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24115—PRINCIPLES OF RADIATION THERAPY FOR PRIMARY BREAST CANCER
Upper Extremity Lymphedema—Com-
bining regional radiation therapy with
axillary surgery will increase the risk of
lymphedema; however, this will depend
on the extent of both. Full axillary radiation after a complete axillary dissection
will result in the highest risk of lymphedema and should be discouraged. When
patients undergo breast surgery along
with an ALND without radiation, they
have a 2% to 10% rate of moderate to
severe arm edema. When radiation therapy is added, just to the breast, the rate
increases to 4% to 13% of patients. This
number jumps to 25% to 30% with nodal
irradiation. The incidence also increases
with obesity and chemotherapy. It is
important to note that patients who had
an SLN biopsy also have a risk of lymphedema, between 5% and 7%.
Brachial Plexopathy—Permanent plexo-
pathy is primarily seen in women who
receive regional nodal radiation. Women
will present with the new onset of numbness, pain, or weakness in the affected
arm. Most women will have complete
resolution of their symptoms by 1 to
2 years; however, 0.25% will have permanent brachial plexopathy.
Pneumonitis—Approximately 1% to 5%
of women receiving breast or chest wall
radiation will have transient lung inflammation and symptomatic pneumonitis.
The risk will increase with increasing lung
volume in the tangent fields. Increased
lung irradiation (and an increased risk of
pneumonitis) will occur when fields are
extended to include the supraclavicular,
axillary, and internal mammary lymph
nodes. In addition, concurrent chemotherapy will increase the risk of pneumonitis. The incidence of radiation
pneumonitis will increase to 8% to 20%
for women receiving nodal radiation and
adjuvant chemotherapy. Women typically
present with cough, low-grade fever, and
dyspnea beginning about 2 to 3 months
after radiation and persisting for several
weeks. In most women these symptoms
will be self-limiting, although in rare cases
steroids may be necessary. Chest x-ray will
show changes confined to the radiation
therapy field. Pulmonary fibrosis typically
follows in the affected portion.
Rib fracture—Rib fracture is rare after
standard radiation. The incidence is
approximately 1%, and most rib fractures
are seen about 1 year after radiation. Treatment is simple, primarily supportive until
healing is completed, however, it is important to differentiate between a rib fracture
and a bone metastasis. In patients with
preexisting collagen vascular disease, they
may develop severe soft tissue ulceration or bone necrosis, and this is one reason why this is a contraindication to
radiation.
Cardiovascular morbidity—The risk of
late cardiovascular events is dependent on
tumor location, technique, and dose. The
excess mortality observed in early trials of
radiation therapy was largely the result
of cardiovascular toxicity; however, more
modern techniques have minimized this
effect. Women with left-sided breast cancers are at increased risk as they have more
myocardium included in the treatment
field.
Secondary malignancies—Potential treat-
ment-induced secondary malignancies following locoregional radiation include
contralateral breast cancers, sarcomas, lung
cancers, and leukemias, all of which are
rare.
Sarcoma—Angiosarcoma, a relatively rare
tumor, can occur in the breast or chest
wall after irradiation. These tumors usually present as multiple reddish, bluish,
and purple nodules or areas of skin discoloration (see Chapter 23).
Lung cancer—Radiation therapy for breast
cancer has been described as a risk factor
for the development of lung cancer, with
relative risks between two and three. This
is dependent on the volume of lung in
the irradiated field. This risk is also
increased by smoking, so women undergoing breast or chest wall irradiation
should be strongly encouraged to quit
smoking.
Acute leukemia—In women undergoing
chest wall radiation therapy, the risk of
acute nonlymphocytic leukemias (ANLL)
appears to be increased. This is related to
the volume of bone marrow in the field,
the total radiation therapy dose, and the
concomitant use of chemotherapy.
Though increased compared to controls,
the absolute risk is quite low, especially
with limited bone marrow in the radiation
therapy field.
Contralateral breast cancer—Limited
data suggest a slight excess of contralateral
breast cancers following breast or chest
242 SURGICAL FOUNDATIONS: ESSENTIALS OF BREAST SURGERY
wall radiation therapy. The risk may be
higher with younger age at treatment.
Although the risk of radiation-associated
contralateral breast cancer is extremely
low, measures to reduce scatter to the
opposite breast are encouraged.
Finally, there is clearly an impact of both
radiation therapy and surgery on cosmetic outcome. Although cosmesis takes a backseat to
oncologic principles and patient safety, clearly
it cannot be completely overlooked as the
driving force for breast conservation therapy
is in part cosmetic. Overall, the overwhelming
majority of patients and their doctors rate the
cosmetic outcome as good to excellent,
although both groups are slightly biased. However, there are several factors that will impact
the cosmetic outcome.
Most factors contributing to cosmetic outcome are predetermined and include the size
of the tumor, the location of the tumor and
the preoperative breast size. Tumors in the
upper inner quadrant will leave more noticeable defects than the upper outer quadrant,
where there is more tissue. The use of chemotherapy and the dose and treatment plan of
the radiation therapy will also impact cosmesis, but these are driven by oncologic principles. Other factors, such as the amount of
tissue that must be removed to achieve negative margins, the size of the scar, and the
location of the scar are controllable by the surgeon, but not at the cost of inadequate surgery. It is believed that the higher local
recurrence rate seen among younger women
is not the result of biology but rather surgeons
compromising their oncologic operation in
the name of cosmetic outcome. The surgeon
has some maneuverability as to where the incision is placed, but excessive tunneling to
remove a cancer is discouraged, and the
trade-off for scar location is the excess tissue
that needs to be removed. If possible, incisions
in the cleavage line should be avoided. Excessively large lumpectomies or quadrantectomies
will compromise cosmetic outcome and are not
necessary for most tumors. Lesions inferior to
the nipple-areolar complex can cause disparity
between the two breasts and lead to excessive
downturning of the nipple. Radial incisions
may help avoid this. Other oncoplastic techniques can further optimize the cosmetic outcome after radiation therapy (Chapter 14).
Finally placing radio opaque clips will help the
radiation oncologist accurately plan the boost,
minimizing its amount.
Partial Breast Irradiation
Although whole breast irradiation after lumpectomy has well-documented, excellent results, it
can often add additional inconvenience and
cost to both the patient and the health care
system. Not every patient lives in close proximity to a radiation oncology center, so the time
and travel involved in coming every Monday
through Friday for 5 to 6 weeks can be overwhelming for some women. For this reason,
some women who are candidates for BCT may
opt for mastectomy to avoid not only the
inconvenience, but also the toxicity of wholebreast irradiation. This has fueled significant
interest in methods to decrease the time needed
for treatment. One such approach is the use of
more rapid fractionation schedules. A randomized trial from Canada demonstrated that a
shorter schedule, in this case 42.5 Gy over 22
days, was equivalent to the standard 45 to
50 Gy over 35 days. But more significant
changes in the radiation component of breast
conservation may be around the corner.
The argument for using whole-breast irradiation after lumpectomy is based on pathologic
studies of mastectomy specimens showing
tumor cells located 2 to 3 cm away from the
primary tumor. However, clinical observations demonstrate that the overwhelming
majority of local recurrences occur close to
the site of the tumor bed. This is the reason
that many radiation oncologists recommend
a boost to the tumor bed to follow wholebreast irradiation, but it raises the question
as to whether radiation of the entire breast is
necessary. It is feasible that patients may
receive the same benefit from irradiating on ly
the tumor bed, sparing the remainder of the
breast. This may not only improve the cosmetic outcome, but also would shorten the
costs associated with treatment and the time
necessary to complete therapy. Several techniques for delivering accelerated partial breast
irradiation (APBI) have been evaluated in
appropriately selected patients (Table 15–2,
Box 15–3).
Interstitial Brachytherapy
The concept of irradiating only the region of
the breast near the tumor is not new. Multicatheter, interstitial brachytherapy has been
around for some time. This involves the placement of multiple hollow catheters within the
breast tissue around the lumpectomy cavity.
TABLE 15–2Relative Advantages and Disadvantages of Methods to Deliver
Accelerated Partial Breast Irradiation
Advantages Disadvantages
Multi-catheter interstitial
brachytherapy
Balloon-catheter
brachytherapy
External beam radiation Uses technology most facilities
Intraoperative radiation Greatly decreases the time needed
Well tolerated
Short treatment time
More clinical experience than other
modalities
Can be used for any size, shape, or
location of cavity
Technically simple
Well tolerated by patients
already have
for therapy
Catheter placement and dosimetry can be
technically complex
May require hospitalization (low-dose rate)
Limited number of clinicians who are
familiar with this technique
Multiple (10 to 25) catheters are disturbing
to patients
Limited by shape of lumpectomy and
distance to skin
May need to radiate larger area than other
methods
Requires special equipment in the operating
room
Skin and chest wall complications
24315—PRINCIPLES OF RADIATION THERAPY FOR PRIMARY BREAST CANCER
A radioactive source is then placed within the
catheters. It is somewhat ironic that the first
use of radiation to avoid mastectomy,
by English surgeon Keynes in the 1920s, used
interstitial radium needles to treat the primary tumor, with or without surger y, so APBI
is not so much a new approach as much as
the field of breast radiation oncology coming
full circle.
There are two approaches for delivering the
radiation, which is typically done by automated
technology to limit the potential radiation
exposure of health care providers. Low-dose
rate (LDR) brachytherapy involves a continuous exposure to a low dose of radiation (45 to
50 Gy at a rate of about 30 to 70 cGy/h). This
typically takes 96 hours, so one drawback to
LDR brachytherapy is that this requires admission to hospital rooms specifically designed
to shield radiation. The other approach is
high-dose rate (HDR) brachytherapy. A total
dose of 34 Gy is delivered in twice daily
fractions of 3.4 Gy. This can be performed on
an outpatient basis and can be completed
over 5 days.
BOX 15–3 CRITERIA OFTEN USED
TO SELECT PATIENTS FOR PARTIAL
BREAST IRRADIATION
Patient age >45
Tumor size <2.0 cm
Nodal status Node negative
Distance from cavity to skin >5to7mm
Balloon-Catheter Brachytherapy
A significant drawback to interstitial brachytherapy is the complexity of placing the 10 to
25 catheters. In addition, many patients are dissuaded away from multi-catheter brachytherapy when they see pictures of patients with
the multiple catheters in place, which can be
quite intimidating. This has limited the use of
brachytherapy and generated interest in alternate methods for delivering radiation directly
to within the lumpectomy cavity. The MammoSite (MammoSite RTS; Proxima Therapeutics,
Alpharetta, GA) is a balloon catheter device that
greatly simplifies brachytherapy. A catheter sits
centrally in a distally located balloon, resembling a Foley catheter. This is placed in the
lumpectomy cavity, either at the time of surgery
or as a second procedure, and inflated. This
catheter is pliableso it can easily be worn within
a bra. Treatment is then delivered with a single,
centralized HDR.
The MammoSite does have some drawbacks.
An adequate distance between the lumpectomy cavity and the skin is needed or skin
injury can result. It is also possible that a large
(50 ml or more) or irregularly shaped lumpectomy cavity cannegatively impact the effectiveness of the MammoSite, limiting the number of
patients who would be ideal candidates. However, early results with MammoSite, though
highly selective, have been promising.
External Beam Radiation
As opposed to brachytherapy, external beam
radiation can be used to deliver PBI. Recent
244 SURGICAL FOUNDATIONS: ESSENTIALS OF BREAST SURGERY
technologic advances in CT-based planning
have allowed the introduction of three-dimensional conformal external beam APBI. This
allows for improved dose homogeneity within
the target volume and does not require additional technology beyond what most radiation
facilities already have. One disadvantage is
that a larger area of normal breast tissue may
need to be irradiated than with other PBI techniques because the breast is a moving target.
One way to improve on this is the use of
intensity-modulated radiation therapy (IMRT),
which delivers radiation using a variableintensity pattern that is determined with the
aid of a computerized optimization algorithm
(Figure 15–6). Although more costly and
labor-intensive than three-dimensional conformal APBI, IMRT delivers a more uniform
and standardized radiation dose without
excessive treatment of the surrounding tissue.
Intraoperative Radiation Therapy
The most efficient method of limiting the time
necessary to deliver the radiation is to do so in
the operating room following lumpectomy.
Initially intraoperative radiation therapy (IORT)
was proposed as an adjunct to whole-breast irradiation, as a more accurate method of delivering
the boost. More recently, it has been examined
Figure 15–6. Intensity modulated radiation treatment (IMRT) delivers radiation using a variableintensity pattern that is determined with the aid of a
computerized optimization algorithm. IMRT delivers
a more uniform and standardized radiationdose without excessive treatment of the surrounding tissue.
as a sole method of radiation treatment. Several
methodsexist fordeliveringthe radiation intraoperatively. One method uses a portable, dedicated linear accelerator. After completion of the
lumpectomy, the skin is dissected off of the surrounding breast parenchyma around the cavity,
and the parenchyma is dissected off of the pectoralis major muscle. This allows adequate
retraction of the skin and the placement of an
aluminum-lead disk to protect the chest wall.
Once this is completed, 21 Gy are delivered. An
alternative approach uses electrons generated
by a mobile linear accelerator.
All of these technologies seem promising, but
clinical experience is limited and long-term
follow-up is not available for the newer
approaches (see Table 15–2). In addition, these
trials are highly selective, and for the most part,
from single institutions. Participation is limited to a patient population with an expected
excellent cosmetic outcome and low risk of
recurrence with whole-breast irradiation (older
patients, node-negative, smaller tumors). PBI is
presently being directly compared to wholebreast irradiation in a randomized trial, which
will hopefully secure the role of PBI in breast
conservation therapy.
Suggested Readings
1. Arriagada R, LeˆMG, Rochard F, et al. Conservative
treatment versus mastectomy in early breast cancer:
patterns of failure with 15 years of follow-up data.
Institut Gustave-Roussy Breast Cancer Group. J Clin
Oncol 1996;14:1558–1564.
2. Blichert-Toft M, Rose C, Andersen JA, et al. Danish
randomized trial comparing breast conservation
therapy with mastectomy: six years of life-table
analysis. Danish Breast Cancer Cooperative Group.
J Natl Cancer Inst Monogr 1992;11:19–25.
3. Buchholz TA, Strom EA, Perkins GH, et al. Controversies regarding the use of radiation after
mastectomy in breast cancer. Oncologist
2002;7:539–546.
4. Fearmonti RM, Vicini FA, Pawlik TM, et al. Integrating partial breast irradiation into s urgical
practice and clinical trials. Surg Clin of N Am
2007;87(2):485–498.
5. Fisher B, Anderson S, Bryant J, et al. Twenty year
follow-up of a randomized trial comparing total
mastectomy, lumpectomy, and lumpectomy plus
irradiation for the treatment of invasive breast
cancer. N Engl J Med 2002;347(16):1233–1241.
6. Fisher B, Redmond C, Poisson R, et al. Eight-year
results of a randomized clinical trial comparing
total mastectomy and lumpectomy with or without
irradiation in the treatment of breast cancer. N Engl
J Med 1989;320(13):822–828.
7. Fyles AW, McCready DR, Manchul LA, et al. Tamoxifen with or without breast irradiation in women
50 years of age or older with early breast cancer.
N Engl J Med 2004;351:963–970.
24515—PRINCIPLES OF RADIATION THERAPY FOR PRIMARY BREAST CANCER
8. Jacobson JA, Danforth DN, Cowan KH, et al. Tenyear results of a comparison of conservation with
mastectomy in the treatment of stage I and II breast
cancer. N Engl J Med 1995;332(14):907–911.
9. Kantorowitz DA, Poulter CA, Sischy B, et al. Treatment of breast cancer among elderly women with
segmental mastectomy or segmental mastectomy
plus postoperative radiotherapy. Int J Radiat Oncol
Biol Phys 1988;15:263–270.
10. Morris MM, Powell SN. Irradiation in the setting of
collagen vascular disease: acute and late complications. J Clin Orthod 1997;15:2728–2735.
11. Poggi MM, Danforth DN, Sciuto LC, et al. Eighteen
year results in the treatment of early breast carcinoma with mastectomy versus breast conservation
therapy: the National Cancer Institute Randomized
Trial. Cancer 2003;98:697–702.
12. Recht A, Edge SB, Solin LJ, et al. Postmastectomy
radiotherapy: clinical practice guidelines of the
American Society of Clinical Onology. J Clin
Orthod 2001;19:1539–1569.
13. Sanders ME, Scroggins T, Ampil FL, et al. Accelerated partial breast irradiation in early-stage breast
cancer. J Clin Orthod 2007;25(8):996–1002.
14. Schnitt SJ, Hayman JA, Gelman RS, et al. A prospective study of conservative surgery alone in the
treatment of selected patients with stage I breast
cancer. Cancer 1996;77:1094–1100.
15. Taghian A, Jeong JH, Mamounas E, et al. Patterns of
locoregional failure in patients with operable breast
cancer treated by mastectomy and adjuvant chemotherapy with or without tamoxifen and without
radiotherapy: results from five National Surgical
Adjuvant Breast and Bowel Project randomized
clinical trials. J Clin Orthod 2004;22:4247–4254.
16. Van Dongen JA, Voogd AC, Fentiman IS, et al.
Long-term results of a randomized trial comparing
breast conserving therapy with mastectomy: European Organization for Research and Treatment of
Cancer 10801 Trial. J Natl Cancer Inst 2000;
92:1143–1150.
17. Veronesi U, Cascinelli N, Mariani L, et al. Twenty
year follow-up of a randomized study comparing
breast-conserving surgery with radical mastectomy for early breast cancer. N Engl J Med 2002;
347(16):1227–1232.
18. Whelan TJ, Julian J, Wright J, et al. Does locoregional
radiation therapy improve survival in breast cancer?
A meta-analysis. J Clin Orthod 2000;18:1220–1229.
16
Principles of Adjuvant Chemotherapy for Breast Cancer
INTRODUCTION
PRINCIPLES OF ADJUVANT
CHEMOTHERAPY
BENEFITS OF ADJUVANT
CHEMOTHERAPY IN BREAST
CANCER
SELECTION OF PATIENTS FOR
ADJUVANT CHEMOTHERAPY
Consensus Groups
Adjuvant Online
CHEMOTHERAPEUTIC
AGENTS USED IN BREAST
CANCER
Principles of Adjuvant Chemotherapy for Breast
Cancer: Key Points
Be familiar with the principles of how cytotoxic chemotherapy
kills cancer cells.
Describe the benefits of adjuvant chemotherapy after surgery and the data
from the EBCTCG.
Understand the important factors in determining the benefits of adjuvant
chemotherapy and the present guidelines clinicians use to guide these
decisions.
Know how to use Adjuvant Online to assess the benefit of adjuvant
chemotherapy for the individual patient.
Anthracycline-Based Regimens
Taxanes
Herceptin
Dose-Dense Chemotherapy
High-Dose Chemotherapy with
Autologous Stem Cell
Support
SIDE EFFECTS OF
CHEMOTHERAPY
Short-Term Toxicity
Long-Term Effects
ON THE HORIZON
247
248 SURGICAL FOUNDATIONS: ESSENTIALS OF BREAST SURGERY
Understand the potential benefit and unanswered questions of using
microarray analysis for making decisions regarding adjuvant therapy.
Be familiar with the various agents used in breast cancer chemotherapy and
the possible side effects.
Understand the mechanism of action and potential benefit of Herceptin in
the adjuvant setting.
Appreciate the future potential of targeted therapies in the systemic
treatment of breast cancer.
Introduction
Breast cancer can essentially be thought of as
two simultaneous problems. The first is the
locoregional disease, the known cancer within
the breast and regional lymph nodes. This is
directly addressed through the use of surgery
and radiation therapy. The second disease is
the possible presence of micrometastatic disease elsewhere in the body. These cells will be
unaffected by local therapies, and so the only
way to eradicate them (and prevent recurrence) is through the use of adjuvant systemic
therapies. These two problems are obviously
not mutually exclusive. Systemic therapies will
have an impact not only on distant recurrence, but locoregional recurrence as well.
Likewise, adequate local control will help minimize the secondary spread of micrometastases
and decrease distant recurrence.
Adjuvant systemic therapy refers to the
administration of chemotherapy or hormonal
therapy following primary surgery for early
stage breast cancer to eliminate or delay the
subsequent appearance of clinically occult
micrometastatic disease. Two observations in
the late 1800s led to the concept of using systemic therapy after surgery. The first was the
realization that even with aggressive surgical
therapy, 20% of patients who were node negative would recur within 5 years, as would 70%
of patients with positive nodes. The second
was the observation of blood-borne tumor
cells post mortem. These led to the awareness
that the only way to improve the outcome
for patients with breast cancer would be
control of the distant micrometastases with
systemic therapies.
The first adjuvant therapy for breast cancer
was hormonal therapy, which will be discussed in the next chapter. The first clinical
trial investigating chemotherapy began in
1958 and was conducted by the National SurgicalAdjuvantBreastandBowelProject
(NSABP).
Adjuvant chemotherapy trials in the late 1960s
and early 1970s focused on single agents in
patients with axillary nodal metastases. With a
clear demonstration of improved survival, trials
of adjuvant chemotherapy have continued to
try to build on these results, examining combination chemotherapy, different treatment durations and schedules, and new agents as they are
discovered. This chapter will focus on the use of
systemic chemotherapy following surgery.
Principles of Adjuvant Chemotherapy
Chemotherapeutic agents inhibit cell growth
and cause apoptosis through interference with
normal cellular functions, primarily progression through the cell cycle (Box 16–1). As such,
they tend to be more effective in treating rapidly
dividingcells. A considerably smaller proportion
of cells in a slowly growing tumor are progressing through the cell cycle when chemotherapy is given. Unfortunately, while aggressive,
BOX 16–1 PRINCIPLES
OF ADJUVANT CHEMOTHERAPY
Chemotherapy kills a constant
fraction of tumor cells (first-order
kinetics) rather than a constant number of
cells (log kill hypothesis). Thus, repetitive
cycles of therapy are necessary.
Combination therapy is superior to
single-agent therapy by overcoming drug
resistance. This will, however, increase
toxicity.
A dose-response effect exists, thus
requiring adequate doses of drug.
Outcome is dependent on the number of
malignant cells present when therapy is
initiated. Even a single metastatic cancer
cell, left alive, can lead to death.
24916—PRINCIPLES OF ADJUVANT CHEMOTHERAPY FOR BREAST CANCER
rapidly growing tumors may have more cells in
the cell cycle, they are also more likely to
acquire resistance to chemotherapy. Chemotherapy not only kills cancer cells, but normal
cells progressing through t he cell cycle are
susceptible, and this is what leads to the
significant toxicity associated with adjuvant
chemotherapy.
The principles of adjuvant chemotherapy
follow several principles that led to the present dosing regimens used. The first is that
chemotherapy works by first-order kinetics.
This means that the drugs kill a fixed fraction
of cells with each cycle and not a fixed number of c ells (referred to as log kill hypothesis).
Ifthelatterweretrue,thenalargeenough
single dose could potentially be effective (if
tolerated). However, because the drugs kill
only a fraction of cells, repetitive cycles are
necessary. The effectiveness of adjuvant therapy is therefore related to how efficacious
the drug is (how large is that fraction of cells
killed), how many cells are there to begin
with, how many cycles are used, and how
quickly the remaining cells grow between
cycles.
There are several other barriers to the efficacy
of adjuvant chemotherapy. The first is resistance. Some cancer cells are inherently resistant
to particular agents; others will gain resistance via mutation. To some degree, resistance
is countered through the use of combination
chemotherapy ratherthan single agents.In general, using agents in combination is more effective and the more common approach when
there is a curative intent, as in the adjuvant
setting. The best combinations include agents
that act synergistically, which are most likely
to occur when they have different mechanisms
of action and resistance. When combining chemotherapy, however, one must also consider
the potential overlapping side effects to avoid
excessive toxicity.
When discussing adjuvant chemotherapy,
there are several endpoints that are relevant
(Box 16–2). Two of the most important endpoints are disease-free survival (DFS) and overall survival (OS). DFS is the time from
treatment to the first evidence of recurrence
or death, whichever comes first. OS is defined
as the time from treatment to death, regardless
of disease recurrence. Although this is relatively straightforward, there are several points
that bear mentioning. DFS and OS are not
linked to the degree that one might expect.
For a disease where recurrence is strongly
linked to inevitable death, then DFS will
BOX 16–2 MEASUREMENTS
OF SURVIVAL
Disease-free survival (DFS): Time from
treatment to first evidence of recurrence
or death.
Overall survival (OS): Time from treatment
to death.
Distant disease-free survival (DDFS): Time
from treatment to first evidence of
distant recurrence.
parallel OS. However, if local recurrence is
common, but highly curable, this would translate to a low DFS but high OS. For this reason,
some studies tend to ignore local recurrences
and focus only on distant disease-free survival
(DDFS).
One might also assume that improving DFS
would improve OS, but this is also not necessarily the case . If a new agent decreases recurrence, but makes subsequent recurrences
more aggressive and less susceptible to treatment, then an improvement in DFS might
have no effect on OS. It is for this reason that
some might argue that OS is the only meaningful endpoint. On the other hand, a delay
in recurrence, eve n in the absence of an OS
benefit, may be of significant benefit to
patients, and justify the use of an adjuvant
therapy.
The benefits of adjuvant chemotherapy are
often described in terms of reductions in the
odds of disease recurrence or death. It is
important to understand the concept of absolute versus proportional reductions when discussing the benefits of systemic therapy.
A proportional reduction of 25% is described
as an odds reduction of 25%, an odds ratio of
0.75, or a hazard ratio of 0.75. But the absolute
benefit of the therapy depends on what the
risk of recurrence or death was without treatment. Therefore, let us say that without adjuvant therapy, the likelihood of death was
40% (an overall survival of 60%). If you start
with 100 patients, 60 will live regardless of
adjuvant treatment. Of the other 40, a 25%
proportional reduction would mean that 10
will now survive and 30 will die. Thus, the
absolute benefit was 10%. If the risk of death
decreases, the proportional benefit stays the
same, but the absolute benefit decreases. If
the likelihood of death is only 20%, the proportional benefit stays the same at 25%, but
the absolute benefit drops to 5%.
250 SURGICAL FOUNDATIONS: ESSENTIALS OF BREAST SURGERY
Benefits of Adjuvant Chemotherapy in Breast Cancer
A lengthy discussion of the early trials and
multiple studies examining adjuvant chemotherapy is well beyond the scope of this book.
The impact of adjuvant chemotherapy on
breast cancer is best demonstrated in the Early
Breast Cancer Trialists’ Collaborative Group
(EBCTCG) data. The EBCTCG is an international group that meets every 5 years to review
the collective data on breast cancer trials. The
1995 overview analysis summarized the results
of randomized chemotherapy trials beginning
before 1990. The analysis involved 18,000
women participating in 47 trials of adjuvant
chemotherapy and revealed several key points
regarding the efficacy of adjuvant chemotherapy in breast cancer.
1. Compared to no adjuvant therapy, polychemotherapy significantly improved OS.
The proportional risk reductions are shown
in Ta ble 16–1 and broken down by
age. Overall, combination chemotherapy
reduces the risk of recurrence by 23.5%
and the risk of death by 15.3%. This
translated to an overall 7% to 11% absolute increase in 10 year OS in women
under age 50, and a 2% to 3% absolute
increase in women aged 50 to 69. There
was no significant difference in either
recurrence or survival for women 70 years
of age or older, however, it should be
mentioned that only a small percentage
of women in the randomized trials were
older than 70.
2. The benefits are true for patients who
are both node negative and node positive.
When first introduced into clinical practice, adjuvant chemotherapy was limited
to patients who were node positive (hence
the importance of the axillary lymph
node dissection [ALND] even in the
absence of a direct survival benefit, as
described in Chapter 13). However, the
Oxford overview clearly shows that the
proportional reductions in recurrence
and death are similar for patients who
are node negative and those who are node
positive. What changes are the risks of
recurrence and death, so that although
the proportional benefit stays the same,
the absolute benefit changes. Thus, the
selection of appropriate patients for adjuvant chemotherapy is based on a more
complex calculation of the patient’s risk
of recurrence rather than node positive
versus node negative.
3. Anthracycline-based chemotherapy is
superior to non-anthracycline based regimens. Initially, one of the most common
regimens used was cyclophosphamide,
methotrexate, and fluorouracil (CMF).
In the Oxford Overview, they identified
11 trials (over 6900 patients) in which
CMF was compared with regimens containing doxorubicin (such as FAC or AC)
or epirubicin (such as FEC). There was a
12% reduction in the odds of recurrence
and an 11% reduction in the odds of
deathwiththeuseofananthracycline
regimen. These benefits were seen in
patients who were both node positive
and node negative. Anthracycline-based
regimens are now the most common regimens in the adjuvant setting, although
CMF is still a reasonable option for some
women.
TABLE 16–1Proportional Risk Reductions Associated with Adjuvant Chemotherapy
in the 1995 EBCTCG Systematic Review on Polychemotherapy
Proportional Reduction in
Recurrence (%)
Polychemotherapy vs.
None- All Ages
<40 37 27
40 to 49 34 27
50 to 59 22 14
60 to 69 18 8
70 or older — —
23.8 15.2
Proportional Reduction in
Mortality (%)
25116—PRINCIPLES OF ADJUVANT CHEMOTHERAPY FOR BREAST CANCER
Selection of Patients for Adjuvant Chemotherapy
Several factors have been identified that can help
select which patients are most likely to benefit
from adjuvant therapy. Factors can be categorized as either prognostic or predictive. A prognostic factor correlates with the clinical outcome at
the time of diagnosis, independent of therapy.
Examples include tumor size and lymph node
status. Larger tumor size and the presence of
nodal metastases correlate with the likelihood of
distant recurrence and death. Prognostic factors
are important because they can help determine
the absolute benefit of chemotherapy. As stated,
ifadrugcanreducethechanceofdyingofbreast
cancer by 25%, it is important to know what the
chance of dying of breast cancer is, based on
prognostic factors. If the chance of dying is only
4%, then the absolute benefit of the drug is
only 1% (meaning 100 women need to be treated
for 1 woman to survive). On the other hand,
if the prognostic signs suggest a 40% chance of
dying, the absolute benefit is 10% (10 women
need to be treated for 1 woman to survive).
A pure prognostic factor, however, does not
give information about the likelihood of a
treatment working. Predictive factors provide
information on the likelihood of a response
to a given modality. These factors are usually
the target of the therapy or related to the
method by which the treatment works.
Many factors may be both predictive and
prognostic. One example is the overexpression
of human epidermal growth factor receptor
2 (Her-2/neu). Her-2 neu status is clearly predictive. Women who are Her-2/neu positive are
likelyto benefit fromHerceptin, whereas women
who are negative will see no benefit. Her-2 neu
status may also predict the response to certain
chemotherapeutic regimens. However,Her-2 neu
status is also prognostic because women with
Her-2 neu overexpressing cancers tend to have
a worse outcome than patients who are
Her-2 neu negative, regardless of treatment.
Although many prognostic and predictive
factors have been examined, only a handful
are used clinically (Box 16–3). The primary factors presently in use include both those factors
that are patient related (age and comorbidities)
and those that are tumor related (size, nodal status, grade, histology, angiolymphatic invasion,
hormone receptors, and HER2/neu status).
Although the standard approach to systemic
therapy is the use of these prognostic and predictive factors, it is an interesting time in cancer
BOX 16–3 AMERICAN SOCIETY
OF CLINICAL ONCOLOGY TUMOR
MARKER GUIDELINES
ER and PgR expression should be
evaluated on every breast cancer to
guide the decision to use hormonal
therapy.
Her-2/neu overexpression should be
evaluated on every breast cancer to help
guide the selection of trastuzumab
(Herceptin) for adjuvant therapy.
The present data is insufficient to
recommend the measurement of p53,
cathepsin D, cyclin E, ploidy, or DNA
content or S phase measurements. There
is also insufficient information at this
time to recommend the estimation of the
proliferative rate, including mitotic rate
counts, S-phase fractions, Ki-67,
proliferating cell nuclear antigen (PCNA),
or argyrophilic nucleolar organizer
regions (AgNOR).*
* Although the American Society of Clinical Oncology
(ASCO) guidelines do not recommend the assessment
of cell proliferation, it is recommended by the College
of American Pathologists, and many institutions do
routinely measure Ki-67.
ER, xxxx; Her-2/neu, xxxxx; PgR, xxxx; p53, xxx.***
therapy, with a shift away from using tumor,
node, and metastasis (TNM) staging for adjuvant therapy decision making and toward
using more detailed genetic information from
the primary tumor. With the introduction of
Onco Type DX, the first foray into more selective targeting of systemic therapy has been
seen. As more research is done and validated,
this is likely to dramatically change how we
approach adjuvant chemotherapy.
Consensus Groups
Adjuvant hormonal therapy, with a favorable
risk-benefit ratio, is generally recommended to
all hormone receptor positive patients (see
Chapter 17). The decision to administer adjuvant systemic therapy must take into account
not only the individual patient’s risk of relapse,
but also the absolute benefits of treatment,
the potential short-term and long-term complications, and the patient’s comorbidities and life
expectancy. This has made the creation of general guidelines for adjuvant chemotherapy use
a challenging problem. One method of addressing the complexities has been through groups
of experts reviewing the available data and
making recommendations.