local management_01

This section describes the multidisciplinary approach to the local
management of breast cancer by addressing the use of mastectomy,
conservative surgery (CS), and RT in a coordinated fashion, as well as
by considering the integration of local and systemic treatment.
Modified radical mastectomy is still the most common surgical
treatment for patients with invasive breast cancer in the United
States.(ref: 230,231) The term modified radical mastectomy is used to
describe a variety of surgical procedures, but all involve complete
removal of the breast, the underlying pectoral fascia, and some of the
axillary nodes. Whereas the modified radical mastectomy may not seem to
differ significantly from the radical mastectomy, it represents a major
departure from Halstedian principles of en bloc cancer surgery. The
switch to modified radical mastectomy occurred when it became
recognized that treatment failure after breast cancer surgery usually
is caused by the systemic dissemination of cancer cells before surgery,
rather than an inadequate operative procedure. In addition, by the
1970s, fewer patients with large tumors with fixation to the pectoral
muscle were being seen, making modified radical mastectomy feasible for
most women. Two prospective randomized trials demonstrated no
difference in survival between patients treated with modified radical
and radical mastectomy. These findings were confirmed in two
prospective randomized trials.(ref: 232,233) Perhaps the most
influential of the studies refuting the Halstedian concept was the
NSABP B-04 trial.(ref: 234) In this trial, clinically node-negative
patients were randomized to radical mastectomy, simple mastectomy and
nodal irradiation, or simple mastectomy with axillary observation and
delayed dissection if positive nodes developed. The failure of this
trial to demonstrate a difference in survival between groups was the
final proof that the Halstedian concept of breast cancer did not apply
to the majority of patients and was a landmark in our understanding of
the local therapy of breast cancer. Today, there are few, if any,
indications for radical mastectomy.
The strategy behind BCT is to remove the bulk of the tumor surgically
and to use moderate doses of radiation to eradicate any residual
cancer. The application of this strategy requires an understanding of
the extent and distribution of cancer in a breast with an apparently
localized tumor. This issue has been clarified as a result of the work
of Holland and coauthors. (ref: 235,236) In their initial study, (ref:
235) mastectomy specimens with unicentric tumors 4 cm or less in size
were evaluated using 5-mm sections, radiography of these thin slices,
and an average of 20 blocks per specimen for histologic evaluation.
Only 39% of specimens showed no evidence of cancer beyond the reference
tumor. In 20%, there was additional cancer, but this was confined to
within 2 cm of the reference tumor. Forty-one percent of cases had
residual cancer more than 2 cm from the reference tumor; of these, two-
thirds had pure intraductal carcinoma and one-third had mixed
intraductal and invasive carcinoma (Fig. 37.2_1). Local recurrence in
the breast occurs at or near the site of the primary tumor in most
cases,(ref: 237-240) emphasizing that this multifocal involvement is
biologically important. In a subsequent study, the amount of residual
intraductal carcinoma was evaluated.(ref: 236) Approximately 10% of
patients had prominent intraductal carcinoma (defined as a total of six
or more low-power fields of intraductal carcinoma) extending more than
2 cm from the reference tumor. These studies indicate that the extent
and amount of microscopic cancer in the vicinity of a primary tumor,
known as multifocality, is variable. These results imply that the
extent of surgical resection required in BCT varies from patient to
patient.
The published results of modern, prospective randomized clinical
trials comparing CS and RT and mastectomy have all shown equivalent
survival between the two treatment approaches, (ref: 241-247) and an
overview of all the trials (including an unpublished one) has
demonstrated comparable survival (ref: 248) (Fig. 37.2_2). These data
demonstrate that survival for most breast cancer patients is not
dependent on choice of local therapy. In addition to the results of
these trials, numerous reports from centers in Europe and North America
on the use of CS and RT have demonstrated high rates of local tumor
control with satisfactory cosmetic results. (ref: 249-253)
Despite the consistency of the evidence, the use of BCT in the United
States has shown relatively slow acceptance and considerable geographic
variation.(ref: 230,231) Studies indicate that fewer than 50% of women
with stage I and II breast carcinoma are treated with BCT. (ref:
230,231) The available data indicate that a minority of patients have
contraindications to BCT,(ref: 254,255) and that these are readily
identified with standard clinical tools, such as physical examination
and mammography including magnification views.(ref: 256) National
studies indicate that physicians continue to use inappropriate
selection criteria for BCT.(ref: 230)
The rates of recurrence in the breast at 7 to 18 years ranged from 7%
to 19% in the randomized studies using widely varying surgical and RT
techniques. (ref: 241-247) In the corresponding patients treated with
mastectomy, 4% to 14% of patients developed local recurrence,
emphasizing that mastectomy does not guarantee freedom from local
recurrence, even in women with clinical stage I and II breast
carcinoma. The nonrandomized studies with the longest follow-up
describe a persistent risk of recurrence in the breast through 20 years
of follow-up. (ref: 251-253,257) These results have been contrasted to
those seen after mastectomy, in which most local failures occur in the
first 3 years following surgery. The annual incidence rate for a
recurrence at or near the primary site is constant for years 2 through
7 after treatment, and then decreases to a low level by 10 years after
treatment. (ref: 253) In contrast, the annual incidence rate for
recurrence elsewhere in the breast increases slowly to a rate of
approximately 0.7% per year at 8 years and remains stable. (ref: 253)
Recurrences in the skin of the treated breast are a rare event
associated with a poor prognosis.(ref: 258) Whole breast irradiation is
effective at eradicating multicentric breast carcinoma, but it does not
prevent the subsequent development of new cancers.
A number of factors have been identified that influence the risk for
local recurrence after BCT. Young age has consistently been observed to
be associated with an increased risk of local recurrence after breast-
conserving surgery and RT. (ref: 259-263) However, young age has
similarly been associated with a worse outcome after mastectomy. (ref:
264,265) In young women with a family history suggestive of an
inherited breast cancer susceptibility, BCT is associated with a higher
rate of opposite breast cancer compared with young women without such a
family history. (ref: 266) This is consistent with the findings of an
increased risk of opposite breast cancer in young patients with
mutations undergoing mastectomy. (ref: 31,267) The rate of local
recurrence in young patients with a positive family history is, if
anything, lower than in patients with a negative family history. This
might be explained by the findings linking BRCA1 and 2 with radiation
repair genes, (ref: 268,269) or by a greater likelihood of localized
(extensive intraductal component-negative) cancers in patients with
mutations compared with patients without mutations.(ref: 270) However,
patients with mutations appear to be at risk for late new primaries in
the treated breast.(ref: 271) Of note, patients with a mutation do not
appear to be at an increased risk for adverse effects from RT. (ref:
272,273) Thus, BCT appears to be an acceptable option for patients with
a suspected or known mutation, although these patients need to be
apprised of the increased risk of a second breast cancer, either in the
opposite or, over time, in the treated breast. Many of these patients,
particularly those with favorable presentations, elect bilateral
mastectomy. A modeling study suggests that bilateral mastectomy may be
associated with a modest gain in survival. (ref: 127)
An extensive intraductal component has been shown to be an important
risk factor for local recurrence when margins of resection are not
evaluated.(ref: 274) An extensive intraductal component has been found
to be a marker for a large residual tumor burden in the involved
quadrant of the breast (ref: 236,275) such that moderate-dose RT is not
able to eradicate it. In such patients, a larger breast resection is
commonly required to ensure adequate removal. Results have shown that
the microscopic margins of resection are the major selection factor for
BCT (Tables 37.2_11 and 37.2_12). Patients with negative margins of
excision (typically defined as the absence of either invasive or ductal
in situ disease directly at an inked surface) have generally been
observed to have low rates of local recurrence following treatment with
CS and RT. (ref: 276-285) In particular, patients with an extensive
intraductal component, but with negative inked margins of excision, are
not at an increased risk of local recurrence.(ref: 279-281,286) The
outcome of patients with close margins of excision has been less clear.
In part, this reflects variability in the definition of close margins
and, perhaps, the effect of institutional policies calling for
escalated radiation doses based on the proximity of cancer cells to the
margin of resection. In the Joint Center for Radiation Therapy (JCRT)
experience shown in Table 37.2_12, there was no significant
difference in recurrence rates between patients with close margins
(less than or equal to 1 mm) compared with patients with margins
greater than 1 mm using similar doses. (ref: 279) Some studies have
suggested a high rate of local recurrence at 10 years in patients with
close margins; however, the number of patients in these series and the
actual follow-up time is limited. (ref: 278,281)
Long-term data on the use of BCT in patients with positive margins
are more limited. In most analyses, positive margins have been
associated with a high risk of breast cancer recurrence. (ref: 276-
280,283-285) At the JCRT, patients with positive margins had a
considerably higher risk of breast cancer recurrence than patients with
negative margins. (ref: 279) The 8-year crude rate of breast recurrence
was 18% for patients with positive margins. However, patients with
focally positive margins (any invasive or in situ ductal carcinoma at
the margin in three or fewer low-power microscopic fields) had a 14%
rate of recurrence compared with a 27% rate in patients with greater
than focally positive margins. These data suggest that patients with
focally positive margins can be considered for BCT. As discussed in
this section, the use of adjuvant systemic therapy results in a large
reduction in local recurrence in patients treated with CS and RT. In
the JCRT series, among the 45 patients with focally positive margins
who received adjuvant systemic therapy, the 8-year local recurrence
rate was 8% (95% confidence interval, 1% to 18%). (ref: 279) Additional
experience is needed to confirm this finding. Patients with more than
focally positive margins require more surgery given the significantly
higher rate of breast cancer recurrence.
The use of adjuvant systemic therapy is an important factor
associated with recurrence in the breast when used in conjunction with
CS and RT. This is most clearly demonstrated in three randomized
clinical trials. In the NSABP B-13 trial, node-negative, ER-negative
patients were randomized to chemotherapy or to a no-treatment control
group. Among the 235 patients treated with CS and RT, the 8-year rate
of recurrence in the ipsilateral breast was 13.4% without chemotherapy
and only 2.6% with chemotherapy. (ref: 287) Similar results are seen
with adjuvant tamoxifen. In NSABP trial B-14, node-negative, ER-
positive patients were randomized to tamoxifen or to a placebo. Among
the 1062 patients treated with CS and RT, the 10-year rate of
recurrence in the ipsilateral breast was 14.7% without tamoxifen and
only 4.3% with tamoxifen. (ref: 288) A similar result was seen in the
Stockholm Breast Cancer Study Group among node-negative patients
randomized to tamoxifen or to a placebo. (ref: 289) Among the 432
patients treated with CS and RT, the 10-year rate of recurrence in the
ipsilateral breast was 12% without tamoxifen and only 3% with
tamoxifen.

Guidelines for Patient Selection

Based on the extensive information available from prospective and
retrospective studies, there is a general consensus on the criteria for
patient selection for the use of BCT. It is now established that, in
most cases, BCT results in a cosmetically satisfactory breast and that
it provides survival rates equivalent to those seen after mastectomy.
The American College of Surgeons, the American College of Radiology,
the College of American Pathologists, and the Society of Surgical
Oncology have jointly provided standards of care for BCT and most
recently published their report in 1998. (ref: 290) Key portions of
this report are summarized here and additional comments are provided in
parentheses.

Contraindications for Breast-Conservation Treatment with Radiation
Therapy

Absolute Contraindications

- Women with two or more primary tumors in separate quadrants of
the breast or with diffuse malignant-appearing microcalcifications are
not considered candidates for breast-conservation treatment.
- A history of previous therapeutic irradiation to the breast
region that, combined with the proposed treatment, would result in an
excessively high total radiation dose to a significant volume is
another absolute contraindication.
- Pregnancy is an absolute contraindication to the use of breast
irradiation. However, in many cases, it may be possible to perform
breast-conserving surgery in the third trimester and to treat the
patient with irradiation after delivery.
- Finally, persistent positive margins after reasonable surgical
attempts absolutely contraindicate BCT with radiation. The importance
of a single focally positive microscopic margin needs further study and
may not be an absolute contraindication (see updated results from the
JCRT in Local Management of Invasive Breast Cancer, earlier in this
chapter).

Relative Contraindications

- A history of collagen vascular disease is a relative
contraindication to BCT because published reports indicate that such
patients tolerate irradiation poorly. (ref: 291) Most radiation
oncologists will not treat patients with scleroderma or active lupus
erythematosus, considering either an absolute contraindication. In
contrast, rheumatoid arthritis is not a contraindication. (ref: 292)
- Patients with multiple gross tumors in the same quadrant and
indeterminate calcifications must be carefully assessed for suitability
because studies in this area are not definitive.
- Tumor size is not an absolute contraindication to BCT, although
few reports have been published about treating patients with tumors
larger than 4 to 5 cm. However, a relative contraindication is the
presence of a large tumor in a small breast in which an adequate
resection would result in significant cosmetic alteration.
- Breast size can be a relative contraindication. Women with large
or pendulous breasts can be treated by irradiation if reproducibility
of patient setup can be ensured and it is technically possible to
obtain adequate dose homogeneity.

Nonmitigating Factors

- The presence of clinical or pathologic involvement in axillary
nodes should not prevent the treatment.
- Concern about not being able to detect a recurrence is not a
contraindication. The changes associated with recurrence can usually be
detected at an early stage by physical examination and mammography.
- The delivery of irradiation to the breast does not result in a
meaningful risk of second tumors in the treated area or in the
untreated area.
- Tumor location is not a factor in the choice of treatment. Tumors
in a superficial subareolar location occasionally may require the
resection of the nipple-areolar complex so that negative margins can be
achieved, but this does not affect outcome. The patient and her
physician need to assess whether such a resection is preferable to
mastectomy.
- A family history of breast cancer is not a contraindication to
breast conservation. Little is known about the risk of breast
recurrence in patients with hereditary breast cancer, but currently
this is not a contraindication to BCT. (However, such patients should
be apprised of their increased risk of a second breast cancer.)
- A high risk of systemic relapse is not a contraindication for
breast conservation, but is a determinant of the need for adjuvant
therapy.

Conservative Surgery without Radiation Therapy

An unresolved question is whether RT is necessary in all patients with
invasive breast cancer after CS. Six randomized clinical trials with
published results have compared CS alone with CS and RT in patients
with early-stage breast cancer. (ref: 241,242,293-296) These trials
vary with regard to patient selection, the details of the surgery and
RT, the use of adjuvant systemic therapy, and the length of follow-up.
The results of these various trials are shown in Table 37.2_13. These
trials all show a large reduction in the rate of local recurrence after
RT, with an average crude rate of reduction of approximately 75%
(range, 63% to 89%). None of the six trials shows a significant
survival benefit for RT; however, in the trials with published data,
the survival rate is slightly better for irradiated patients than for
nonirradiated patients. A large trial (or perhaps a metaanalysis of
multiple smaller trials) is necessary to detect a small, but clinically
significant difference in survival, if it in fact exists.
Attempts have been made to identify a subgroup of patients (based on
various clinical and histologic features) that has a low risk of local
recurrence after CS alone. It was not possible to identify such a
subgroup within the Ontario and NSABP randomized trials. Local
recurrence rates are generally lower in trials using more extensive
surgery than in those using lumpectomy and in older patients than in
younger patients. The JCRT attempted to identify such a subgroup in a
prospective single-arm trial in which patients with favorable disease
were offered the option of CS alone. The criteria for entry onto this
protocol were tumor size of 2 cm or less, histologically negative
axillary nodes, absence of both lymphatic vessel invasion and an
extensive intraductal component in the cancer, and no cancer cells
visualized within 1 cm of inked margins. (ref: 297) All but one patient
had a negative reexcision. This trial was stopped shortly before
reaching its accrual goal of 90 patients because of stopping rules
ensuring against an excessively high local recurrence rate. The latest
analysis includes the results in 81 patients. The median age of
patients in this trial was 66 years, and median pathologic size of the
cancers was 9 mm. With a median follow-up of 92 months, 19 of the
patients have developed a recurrence in the ipsilateral breast, for a
crude local recurrence rate of 23%. Based on the results of this
prospective study, it was concluded that, even in a highly selected
group of breast cancer patients, there is a substantial risk of early
local recurrence after treatment with wide excision alone.
The use of adjuvant systemic therapy substantially reduces the rate
of local recurrence in patients treated with CS and RT, (ref: 287-289)
but does not seem to reduce greatly the rate of local recurrence after
CS alone. There are no published trials directly comparing CS with and
without either chemotherapy or tamoxifen. Information on this is
available from indirect comparisons within randomized clinical trials
for both adjuvant chemotherapy and tamoxifen. In the NSABP trial B-06,
an indirect comparison of the effect of adjuvant chemotherapy can be
made. Node-positive patients treated with lumpectomy and adjuvant
chemotherapy but without RT had a 12-year rate of recurrence in the
breast of 41% compared with only 5% for node-positive patients treated
with lumpectomy, RT, and chemotherapy (P <.001). (ref: 241) In
comparison, node-negative patients treated with lumpectomy without RT
had a 12-year rate of recurrence in the breast of 32% compared with 12%
for node-negative patients treated with lumpectomy with RT. A similar
observation, suggesting that systemic therapy further decreases the
rate of local recurrence when combined with RT, but not in its absence,
is also seen in indirect comparisons within the Milan trials. (ref:
242) In the Scottish trial, patients with ER-negative cancers were
treated with adjuvant cyclophosphamide, methotrexate, and 5-
fluorouracil (CMF) chemotherapy. With a median follow-up of
approximately 5.7 years, the crude rate of local regional recurrence
was 44% among patients treated with CS, but without RT, compared with
only 14% among patients treated with RT.(ref: 295)
There is particular interest in avoiding RT in older patients. It is
often less convenient for such patients to receive RT, and their local
recurrence rate appears lower after CS alone compared with younger
patients.(ref: 298-300) The results of retrospective studies of CS
alone with or without adjuvant tamoxifen have shown variable results.
(ref: 301-302) The Cancer and Leukemia Group B (CALGB) and other groups
in North America have completed a prospective randomized clinical trial
testing the value of RT in older breast cancer patients treated by CS
and tamoxifen; at this time there are no results from the trial. In
NSABP B-21, women with tumors smaller than 1 cm with negative axillary
lymph nodes were randomized to tamoxifen alone, breast irradiation
alone, or breast irradiation plus tamoxifen. With an average follow-up
of 73 months, 24.4% of women in the tamoxifen-only arm had an
ipsilateral recurrence, compared to 11.7% of women who received breast
irradiation plus tamoxifen. The difference was highly statistically
significant. Based on these results, the investigators thought it
unlikely that tamoxifen could be substituted for radiation in this
patient population.(ref: 300a)
In conclusion, the use of breast irradiation after CS is associated
with a large reduction in the rate of local recurrence. The available
data from the randomized trials do not show a survival benefit;
however, none of the available trials has the statistical power to
eliminate a small survival difference. A subset at low risk of local
recurrence following CS has not been clearly identified, and RT is
currently considered standard. The addition of adjuvant systemic
therapy to CS alone has not been demonstrated to decrease local
recurrence. In elderly patients, particularly those with significant
comorbidity, RT is commonly omitted because of the practical
difficulties of delivering such therapy in this group of patients.