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470 M. D’Angelica et al.
Council and the European Organization for the Research and
Treatment of Cancer compared HAI 5-FU/LV with systemic
5-FU/LV. This trial did not allow crossover, and showed similar response rates, time to progression, and overall survival.
Again, only 66% of those patients assigned to HAI
chemotherapy received the assigned therapy; additionally,
HAI chemotherapy was with 5-FU rather than FUDR.
71
Cancer and Leukemia Group B (CALGB) trial comparing
HAI FUDR to systemic 5-FU/LV without crossover has
recently been completed. Response rates were demonstrated
to be significantly higher with HAI FUDR (48% versus 25%),
as was overall survival (22.7 months versus 19.8 months).
72
One of the major lessons learned from trials evaluating
HAI chemotherapy was that, although control of hepatic disease was excellent, there was significant extrahepatic failure.
Currently, with the explosion of new active systemic agents, a
new paradigm has developed in the treatment of hepatic colorectal metastases. Many phase I and II trials are now evaluating combinations of HAI FUDR with systemically
administrated 5-FU/LV with irinotecan and/or oxaliplatin.
Even in pretreated patients, impressive response rates in
excess of 80% are being seen.
73
Although recent advances in
cytotoxic chemotherapy for colorectal cancer over the last
decade have been very exciting, the development of targeted
molecular-based therapy provides even greater hope for more
effective systemic treatments. Studies continue to focus on
immune-based therapy including vaccines, monoclonal antibodies, and immunotoxins. Anti-angiogenic therapy with
anti–vascular endothelial growth factor antibodies (bevacizumab) are also currently being evaluated. Inhibitors of the
receptor for epidermal growth factor, a tyrosine kinase receptor, has also shown promising results, and drugs such as
cetuximab (C225), ZD1839 (Iressa), and OSI774 (Tarceva)
are actively being studied. Results of current clinical trials are
anxiously awaited to see where these molecular-based targeted therapies will ultimately fit in among the armamentarium of systemic therapy for colorectal cancer.
62
Resection
As described above, it is clear that patients with untreated
hepatic colorectal metastases have poor survival. Although
response rates to chemotherapeutic regimens are improving,
the only therapy ever shown to be potentially curative for
A
hepatic colorectal metastases is complete resection. When surgeons began attempting resections for metastatic colorectal
cancer they were met with some skepticism.
treating what is generally acknowledged to be a “systemic”
problem with “locoregional” therapy was certainly questionable. Additionally, liver resection performed in the 1970s and
1980s was associated with high morbidity and mortality, making its role in the treatment of advanced cancer suspect at that
75
time.
Over the last 20 years, however, large series have
demonstrated that liver surgery can now be practiced with
acceptable safety, and that patients with isolated and resectable
hepatic metastases have the potential for long-term survival.
In modern series, mortality rates for hepatectomy for
metastatic colorectal cancer are uniformly 5% or less (Table
34-3). Nonetheless, morbidity for these operations remains
substantial, and is usually reported between 20% and 50%.
Fortunately, this morbidity does not generally translate into
long hospital stays, intensive care unit stays, long-term disability, or early mortality. The most ominous complications,
such as liver failure and significant hemorrhage, are now distinctly uncommon, thanks to better surgical technique and
postoperative care. A recent review of more than 1800 liver
resections (57% of a lobe or greater) over the last decade at
our institution found that the median hospital stay was 8 days,
morbidity was 45%, and mortality was 3%. Furthermore, of
the 1245 hepatectomies performed for metastatic disease,
mortality was 2.4%.
76
Liver resection for metastatic colorectal cancer was performed sporadically in the 1970s, but was an unproven and suspect therapy. Dr. James Foster traveled to medical centers in
the United States recording outcomes in patients undergoing
74
The concept of
TABLE 34-3. Surgical series of hepatectomy for metastatic colorectal cancer with 100 or more patients
Author No. of patients Operative mortality (%) 1-y survival (%) 5-y survival (%) 10-y survival (%) Median survival (mo)
Adson et al.
Hughes et al.
Schlag et al.
Doci et al.
Gayowski et al.
Scheele et al.
Fong et al.
Jenkins et al.
Rees et al.
Jamison et al.
Fong et al.
Minagawa et al.
Figueras et al.
Choti et al.
Laurent et al.
170
171
82
80
173
174
175
176
84
180
181
172
177
178
179
141 2 82 25 — 24
607 — — 33 — —
122 4 85 30 — 32
100 5 — 30 — 28
204 0 91 32 — 33
469 4 83 33 20 40
577 4 85 35 — 40
131 4 81 25 — 33
150 1 94 37 — —
280 4 84 27 20 33
1001 3 89 37 22 42
235 0 35 26 37
235 4 87 36 — —
226 1 — 40 26 46
311 3 86 36 — 40
34. Colorectal Cancer: Metastatic (Palliation) 471
hepatectomy for colorectal metastases and, for the first time,
documented 5-year survival rates of 25%.
77
Major institutional
and multi-institutional reviews of patients undergoing hepatectomy for metastatic colorectal cancer have now clearly documented that, in well-selected patients, 5-year survival ranges
from 25% to 40%, 10-year survival ranges from 20% to 26%,
and median survivals range from 24 to 46 months (Table 34-
4). These results obviously compare favorably to the results of
no treatment (median survival 5–10 months) and to those of
chemotherapy (median survival 10–14 months). Despite
recent improvements in chemotherapy resulting in median survivals as high as 20 months (see above), complete resection
still provides the best outcomes. True long-term cure from
chemotherapy is extraordinarily rare, whereas at least half of
the long-term survivors after liver resection are disease-free
and presumably cured.
78
For these reasons, no trial has ever
compared hepatectomy to no treatment or chemotherapy
alone. Liver resection for resectable hepatic colorectal
metastases is the treatment of choice.
Many studies of patients undergoing liver resection for isolated hepatic metastases have evaluated prognostic factors to
help select those patients most likely to benefit from hepatectomy and, conversely, to identify those unlikely to benefit.
The two most consistent negative prognostic factors are the
presence of extrahepatic disease and the inability to resect all
tumor; these two factors remain contraindications to hepatectomy. The exception to this rule is the patient with limited
pulmonary metastases or colonic anastomotic recurrence,
who may undergo combined resections with some success.
Although there are many inconsistencies in the major
reported series, a list of other poor prognostic factors exist;
these include lymph nodes involved by the primary colorectal
tumor, synchronous presentation [or shorter disease-free
interval (DFI)], larger number of tumors, bilobar involvement, CEA elevation greater than 200 ng/mL, and involved
histologic margins.
79–83
Although it seems to be true that the
stage of the primary tumor, the interval in which metastatic
disease has developed, and the bulk of tumor in the liver
(measured by size, number, and/or CEA level) can provide
prognostic information on outcome after hepatectomy, none
of these findings in and of themselves preclude the potential
for long-term survival. We recently published a multivariate
analysis of 1001 patients who underwent potentially curative
hepatectomy, and identified five factors as having the most
84
influence on outcome.
These included size greater than
5 cm, DFI of less than 1 year, more than one tumor, lymph
node-positive primary, and CEA greater than 200 ng/mL.
Utilizing these five factors, we have developed a risk score
predictive of recurrence after liver resection (Table 34-4).
Recurrence after hepatectomy for colorectal metastases is
common, occurring in more than two-thirds of patients. In
fact, long-term survival does not necessarily imply that there
has been no recurrence. In a study of 96 actual 5-year survivors, nearly half had experienced a recurrence at some point
and received further therapy.
78
In patients who do recur, the
liver is the most common site of recurrence and is involved
approximately 45% of the time. Most of these recurrences are
isolated to the liver. Other common sites are lung, bone, and
various intraabdominal sites.
85
Because many recurrences are
isolated to the liver, repeat liver resection has been attempted
by several surgeons with some success. Unfortunately, only
5%–10% of patients are candidates for a second liver resection, underscoring the importance of patient selection.
Currently, at least 14 series reporting on more than
700 patients have documented that repeat hepatectomy for
metastatic colorectal cancer is safe and effective in wellselected patients. Mortality is less than 5%, median survival
from the time of the second liver resection ranges from 23 to
46 months, and 5-year survival ranges from 30% to 41%.
The factors most often associated with a poor outcome after
42
repeat hepatectomy are size and number of tumors, as well as
short DFI. Because of the potential for further effective therapeutic interventions after primary liver resection, patients
eligible for such treatment should be followed with serial
CEA and imaging studies to detect recurrences at an early and
potentially treatable phase.
Because recurrence after hepatectomy for metastatic colorectal cancer is common, there is a sound rationale for use of
adjuvant therapy. Indeed, adjuvant 5-FU-based systemic
chemotherapy after liver resection was often given, but its use
was not supported by prospective trials. A number of retrospective comparisons have been performed, but no definitive
published data support the routine use of adjuvant postoperative 5-FU-based systemic chemotherapy. The effect of newer,
86
T
ABLE 34-4. Clinical risk score
tic colorectal cancer
Score 1-y survival (%) 3-y survival (%) 5-y survival (%) Median survival (mo)
093 72 60 74
191 66 44 51
289 60 40 47
386 42 20 33
470 38 25 20
571 27 14 22
Source: Adapted from Fong et al.
*
Each of the following five risk factors equals one point: node positive primary, DFI <12 mo, >1 tumor, size
>5 cm, CEA >200 ng/mL. Score is total number of points in an individual patient.
*
and survival in 1001 patients undergoing liver resection for metasta-
84
472 M. D’Angelica et al.
more effective chemotherapeutic regimens on long-term survival after hepatectomy is not known, but is promising.
Because hepatic metastases derive their blood supply from
the hepatic artery and the most common site of recurrence
after hepatectomy is within the remnant liver, there is a strong
argument for the use of HAI chemotherapy. Three randomized trials have addressed the efficacy of adjuvant HAI
chemotherapy. In the German Cooperative multicenter study,
HAI 5-FU/LV was compared with no treatment after hepatectomy. No significant differences in outcome were found;
however, many patients in the HAI arm did not receive therapy, and 5-FU is not considered the optimal therapeutic for
HAI chemotherapy.
87
In the recently published Intergroup
study, adjuvant HAI FUDR combined with systemic 5-FU
was compared with no treatment. A significant improvement
in survival (46% versus 25% 4-year survival, P = .04) was
demonstrated only when analyzed by actual treatment
received. There was no significant difference in outcome
when analyzed in an intent-to-treat manner.
88
The third trial,
performed at Memorial Sloan-Kettering Cancer Center
(MSKCC), compared systemic 5-FU/LV to systemic 5-FU/LV
combined with HAI FUDR. Ninety-two percent of patients
received therapy as assigned, and there was a significant
improvement in 2-year survival (the primary endpoint) favoring the addition of HAI FUDR (86% versus 72%).
89
Given the growing number of chemotherapeutic options for
patients with metastatic colorectal cancer, there are many
options for the patient who has had all of his or her liver metastases resected. Because HAI FUDR combined with systemic
5-FU/LV is the only therapy ever shown to improve survival in
this setting, there is a strong argument for the use of this modality; however, the surgeon and medical oncologist need to have
experience with pump implantation and management. With the
advent of more effective systemic chemotherapy, such as
irinotecan and oxaliplatin, as well as molecular targeted agents,
new trials are needed to assess optimal adjuvant therapy.
Because the majority of patients with hepatic colorectal
metastases are technically unresectable, the development of
more effective chemotherapy has inspired many oncologists to
use a “neoadjuvant” chemotherapy strategy in an attempt to
render patients resectable. In a series from France, 701 patients
with unresectable liver metastases received chronomodulated
5-FU/LV and oxaliplatin. Ninety-five (14%) of these patients
became resectable, secondary to chemotherapeutic response,
and underwent staged resection. The resections used techniques such as portal vein embolization and intraoperative
ablation to extirpate all tumor, and achieved an actuarial 5-year
survival rate of 35%.
44
Another study analyzed 23 previously
treated patients with unresectable liver metastases. HAI FUDR
was administered, and six patients (26%) were ultimately able
to undergo an R0 resection.
45
These early studies suggest that
patients with unresectable liver metastases should be treated
aggressively with chemotherapy and reevaluated at intervals
for the possibility of resection.
Although resection has become the gold standard for treat-
ment of liver metastases, other methods of tumor destruction
using thermal ablation techniques have also been developed.
Cryotherapy has been used for decades, and utilizes probes to
freeze tumors and surrounding normal hepatic parenchyma.
Cryotherapy generally requires a laparotomy, and complications such as bleeding, liver cracking, and a cryoshock phenomena characterized by thrombocytopenia and disseminated
intravascular coagulation can occur. More recently, radiofrequency ablation (RFA) probes have been developed that can
heat liver tumors and a surrounding margin of tissue to create
coagulation necrosis. RFA can be used percutaneously, laparoscopically, and at laparotomy under ultrasound, CT, or MRI
guidance. Furthermore, RFA has low morbidity that generally
ranges around 10% and is rarely serious. Although RFA can be
used near blood vessels, because the heat-sink effect of blood
flow protects the endothelium, major bile ducts can be seriously injured, limiting the use of RFA in central tumors situated near major bile ducts. Local recurrence after RFA is a
significant problem, and seems to be strongly correlated with
tumor size. Generally, recurrence is more common in tumors
greater than 4 or 5 cm in diameter and in tumors abutting
major blood vessels. With improvements in localization and
monitoring of thermal application, however, these therapies
are very promising alternatives to surgery. Perhaps the greatest
application of ablative techniques will be in their use as additions to resection in patients with multiple bilobar tumors.
Ongoing studies are currently evaluating these strategies.
90,91
Lung Metastasis
It has been estimated that approximately 10% of patients with
colorectal cancer will develop lung metastasis. Of these, only
10% will have metastases isolated to the lung; and of those
patients with isolated lung metastases, only a small proportion (probably another 10%) will be considered candidates for
pulmonary metastasectomy.
that the majority of patients with metastatic colorectal cancer
to the lung have advanced disease, and are thus treated with
systemic chemotherapy or best supportive care. Few patients
will be candidates for metastasectomy; this tiny proportion
reflects extremely careful patient selection.
Data on the results of metastasectomy for colorectal lung
metastases are inherently flawed because they have been retrospectively collected over long periods of time, and mostly
reflect patient selection and tumor biology. There are no adequate control groups to compare survival; therefore, survival
statistics are difficult to interpret. However, some patients
who undergo pulmonary metastasectomy are cured, and
long-term survival without complete resection is very rare,
suggesting that patients do occasionally benefit.
Modern series of lung resection for metastatic colorectal
cancer uniformly report operative mortalities of less than 2%
(Table 34-5). Five-year survival rates range from 16% to 64%,
but generally cluster around 30% to 40%. Most studies evaluate factors associated with outcome; however, given the limited number of cases, the statistical power of these studies to
92
These estimates demonstrate
34. Colorectal Cancer: Metastatic (Palliation) 473
TABLE 34-5. Outcome of patients undergoing pulmonary metastasectomy for colorectal cancer
Author n Operative mortality (%) 5-y survival (%) Significant risk factors
Mori et al.
McCormack et al.
McAfee et al.
Yano et al.
Saclarides et al.
van Halteren et al.
Shirouzu et al.
Girard et al.
Okumura et al.
Zanella et al.
Zink et al.
Source: Adapted from Rizk and Downey.
LN, lymph nodes.
182
183
93
184
185
186
187
188
189
190
191
35 — 38 None found
144 0 44 Margin
139 1 31 No. of lesions, CEA
27 — 41 No. of lesions
23 — 16 No. of lesions
38 — 43 DFI
22 — 37 No. of lesions, size
86 1 24 CEA, margin
159 2 41 No. of lesions, LN status
22 0 62 None found
110 0 33 Size, CEA
96
detect significant factors is limited. Generally, the pathology
of the primary tumor (grade, location, stage) has not been
associated with outcome. The most frequently cited significant factors associated with adverse outcome are number and
size of lung tumors, short DFI, increased CEA, and incomplete resection.
Although the majority of series evaluate disease limited to
the lungs, several series have evaluated patients with both
liver and lung metastases. Some authors advocate resection of
synchronous limited extrapulmonary disease,
93
but the majority of studies that have analyzed synchronous liver and lung
metastases report a uniformly poor outcome after combined
resections. Long-term survival is very uncommon in this situ-
94,95
ation.
In the setting of isolated pulmonary recurrence after
potentially curative partial hepatectomy, outcomes for pulmonary metastasectomy are more favorable and are similar to
those for the initial hepatectomy.
94–96
The surgical approach to patients who are potential candidates for pulmonary metastasectomy has been somewhat controversial. Based on older studies reported in the 1980s citing
a 38% yield of contralateral thoracotomy in finding radiographically occult disease, routine bilateral thoracotomy had
been advocated.
97
With modern-day CT, such an approach is
not justified; indeed, the majority of surgeons perform pulmonary metastasectomy through a unilateral standard thoracotomy. The use of video-assisted thoracoscopic surgery (VATS)
has increased in recent years, and is often used in metastasectomy when a minimal parenchymal resection is necessary. One
problem with VATS is its inability to palpate the lung
parenchyma; a prospective study evaluating confirmatory thoracotomy after VATS showed that 22% of lesions can be
98
missed.
However, with improvements in radiology and VATS
technique, a minimally invasive approach can be justified.
Peritoneal Metastasis
The peritoneal surface is involved in approximately
10%–15% of patients with colorectal cancer at time of initial
presentation (synchronous metastases) and in 20%–50% of
patients who develop recurrence (metachronous metas-
99–102
tases).
As a site of colorectal cancer metastasis, the peritoneal surface ranks second only to the liver. Peritoneal
metastasis occurs by direct implantation of cancer cells via
one of four mechanisms: 1) spontaneous intraperitoneal (IP)
seeding from a T4 colorectal cancer that has penetrated the
serosal surface of the colon
103
; 2) extravasation of tumor cells
at the time of colon perforation from an obstructing cancer; 3)
iatrogenic tumor perforation through an area of serosal injury
or enterotomy at the time of colon resection; 4) leakage of
tumor cells from transected lymphatics or veins at the time of
colon resection.
104
The risk of peritoneal metastasis is there-
fore highest in the setting of locally advanced cancers.
Peritoneal metastases are clinically important because of
their frequent progression to malignant ascites and/or malignant bowel obstruction. In a French multicenter prospective
study to assess the natural history of peritoneal carcinomatosis, 118 patients with T3 or T4 colorectal cancers were among
the 370 study patients with nongynecologic malignancies.
105
Synchronous peritoneal carcinomatosis was found in 58.5%
of the patients with colorectal cancer. The most frequent
symptoms were ascites (29.7%) and bowel obstruction
(19.5%).
Preoperative detection of peritoneal metastases is not reliable. Noninvasive imaging frequently misses small peritoneal
lesions, even when these are widely disseminated. The sensitivity of CT scanning for lesions smaller than 5 mm is only
28%, as compared with 70% for lesions 2 cm or greater.
106
Thus, indirect signs such as bulky primary tumor, ascites, or
bowel obstruction are important clues.
The extent of carcinomatosis is a major prognostic factor,
and is best assessed by either laparoscopic or open exploration. Two different peritoneal carcinomatosis staging systems (Gilly’s classification and Peritoneal Cancer Index of
Sugarbaker) can be used to assess the extent of carcinomato-
107,108
sis.
These staging systems have both shown utility in
determining the prognosis and treatment of patients with peritoneal carcinomatosis. By Gilly’s classification, carcinomatosis is classified principally by the dimensions of the peritoneal
tumor implants: Stage I, tumor nodules <5 mm in diameter
474 M. D’Angelica et al.
localized in one part of the abdomen; Stage II, tumor nodules
<5mm disseminated widely through the abdomen; Stage III,
tumor nodules 5 mm to 2 cm in diameter; Stage IV, tumor
nodules >2 cm. The Peritoneal Cancer Index scores the extent
of carcinomatosis on the basis of tumor size and location
within 13 regions of the abdomen and pelvis. The lesion with
the largest size in each abdominopelvic region is scored on a
scale of 0–3 (0, no tumor; 1, tumor up to 0.5 cm; 2, tumor up
to 5.0 cm; 3, >5 cm or confluence). The total score of the
Peritoneal Cancer Index can vary from 0 to 39. The Peritoneal
Cancer Index is shown to correlate with survival. Median survival and 5-year survival after surgical debulking and IP
chemotherapy were 48 months and 50% for peritoneal index
<10, compared with 12 months and 0% for index >20.
109
Standard management of patients known to have peritoneal
metastases at initial presentation is systemic chemotherapy.
Colon resection has an important role for patients with
obstructing primary cancers, and also for patients with occult
metastases that are first detected in the operating room.
Historically, the median survival for patients with unresected
peritoneal metastasis treated with 5-FU-based systemic
chemotherapy was very poor (6–8 months).
102,105,110
However,
patient survival is highly variable, depending on the extent of
metastatic disease and response to chemotherapy.
111,112
Contemporary combination chemotherapy regimens have significantly greater efficacy, and can produce long periods of
disease control in certain patients.
6
In the past decade, a more aggressive treatment approach
utilizing cytoreductive surgery and IP chemotherapy has been
pioneered by Sugarbaker.
113
The goal of cytoreductive surgery is to remove all macroscopic disease with peritonectomy
procedures and visceral resections. Perioperative IP
chemotherapy is then used to destroy residual microscopic
disease. IP delivery offers a pharmacokinetic advantage over
standard intravenous delivery by producing high regional
concentrations of drug while simultaneously minimizing systemic toxicities.
114,115
The most widely reported method of IP
chemotherapy is intraoperative delivery of mitomycin in a
hyperthermic (41C) circuit for 90 minutes.
116
An alternative
approach is postoperative infusion of FUDR via an implanted
IP catheter.
117
Although few prospective trials have been completed for
colorectal carcinomatosis, the available evidence suggests a
survival benefit for cytoreductive surgery and IP chemotherapy. Phase II studies report 5-year survival rates ranging
between 19% and 28%.
117,118
The most consistent and important prognostic factor in these studies is the ability to achieve
complete resection of all gross disease. Five-year survival
rates reported for patients with completely resected disease
range from 27% to 54%.
117,119
A phase III study conducted by the Netherlands Cancer
Institute randomized 105 colorectal cancer patients with peritoneal carcinomatosis to either standard treatment (systemic
5-FU/LV with or without palliative colectomy) or experimental therapy (aggressive cytoreductive surgery, hyperthermic IP
120
mitomycin, and systemic 5-FU/LV).
In the experimental
arm, median operation time was 585 minutes, treatment toxicity was high, and treatment-related mortality was 8%. After
a median follow-up of 22 months, median survival was 12.6
months in the standard therapy arm and 22.3 months in the
experimental therapy arm. It is not known if the survival benefit observed in the experimental therapy arm is attributable to
surgical debulking, IP chemotherapy, or both.
In summary, the standard therapy for patients with peritoneal metastases is systemic chemotherapy. However, there
is evidence that aggressive surgical cytoreduction and IP
chemotherapy will benefit patients with limited peritoneal
tumor burden. Additional clinical trials are needed to define
optimal use of this aggressive treatment approach.
Ovarian Metastasis
Approximately 7%–30% of ovarian neoplasms are metastatic
cancers, the most common being colorectal and breast can-
121–124
cer.
mary colorectal cancer, ovarian metastases are discovered
either at the time of colon surgery or during follow-up.
However, the risk of developing ovarian metastasis is substantially higher in woman with Stage IV disease, and
approaches 90% in women with established peritoneal
metastases. In addition, women with adenocarcinoma of the
vermiform appendix have a very high risk of ovarian metastasis. Thus, in a woman with recent diagnosis of advanced
colorectal cancer, any ovarian mass should be considered a
metastasis from colorectal cancer until proven otherwise.
The pathogenesis of colorectal cancer ovarian metastasis is
variable. Metastatic spread occurs primarily through the peritoneum, but can also occur via the blood stream, through lymphatic vessels, or by direct extension. Careful intraoperative
assessment of the ovaries at the time of colon cancer surgery
is essential. Synchronous metastases occur in 0%–8.6% of
patients in various clinical studies,
nous metastases develop in 1.4%–6.8% of colorectal cancer
cases,
resection.
large, and at least half of the cases have bilateral ovarian
involvement.
have associated extraovarian pelvic metastasis.
Distinguishing a metastatic colorectal cancer from primary
ovarian tumor is difficult by gross assessment alone, but a correct diagnosis can generally be determined through integration of clinicopathologic, immunohistochemical, and
cytogenetic features. Most metastatic colorectal lesions are
CK20
neoplasms are CK20
Clinical studies attempting to document the benefit of ovarian metastasectomy in patients with colorectal cancer are
small and retrospective.
asymptomatic when first detected in the operating room or on
In approximately 1%–7% of all women with pri-
125–127
128–132
whereas metachro-
126,127,133,134
129,135,136
+
/CEA+/CK7−on staining, whereas primary ovarian
usually within 2 years after the primary
Most often these metastatic lesions are
136,137
Approximately 40% of these patients also
−
/CEA−/CK7+.
126,127,142,143
138–141
Although generally
136
34. Colorectal Cancer: Metastatic (Palliation) 475
CT scan, ovarian metastases can compress or invade adjacent
organs (ureter, bladder, bowel), rupture, and on rare occasions
bleed. Survival of women with synchronous ovarian colorectal metastases is significantly worse than that of patients without such metastases.
126,144
In addition, ovarian metastases are
frequently resistant to systemic chemotherapy even when
other sites of metastatic disease are responding. Therefore,
resection of synchronous ovarian metastases should be performed when encountered in the operating room. Bilateral
oophorectomy and complete resection of gross disease is recommended. Reoperation for metachronous metastases should
be considered in selected patients with good performance status and limited tumor burden elsewhere. The goal of metastasectomy is to prevent local tumor progression. Therefore, an
aggressive surgical approach should be undertaken to achieve
complete resection when possible, especially if disease is
confined to the pelvis. The survival benefit of removing ovarian metastases has never been well documented. Complete
metastasectomy is associated with significantly better outcome when compared with palliative debulking, especially in
the setting of metastatic disease confined to the pelvis only.
However, complete resection is only possible in 50% of these
cases. For women with isolated ovarian metastases, median
postresection survival is 18 months.
145
Women with other
sites of disease have shorter survival, however, and 5-year
survival after resection of established ovarian metastases is
146,147
rare.
Although postresection chemotherapy with 5-FU
was considered ineffective in studies done in the 1970s and
1980s, systemic chemotherapy should be strongly considered,
particularly when residual disease is present. With the availability of stronger chemotherapeutic regimens containing
oxaliplatin, irinotecan, and/or bevacizumab, better survival
can be expected.
6,57,59,61
The role of prophylactic oophorectomy in the absence of
macroscopic disease is not well defined. Several clinical
studies have failed to show a survival advantage, although the
majority of evaluated patients were postmeno-
128,129,148,149
pausal.
A randomized, prospective study comparing prophylactic oophorectomy versus no oophorectomy in
Stage II or III colorectal cancer demonstrated an improvement in 5-year disease-free survival for the oophorectomy
group (80%) compared with no oophorectomy (65%), but the
benefit was not statistically significant (P = .16).
149
Some jus-
tification and benefits for prophylactic oophorectomy can be
150–152
found in retrospective studies.
These studies have
shown reduction in the incidence of ovarian carcinoma, resection of synchronous microscopic ovarian metastases, and prevention of metachronous ovarian metastases in the future.
Based on the available data, it is reasonable to offer prophylactic oophorectomy to all postmenopausal patients. For premenopausal patients, only those with established peritoneal
metastases, those with a clearly increased risk of developing
ovarian carcinoma (strong family history, known carriers of
breast cancer [BRCA] or hereditary nonpolyposis colorectal
cancer [HNPCC] mutation), or those who have already
completed their families should be considered for prophylactic
oophorectomy.
Bone and Brain Metastases
Bone metastases from colorectal cancer reportedly occur in
7%–9% of cases, and most often present in the context of
widespread metastatic disease.
imaging is not indicated in colorectal cancer patients, however, unless there are specific bone-related symptoms. There
are no curative modalities, but palliation of pain, fractures, or
spinal cord involvement are important issues for these
patients. Symptomatic relief from bony metastases can usually be accomplished with radiation and medical therapy.
However, pathologic fractures are best treated by operative
internal fixation. The systemic issues related to bone metastases are serious and include debilitation, immobility, hypercalcemia, and thromboembolic disease.
Cerebral metastases from colorectal cancer are uncommon,
occurring in 1%–4% of colorectal cancer cases.
Colorectal tumors account for approximately 3% of all
metastatic brain tumors.
context of widespread metastases to multiple organ sites, but
on rare occasion can present as an isolated brain metastasis.
There is no role for routine brain imaging at primary presentation or at presentation with metastases elsewhere, unless
there are specific neurologic symptoms. Once brain metastases occur, symptoms are common; palliative therapies
include steroids to decrease swelling and anticonvulsants to
control seizures. Definitive therapy of colorectal brain metastases usually involves surgery, radiation, or a combination of
the two. For isolated, single brain metastases, resection can
result in survival beyond 1–2 years.
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