general management

General Management

Since the beginning of this century, based on Halsted's hypothesis of
tumor spread, the prevalent surgical treatment for carcinoma of the
breast was radical mastectomy (with several modifications). [ref: 216]
Halsted [ref: 319] postulated that breast cancer spreads by direct
extension rather than by tumor cell embolization; based on this
premise, it was incorrectly thought that the wider the surgical
extirpation, the greater the chance for cure. McWhirter [ref: 491]
popularized a lesser surgical procedure (total mastectomy) in
combination with irradiation to the chest wall and regional
lymphatics, a technique that yielded results comparable to those of
radical mastectomy. [ref: 220,380]

Another treatment of breast cancer, initially described by Keynes
[ref: 393] in 1929 and 1937, combined conservation surgery (ranging
from biopsy to wide local tumor excision to segmental mastectomy or
quadrantectomy) and definitive irradiation. [ref: 9,95,330,564,817]
This approach, popular in Europe since 1950, has progressively gained
acceptance in the United States in the past 20 years and will be
extensively discussed in this chapter.

Patients with positive axillary lymph nodes and selected high-risk
node-negative patients are treated with adjuvant chemotherapy.
Patients with positive hormonal receptors receive tamoxifen.

Von Rueden and Sessions [ref: 821] treated 32 women over the age of 65
who had invasive breast cancer with quadrantectomy and tamoxifen as
the sole treatment (no axillary dissection, irradiation, or
chemotherapy) and compared them with 110 women of similar age treated
with standard therapy (total mastectomy or segmental resection with
axillary dissection and breast irradiation). With a mean follow-up of
52 months, disease-free survival in the patients treated with breast
conservation therapy (quadrantectomy) and tamoxifen was 92%, and
overall survival was 67%, with no patient developing a recurrence. In
the 110 women treated with standard therapy, disease-free survival was
83%, overall survival was 82%, and 5% developed local recurrence.
Thus, selected groups of older women may be treated with less
aggressive therapy with satisfactory results. [ref: 515]

Ductal Carcinoma in Situ and Lobular Carcinoma in Situ

Ernster and colleagues [ref: 193] observed a substantial increase in
diagnosis of DCIS in the United States (200% higher in 1992 than in
1983). During the same years there was a marked decline in the
proportion of these patients treated with mastectomy (from 71% to
43.8%) and an increase in the proportion treated with lumpectomy (from
25.6% to 53.3%). In 1992, 30% of patients were treated with lumpectomy
alone and 23.3% with lumpectomy and breast irradiation. Nevertheless,
the number of patients treated by mastectomy may be inappropriately
high (> 50% in many stages).

Autopsy studies show that up to 16% of asymptomatic women have DCIS.
[ref: 525] Two series reported a 15% to 20% incidence of intraductal
carcinoma in women undergoing mammography for screening. [ref: 33,798]

As defined by Broders, [ref: 79] the essential histologic feature of
DCIS is confinement of malignant epithelial ductal cells within their
natural basement membrane. Frykberg and Bland [ref: 274] describe four
distinct histologic DCIS patterns, probably representing an evolution
toward invasive carcinoma: papillary, cribriform, solid, and classic
comedo carcinoma. A micropapillary pattern has been described.

Estrogen receptors have been documented in 60% of cases of DCIS, the
same incidence as in invasive breast cancer. [ref: 274]

Natural History

Despite fragmented studies in a small number of patients, with
selection bias and inclusion of some invasive lesions, a few long-term
follow-up reports document a 30% to 50% risk of subsequent development
of invasive breast cancer after untreated DCIS that generally develops
within 10 years (Table 50-12). Patients with LCIS also have a
propensity to develop invasive lesions (35% to 45% in 10 to 20 years).
[ref: 55,202,241,423,552,617] Microscopic study of breast specimens in
patients with DCIS treated by mastectomy have shown residual
noninvasive DCIS in the original biopsy site in up to 77% of cases.
[ref: 621,855]

Patients with DCIS who present with a large mass (> 2.5 cm) have
significantly higher potential for occult invasion, multicentricity,
axillary lymph node metastases, local recurrence, and ultimately worse
survival than patients who have nonpalpable microscopic lesions at
diagnosis of DCIS. Multicentricity (occult malignancies located
outside the quadrant of the primary tumor) should be differentiated
from multifocality (malignant foci within the same quadrant as the
primary tumor or residual disease). [ref: 241] Rates of
multicentricity in patients with DCIS range from 15% to 78% (average,
35%). [ref: 356,668,770,822] Fisher and associates [ref: 241] reported
multicentricity in 27 (39.7%) of 68 patients with intraductal
carcinoma treated with total mastectomy in NSABP Protocol B-06.

In serial analysis of 82 mastectomy specimens (5-mm whole-organ
sections), Holland and co-workers [ref: 356] found that DCIS involved
one breast quadrant in 66%, extended over more than one quadrant in
23%, and was centrally located in 11% of patients. The nipple or
subareolar area was more frequently involved by comedo carcinoma (32
of 50, 64%) than by micropapillary and cribriform (11 of 32, 34%).
Nine patients had manifestations of Paget's disease.

Bellamy and associates, [ref: 50] in a review of 130 specimens,
observed more frequent single-quadrant involvement with the comedo,
solid, or cribriform subtypes of DCIS than with micropapillary DCIS,
which tended to have more diffuse involvement.

Schwartz and colleagues, [ref: 671] in an analysis of 50 breasts with
nonpalpable DCIS, noted that the solid and cribriform patterns were
rarely multicentric or microinvasive, whereas papillary and
micropapillary patterns were often multicentric and more diffuse but
rarely microinvasive; others have pointed out similar findings. [ref:
333] Comedo carcinoma was more likely to be both microinvasive and
multicentric. Comedo carcinomas also have a high incidence of
HER-2/neu-protein overexpression [ref: 790] and a high proliferative
index on thymidine-labeling studies. [ref: 498] Analysis of the
pathologic data in NSABP B-17 protocol showed that the only predictors
for ipsilateral breast recurrence were comedo-type necrosis and
involved or uncertain margins. [ref: 237] Patchefsky and colleagues
[ref: 557] also found that papillary and cribriform tumors were less
frequently associated with microinvasion.

Clinical significance of multicentricity or bilaterality in breast
cancer is controversial. As many as 96% of all local breast
recurrences after DCIS are found in the same quadrant as the primary
lesion, implicating residual disease rather than multicentricity,
[ref: 241,254,422,552] and this feature has not been shown to have an
impact on survival. [ref: 423,621] Synchronous occurrence of two or
more clinically evident breast malignancies in one patient is
extremely rare (approximately 0.1%). [ref: 238]

Clinical Presentation and Diagnosis

DCIS may present as a palpable mass, although more frequently these
lesions are diagnosed on screening mammography in a nonpalpable stage.
Microcalcifications are seen in up to 34% of cases. [ref: 293,668,678]
Almost 95% of all in situ breast cancers detected by mammography are
associated with microcalcifications. In addition, 90% of all
carcinomas that present as mammographic calcifications are in situ,
and 80% are DCIS. [ref: 293,678]

Patchefsky and colleagues [ref: 557] showed that microcalcifications
are more frequent in comedo carcinoma and may be associated with
microinvasion in 63% of cases. Holland and associates [ref: 356] noted
that mammography did not adequately predict extent of micropapillary
and cribriform tumors, with histologic extent more than 2 cm beyond
that predicted on the mammogram in 47% of cases. Microcalcifications
were present in 40 (80%) of 50 cases of predominantly comedo DCIS,
compared with only 5 (16%) of 32 micropapillary or cribriform tumors.

Ikeda and Andersson, [ref: 367] in a study of 190 women with
biopsy-proven DCIS, found 117 patients (62%) who showed suspicious
clustered microcalcifications on mammograms; 30 (16%) had negative
mammograms. Forty-three patients (23%) showed other abnormalities: 15
had circumscribed masses, 12 had focal nodular patterns, and the
remaining 16 patients showed dilated retroareolar ducts, ill-defined
round tumors, subareolar mass, or focal architectural distortion.

Treatment of DCIS

The optimal treatment of patients with DCIS must be individualized,
based on the natural history of the disease, tumor extent, histologic
features, and patient preference. Important prognostic factors to be
considered in therapeutic decisions include tumor size, pathologic
subtype, nuclear grade, presence of necrosis, extent of microscopic
tumor, and status of surgical margins. [ref: 237,422,687,722]

Silverstein and colleagues, [ref: 687] in an analysis of 181 women,
noted that larger tumor size (>/= 2.5 cm) and comedo carcinoma subtype
carried a greater tendency toward positive initial histologic margins
and residual intraductal breast carcinoma, although this trend was not
statistically significant (P < 0.1).

The incidence of residual DCIS after biopsy is high, an important
consideration if local excision only is advocated for treatment. Rosen
and associates [ref: 621] observed a 57% incidence of residual DCIS
after biopsy in 53 women treated with mastectomy. Wanebo and
co-workers [ref: 831] and Carter and Smith [ref: 100] described
residual DCIS after biopsy in 60% and 66% of mastectomy specimens,
respectively. However, it is uncertain whether the surgeons had
attempted to obtain negative margins at the time of biopsy.

In several reports of patients treated with biopsy only, recurrences
ranged from 8% in selected patients [ref: 423] to 75% [ref: 404,444]
(Table 50-13).

Updated NSABP results in 48 patients treated with lumpectomy
(follow-up, 83 months) showed breast relapses in only 2 (7%) of 27
patients receiving irradiation, compared with 9 (43%) of 21 patients
treated with lumpectomy alone, and none in 27 patients treated with
mastectomy. [ref: 240]

Page and colleagues [ref: 552] reported that 7 (28%) of 25 women
monitored for longer than 3 years after biopsy only of DCIS of the
breast developed invasive lesions during a follow-up period of
approximately 15 years.

On the other hand, Lagios [ref: 420] reported a 12.6% incidence of
local recurrence in 79 selected patients with DCIS treated with local
excision alone. Arnesson and associates [ref: 19] in Sweden observed a
13% recurrence rate in 38 women treated with local excision alone
(mean follow-up, 60 months). Schwartz and colleagues [ref: 670]
treated 70 patients with DCIS with local excision and surveillance
alone. With a mean follow-up of 49 months (maximum, 168 months), 11
patients (15.3%) developed a recurrence (8 to 85 months after initial
diagnosis). Ten of the 11 patients with recurrent tumor had comedo
carcinoma initially. Half of the recurrences in Lagios' series were
invasive, as frequently reported, compared with only 2 of 11 in the
Schwartz report.

More effective treatment options for DCIS include total mastectomy or,
more recently, wide tumor excision followed by breast irradiation.
Surgeons should make every attempt to excise the entire lesion with
clear histologic margins to lower the incidence of posttreatment
recurrence.

As in invasive carcinoma, Coleman and associates [ref: 124] showed
regional variations in the use of breast-conserving therapy for DCIS:
54% in Seattle and San Francisco, 48% in Connecticut, 26% in Iowa, 29%
in Atlanta, and 31% in Hawaii. Winchester and associates, [ref: 852]
in a review of the data from the National Cancer Data Base, noted an
increased use of partial mastectomy without lymph node dissection from
12.6% of patients in 1985 to 23.2% in 1991 in the treatment of
carcinoma in situ of the breast. The use of total and modified radical
mastectomy was essentially unchanged (5.8% to 8.7% and 41.8% to 42%,
respectively).

Routine node dissection has been eliminated for DCIS because so few
patients have positive nodes. A possible exception is the large or
extensive intraductal cancer (e.g., >/= 4 cm), which is known to have
a small but finite incidence of axillary spread, probably the result
of pathologic sampling error (undetected invasive carcinoma).
Silverstein and associates [ref: 688] analyzed axillary node
positivity, disease-free survival, and breast cancer-specific survival
in six breast cancer subgroups by tumor stage (T) category. Nodal
positivity for DCIS was 0% in 189 patients. In multiple series
totaling more than 1000 patients, the incidence of positive axillary
lymph nodes was less than 1% (Table 50-14). [ref: 21,100,241,395,692]
Therefore, only the breast needs to be addressed when considering
treatment, whether by total mastectomy or tumor excision with or
without irradiation. Results described with mastectomy are shown in
Table 50-15. Occasionally chest wall recurrence of DCIS has been
reported after mastectomy. [ref: 148,234]

Several reports have described satisfactory outcome in women treated
with local excision and irradiation for intraductal cancers. Kuske and
colleagues [ref: 417] described results in 76 women with 77 DCIS
treated with breast conservation surgery and irradiation. With median
follow-up of 4 years, overall 5-year survival was 99%, disease-free
survival 89%, and the breast tumor-control rate 93%. Comedocarcinoma
had a 5-year actuarial tumor control rate of 88% in 70 irradiated
patients compared with 98% for all other histologic subtypes of DCIS
(P < 0.03). All six patients with local failure were successfully
salvaged by further surgery.

Fourquet and associates [ref: 253] treated 67 patients with DCIS with
breast-conserving therapy. With a follow-up of 104 months, the 10-year
breast recurrence rate was 10.4%. Five of seven recurrences were
invasive ductal carcinoma. The only factor associated with risk of
local recurrence was total dose of irradiation to the tumor bed; all 7
recurrences occurred in 41 patients who received less than 63 Gy,
whereas 26 patients treated with higher doses had no recurrences (P <
0.02).

Solin and co-workers [ref: 720] reported 261 breasts with DCIS in 259
women from nine institutions in Europe and the United States treated
with local excision and irradiation. The 10-year actuarial rate of
local failure was 16%, and of distant metastasis, 4% (Figure 50-9).
The authors updated the results with 15-year follow-up. [ref: 718] The
cause-specific survival rate was 96%, the breast relapse rate was 19%,
and the incidence of distant metastasis was 3%. Although the comedo
carcinoma plus nuclear grade 3 lesions had a greater incidence of
local failure in the earlier years, by 10 years there was no
significant difference from other histologic subtypes (18% and 15%,
respectively). Of 45 patients with local recurrence, 24 (53%) had
invasive ductal carcinoma, and 21 (47%) had DCIS (one associated with
Paget's disease). Treatment of local recurrence consisted of
mastectomy in 42 patients, local excision and axillary dissection in
1, local excision alone in 1, and other treatment in 1 patient with
associated distant metastases. Of 26 patients who had assessable lymph
nodes, one had positive axillary lymph nodes.

Solin and colleagues [ref: 717] also described results of a large
multiinstitutional study of 110 women with unilateral nonpalpable
mammographically detected DCIS of the breast who were treated with
breast-conserving surgery and irradiation. With a median follow-up of
9.3 years, the local recurrence rates were 7% (3 of 42) in patients
with negative final pathologic margins, 29% (5 of 17) in those with
positive or close margins, and 14% (7 of 51) in those with unknown
final margins. Local recurrence developed in 14 (25%) of 56 women
younger than 50 years of age but only in 1 (2%) of 54 older women;
median interval to local recurrence was 4.9 years in the younger group
and 8.7 years in the older group. There was no significant difference
in 5-year local recurrence according to histologic subtype (8% for
comedo and 2% for other). The 10-year actuarial cause-specific
survival rate was 96%. A subgroup of 21 patients was identified with
characteristics similar to those detailed by Lagios and colleagues
[ref: 422] (mammographic detection with microcalcifications alone,
pathologically confirmed negative margins of excision, tumor size <
2.5 cm); these patients were treated with breast-conserving surgery
(local excision) and irradiation, and there were no local recurrences
during a median follow-up period of 8.7 years.

Fowble and associates, [ref: 258] in 110 women with mammographically
detected DCIS treated with breast conservation therapy (50 Gy) with
boost to the primary site (10 Gy), reported a 10-year actuarial breast
recurrence rate of 15% and a cause-specific survival rate of 100%.
Three ipsilateral recurrences were invasive ductal carcinoma. Two
patients developed contralateral invasive breast cancer. Vicini and
colleagues, [ref: 812] in 104 breasts in 102 women treated in a
similar manner with median follow-up of 6.1 years, noted a 10-year
actuarial tumor control rate of 94%. Three recurrences were invasive,
and two were DCIS. All patients failing in both series were treated
with mastectomy.

Treatment of DCIS (Continued)
(1 of 1)

In 172 women with DCIS who were treated with breast-conserving surgery
and definitive breast irradiation at multiple institutions in Europe
and the United States, the only pathologic parameter that correlated
with the rate of local recurrence was the presence or absence of the
combination of comedo carcinoma plus nuclear grade 3; the 8-year
actuarial rate of local recurrence was 20% with this combination
versus 5% for other lesions (P = 0.009 on univariate analysis; P =
0.017 on multivariate analysis). [ref: 722] None of the pathologic
parameters evaluated correlated with overall survival (all P >/=
0.16), cause-specific survival (all P >/= 0.13), or freedom from
distant metastasis (all P >/= 0.13).

Silverstein and co-workers [ref: 686] reported on 227 selectively
treated patients with DCIS without microinvasion. The 98 patients with
least favorable lesions (large tumors with involved biopsy margins)
were treated with mastectomy, and the 129 with most favorable lesions
(small tumors with clear margins) were treated with breast
preservation. The preservation group was further subdivided into those
who received excision plus irradiation and those received excision
alone. One local invasive recurrence and no deaths occurred in the
mastectomy group; the 7-year actuarial disease-free survival rate was
98%. In the excision and irradiation group (103 patients), 10 patients
(10%) had local recurrence (5 invasive and 5 noninvasive), and 1
patient died; the 7-year actuarial disease-free survival rate was 84%
(P = 0.038). In the excision-alone group (26 patients with an average
lesion size of 1 cm), there were two local recurrences (8%), one of
which was invasive; there were no deaths, but only 3 patients had been
followed for longer than 4 years at the time of the report. A total of
163 axillary node dissections were done; all were negative. Six (50%)
of 12 local recurrences in the conservatively treated patients were
invasive. There was no difference in overall survival in any subgroup
regardless of treatment.

In another study of 70 cases of DCIS, 34 were treated with modified
radical mastectomy; 36 were treated with either local excision (2
patients), lumpectomy (26 patients), or quadrantectomy (8 patients),
with complementary irradiation in 34 of the 36 cases (and boost in
32). [ref: 137] The main histologic subtype was comedo carcinoma (25
of 70 cases). One local relapse (3%) in the radical surgery group and
three (9%) in the conservation treatment group were noted at 55
months. The obvious factor influencing local recurrence was inadequate
surgical excision.

NSABP Protocol B-17 randomly assigned 391 women to be treated with
lumpectomy alone; 64 (16.4%) of this group developed ipsilateral
breast cancer, compared with 28 (7%) of 399 women treated with
lumpectomy and breast irradiation. [ref: 223] The 5-year cumulative
incidence of second cancers in the ipsilateral breast was reduced by
irradiation from 10.4% to 7.5% for noninvasive cancer and from 10.5%
to 2.9% for invasive lesions (P = 0.055 and P < 0.001, respectively)
(Fig. 50-10A). Among the 64 women who developed breast relapse after
lumpectomy alone, 32 had invasive and 32 had noninvasive carcinoma. Of
the 28 women treated with lumpectomy and breast irradiation who
developed a recurrence, 8 (28.6%) had invasive and 20 (71%) had
noninvasive carcinoma. The 5-year event-free survival rate was better
in women receiving breast irradiation (84.4%) than in those treated
with lumpectomy alone (73.8%) (P = 0.001; Fig. 50-10B). Among 63 women
whose primary DCIS was treated by lumpectomy only and in whom a second
breast tumor developed, 28 (43.8%) were treated by repeat lumpectomy
and 36 (56.3%) by mastectomy. The percent of women treated by second
local excision was similar regardless of whether the second tumor was
invasive (42.8% in both groups). Of 28 women receiving irradiation who
subsequently developed tumors in the ipsilateral breast, 10 of the 20
whose second tumors were noninvasive were treated with lumpectomy and
10 with mastectomy; all 8 women whose second tumors were invasive were
treated with mastectomy. Eight women in the lumpectomy group and 10 in
the lumpectomy plus irradiation group developed a contralateral breast
cancer as the first failure event (11 were invasive, 7 were DCIS).
Fourteen of 18 contralateral tumors were treated by lumpectomy, 3 by
mastectomy, and 1 (an inflammatory cancer) by systemic therapy and
mastectomy. Longer follow-up is needed before a final analysis of
these data can be carried out. Swain [ref: 746] pointed out that 42%
to 45% of tumors in Protocol B-17 were microscopic (< 0.1 cm), and
another 30% were 1 cm or less in diameter, so the results of this
trial cannot be extrapolated to larger tumors, which tend to be
multicentric and may have areas of invasion.

Patient selection in clinical trials was documented by Fentiman and
associates. [ref: 210] They identified 207 women with pure DCIS on
biopsy who were eligible for European Organization for Research on
Treatment of Cancer (EORTC) Trial 10853 (randomization to observation
or breast irradiation of 50 Gy), only 77 of whom (36%) were registered
for the study. Major reasons for nonentry were too-extensive DCIS (76
of 139, 55%), history of previous breast cancer (18%), a lump larger
than 3 cm (4%), and patient refusal (4%). These exclusions may make
the results of the trial applicable only to a minority of patients
with DCIS.

Silverstein and associates [ref: 691] published a review of 425
patients with DCIS who were treated with either mastectomy or
breast-conserving surgery and irradiation; among the latter group,
they noted a recurrence rate of 3.9% in patients who had
non-high-grade DCIS without necrosis, 11.1% in those who had
non-high-grade DCIS with necrosis, and 26.5% in those who had
high-grade DCIS. The 8-year actuarial disease-free survival rates were
93%, 84%, and 61%, respectively (P treated with excision and breast irradiation, the 10-year disease-free
survival rate was 75%, compared with 20% in 31 patients treated with
excision alone.

The reported incidence of local recurrence after treatment of DCIS
with conservation surgery and breast irradiation is higher but not
significantly different from that seen after mastectomy (Table 50-16).
More importantly, survival rates are comparable, and patients who have
recurrences after lumpectomy and irradiation can be salvaged with
mastectomy.

Solin and associates [ref: 711] analyzed 42 local failures in the
breast after initial treatment of DCIS with breast-conserving surgery
and irradiation in 274 women; 23 patients (55%) had invasive ductal
and 19 (45%) had intraductal carcinoma, 1 with associated Paget's
disease. Overall, 20 recurrences (48%) were detected by mammography
only, 11 (26%) by physical examination only, and 11 (26%) by
mammography and physical examination. Of the 19 intraductal
recurrences, 14 (74%) were detected by mammography only. Thirty
recurrences (71%) were at the initial tumor excision site; 10 (24%)
were elsewhere in the breast, and 2 (5%) were diffuse or multifocal.
Of the recurrences, 20 (48%) occurred within 5 years, 17 (40%) between
5 and 10 years, and 5 (12%) 10 years after treatment of the original
lesion. Surgical treatment at the time of local recurrence included
mastectomy (39 patients), excision (2 patients), and other (1
patient). Adjuvant systemic therapy at the time of local recurrence
included chemotherapy in 2 patients and hormonal treatment in 7; 1
patient received both; 32 patients received none. Median follow-up
after salvage treatment was 3.7 years (mean, 4 years; range, 0.1 to
9.5 years). The 5-year actuarial survival rate after salvage treatment
for the 42 patients with local recurrence was 78%, the rate of
cause-specific survival was 84%, freedom from distant metastases was
86%, and freedom from chest wall recurrence after salvage mastectomy
was 92%. All three patients who developed chest wall recurrence after
salvage mastectomy also developed distant metastatic disease.

Fisher and colleagues, [ref: 237] in analysis of 573 patients of 790
with DCIS enrolled in NSABP Protocol B-17, identified 53 patients who
had second ipsilateral breast tumors; 38 occurred in the group treated
with lumpectomy only and 15 in patients treated with lumpectomy and
irradiation. The overall incidence of breast relapse was 13.9% and 5%,
respectively, in the two treatment groups. Significant prognostic
factors in the patients treated with lumpectomy and irradiation were
moderate to marked comedo necrosis and indistinct or involved
lumpectomy margins.

In contrast to LCIS, with risk of contralateral carcinoma of the
breast with intraductal lesions is small. The rate of bilateral breast
cancer associated with DCIS is 10% to 15%, although some have reported
rates as high as 30%. [ref: 742] Most of these occult contralateral
malignancies are also carcinoma in situ. [ref: 268,582] Webber and
co-workers [ref: 834] showed a risk of contralateral breast cancer of
3.4% with an average follow-up of 9 years (4 of 116 patients). Kinne
and associates [ref: 395] reported on 25 patients with bilateral in
situ carcinoma of the breast; 8 patients developed metachronous
invasive carcinoma, including 2 with positive axillary lymph nodes,
probably the result of undetected invasive carcinoma.