premenopausal
women. It can be used as an adjuvant treatment alone or to
induce menopause in very high risk premenopausal women to
allow the use of adjuvant aromatase inhibitors.
Chemotherapy
Chemotherapy has been shown to substantially improve the longterm,
relapse-free, and overall survival in both premenopausal and
postmenopausal women up to age 70 years with lymph nodepositive
and lymph node-negative disease irrespective of the
hormone receptor status.
The administration of polychemotherapy (two or more agents) is
superior to the administration of single agents. Four to six courses
of treatment (3–6 months) appear to provide optimal benefit, with
the administration of additional courses adding to toxicity without
substantially improving overall outcome. Popular regimes include
CMF (cyclophosphamide, methotrexate,fluorouracil), CAF, AC,
FEC. Anthracycline based adjuvant therapy (with doxorubicin or
epirubicin) result in a small (4-5%) but statistically significant
improvement in survival compared with non-anthracyclinecontaining
regimens. 100 .
Trials using accelerated or dose dense chemotherapy (two
weekly interval instead of the standard three weeks) with
granulocyte colony stimulating factor (GCSF) support to overcome
the risk of neutropenic sepsis has been demonstrated to improve
both disease free survival and overall survival with fewer
neutropenic crises.
Trials using high dose chemotherapy with haemopoietic stem
cell rescue on the other hand showed high morbidity and no
benefit from this approach.
Around 20% of breast cancers over express HER2, and this is
associated with an adverse prognosis. Trastuzumab is a
humanised monoclonal antibody directed against the external
domain of the receptor with clinical activity as a single agent
inpatients whose cancers over express HER2.
Trastuzumab in combination with Taxanes and other drugs have
shown considerable improvement in metastastic breast cancer. Its
role in the adjuvant setting in early breast cancer has been so
successful in HER2 positive breast cancer showing significant DFS
and OS. Unfortunately, the cost implication is a drawback to its
use in countries with limited resources.
Bisphosphonates are drugs that inhibit osteoclast mediated
bone resorption induced by tumors. Some adjuvant trials indicate
that two years of oral clodronate reduces the incidence of bone
metastases. One trial showed a small, but significant,
improvement in overall survival. Further trials are underway with
clodronate and the newer, more potent bisphosphonate
zoledronate to define their long term effectiveness.
They are very useful in patients taking Aromatase inhibitors
because of the risk of bone loss and fractures.
Advanced Breast Cancer (Stages III and IV):
This includes Locally Advanced Breast Cancer (LABC),
metastastic cancer and recurrent cancer. (see Figure 1)
LABC
LABC refers to Stage III tumors according to the TNM staging.
Locally advanced breast cancer (LABC) accounts for at least half
Hospital and Healthcare Innovation Book 2009/2010 99