<p class="first" id="P1">Colorectal cancer commonly metastasizes. The liver is the
most frequent site of metastases
and dominates the length of survival for this disease. As surgical and systemic therapies
have become accepted and now are proven to be potentially curative, other sites of
metastases have become more clinically relevant in terms of clinical symptoms and
influence on survival. Treatment of extrahepatic metastases by surgical and ablative
procedures is increasingly accepted and is proving to be effective at palliating symptoms,
as well as life prolonging. In this review, we will first summarize key issues with
metastatic colorectal cancer to the liver and available treatments. We will then discuss
surgical and ablative treatments of other sites of disease including lung, lymph nodes,
peritoneum, bone, and brain. Best available evidence for treatment strategies will
be presented as well as potential new directions.
</p><p id="P2">Colorectal cancer commonly metastasizes. Most commonly this occurs
by five means:
direct extension, lymphatic spread, portal venous spread to liver, peritoneal dissemination,
and vascular spread to distant organs including lung, bone, and brain. The liver is
the most frequent site of metastases and dominates the length of survival for this
disease. Nearly one-half of patients diagnosed with colorectal cancer will be found
to have liver metastases at some point during their disease. When untreated, patients
with liver metastases have a median survival of 6–9 months. Even with the best chemotherapy,
median survival of unresectable disease is 13–18 months. In the last three decades,
treatment of extrahepatic metastases by surgical and ablative procedures has proven
to be effective. It is increasingly accepted and is effective at palliating symptoms,
prolongs life, and can be potentially curative. The fact that liver resection is affecting
outcome is also highlighted by the fact that over 70% of patients with unresectable
liver metastases die of their liver metastases. In patients treated by hepatectomy,
approximately 30% ultimately die of liver metastases.
</p><p id="P3">The median survival of patients after hepatectomy for stage IV metastatic
colorectal
cancer in the liver is over forty months. Consequently, other sites of metastases
are not only more likely to become apparent, but also more likely to cause symptoms
and influence survival. Thus, management of liver metastases has made enough progress
so that other sites of metastases have become more clinically relevant. In this review,
we will first summarize the natural history of colorectal cancer metastases. We then
will address key issues with metastatic colorectal cancer to the liver and available
treatments. This is followed by a discussion of surgical and ablative treatments of
other sites of disease including lung, peritoneum, bone, lymph nodes and brain. Best
available evidence for treatment strategies will be presented as well as potential
new directions.
</p><p id="P4">At presentation, 20–25% of patients will have distant metastases, most
to the liver.
Another 20–25% will later develop liver metastases. Of patients who succumb to the
disease, 49% will have liver dominant disease, and 83% will have some liver involvement.
Disease specific survival is also significantly shorter for those who die of liver
metastasis, compared to patients who die from other metastatic sites. Thus, addressing
liver metastases initially is the most clinically relevant, since this is the most
life limiting. Currently, patients who do not undergo surgical treatment of liver
metastases typically live less than 18 months, with no 5-year survivors. By comparison,
those who are resected but recur have a median survival of 40 months, and have a 17%
5-year survival. As such, liver directed therapies shift the cause of death to other
sites at a later time point. For this reason, having metastases at other sites does
not change survival for patients with liver metastases, as long as they are candidates
for surgery. Understanding patient prognosis after treatment of liver metastases goes
beyond American Joint Committee on Cancer (AJCC) staging due to patient heterogeneity.
Clinical risk scores have been developed to facilitate this, and show that survival
is based on primary cancer metastases to lymph nodes, length of disease free interval
(if liver disease was not identified at diagnosis), number of metastases within the
liver, and serum carcinoembryonic antigen level.
</p><p id="P5">Most major centers report operative mortality of <5% for those undergoing
hepatectomy
for colorectal cancer liver metastases. Indications for surgery are expanding, which
is no longer limited to younger patients without comorbidities. Number of liver metastases
is less important for determining resectability than is the existence of adequate
vascular inflow and outflow of the remaining liver remnant. Smaller lesions within
the planned liver remnant can be treated with microwave ablation or irreversible electroporation.
The post-operative functional liver remnant must, however, be 20–40% of the pre-operative
liver volume depending on hepatocyte functionality. This is dependent on exposure
to previous chemotherapy and pre-existing cirrhosis. If the functional liver remnant
is insufficient at presentation, it can be augmented by pre-operative portal venous
embolization. Expanding on this concept, some surgeons perform a two-staged procedure
that begins with liver partition and portal vein ligation to promote growth of the
functional liver remnant, which can initially be as small as a single liver segment.
If metastatic disease is limited to the liver, but is too extensive to resect, a hepatic
artery infusion pump that delivers floxuridine directly and only to the liver may
also be considered. Patients who are not considered operative candidates up front
can be converted to resectable with neoadjuvant chemotherapy. It should be noted that
70% of patients who receive neoadjuvant chemotherapy and have so called “disappearing
liver metastases” will have microscopic residual foci of disease in the liver, which
is the site of local recurrence in 59% of these patients.
</p><p id="P6">Surgical treatment of liver metastases can be performed synchronous
with resection
of the primary disease, or at different times. If resectability of the colorectal
disease is in question, this should be performed first to ensure an R0 resection prior
to addressing the metastatic disease. If the colorectal disease is clearly resectable,
then the liver should be approached first to ensure low central venous pressure during
this portion of the procedure without compromising blood flow to an intestinal anastomosis.
A minimally invasive approach may be appropriate depending on the location of planned
resections. Given the number of variables that go into determining optimal treatment
of colorectal cancer liver metastases, decisions must be made in a multidisciplinary
environment that includes team members with expertise in radiology, interventional
radiology, chemotherapy, and surgery. Currently, there are wide discrepancies in referral
of patients for surgical intervention versus patients who are considered resectable
by liver surgeons, reinforcing that multidisciplinary care is of utmost importance.
</p><p id="P7">Lung metastases are the second most common site of colorectal cancer
metastases, but
are rarely (<10%) found in isolation. Five-year survival is best for patients who
have lung metastases resected, compared to patients where the lung disease is left
in situ and only liver disease is removed (13% vs. 57%). Existing data, however, are
largely retrospective. A randomized phase III trial to examine the effect of concurrent
lung metastasectomy (PulMiCC trial) is currently underway. Similar to liver disease,
criteria for resectability have expanded in the last few decades. It is currently
considered acceptable to treat colorectal cancer lung metastases if there is complete
treatment of the primary tumor as well as complete resection of all pulmonary metastases
while maintaining adequate pulmonary function. Pre-operative lung function tests are
used to assess anticipated post-operative pulmonary function and need for supplemental
oxygen. Treatment consists of removal of the minimum amount of lung necessary to completely
remove the metastatic deposit. Some consider thoracotomy superior to video assisted
thoracoscopic surgery due to the ability to palpate the lung for additional deposits.
No studies, however, show a survival advantage with an open compared to a thoracoscopic
approach. Propensity score matched retrospective studies in fact suggest the opposite.
Methylene blue staining of nodules via CT guidance or navigational bronchoscopy can
also be used to assist with intraoperative tumor identification. Approach to thoracic
lymph nodes is variable and of uncertain survival benefit. Positive lymph nodes do
indicate significantly poorer prognosis. For this reason, lymph node examination is
generally recommended for completing staging and to help determine prognosis, which
may guide further therapies. Patients who have unresectable disease can alternatively
be treated with radiofrequency, microwave, or cryoablation, or stereotactic radiation.
</p><p id="P8">Of patients who die of metastatic colorectal disease, it is believed
that 25% have
peritoneal carcinomatosis. Treatment of peritoneal carcinomatosis by cytoreduction
and hyperthermic intraperitoneal chemotherapy (HIPEC) is of particular interest because
progression leads to patient suffering from malignant bowel obstruction, weight loss,
and symptomatic ascites. This can result in chemotherapy interruptions and repeated
hospitalizations. Peritoneal carcinomatosis occurs more often in patients with right
sided colon cancers, T3 tumors, involved mesenteric lymph nodes, and those who developed
obstruction or perforation. Identification of peritoneal disease is variable because
it is difficult to assess by existing imaging modalities, but is suggested by omental
caking, scalloping of the diaphragm, peritoneal nodules, and ascites. [18F]-Fluoro-deoxyglucose
positron emission tomography (FDG-PET) can be used to confirm inconclusive imaging
findings, but the gold standard of assessment is operative exploration. A study of
high risk patients with negative imaging identified peritoneal carcinomatosis in 68%.
Diagnostic laparoscopy may be used to avoid exploration in patients without carcinomatosis,
or with too extensive carcinomatosis to treat surgically (often because of disease
within the mesentery and porta hepatis). Two prospective systematic second look operations
studies (CEA Second Look and PROPHYLOCHIP) failed, however, to show a survival advantage.
A randomized trial of cytoreduction and HIPEC versus systemic chemotherapy alone showed
near doubling of survival in the cytoreduction and HIPEC group. This study was published
prior to the widespread use of oxaliplatin and irinotecan though, limiting its applicability
to our current patient population. A more recent randomized trial of systemic chemotherapy
with cytoreduction with or without HIPEC failed to show a survival advantage in the
HIPEC group, but showed a remarkable median survival of 41 months without HIPEC. Of
note, no randomized trial to date shows the additive benefit of cytoreductive surgery
to modern chemotherapy. Cytoreduction and HIPEC for peritoneal disease remains a popular
strategy in select centers because of acceptable morbidity and mortality, along with
reported 5-year survival of 27%.
</p><p id="P9">Bone metastases are important to address due to the pain they cause
impacting patient
quality of life. Tumor related factors not only affect the bone where they are deposited,
but also can make adjacent nerves more sensitive to painful stimuli. Further, local
therapy can be used in situations where most of the patient’s disease is controlled
with systemic therapy, but bone lesions progress. External beam radiation therapy
(EBRT) is first line because it is non-invasive and operator independent, but can
only be used in patients who can tolerate long periods of immobility while the therapy
is being delivered. Pain relief is experienced by 60–80% of patients after EBRT, but
can take up to 6 weeks for full effect, and recurs in 50% of patients by 18 weeks.
Radiofrequency and microwave ablation can be used for local bone metastases when EBRT
is not possible or fails, and improve symptoms in 90% of patients. Radiofrequency
ablation has several limitations including dependence on tissue conductivity and predisposition
to heat loss from adjacent blood vessels. Microwave ablation can achieve higher temperatures
and generate larger ablation zones, however prospective data comparing radiofrequency
to microwave ablation for this purpose are lacking. Cryoablation alternatively can
be used to freeze tumor tissue. Advantages with cryoablation include a readily visible
ablation zone, with less procedurally related pain compared to hyperthermic techniques.
Disadvantages include absence of vessel coagulation that can lead to bleeding, and
longer procedural time needed for repeat freeze-thaw cycles that are required. High
intensity focused ultrasound (HIFU) is a newer technology that uses targeted high
energy ultrasound waves on a focused point to induce thermal injury. It is non-invasive
and is performed under magnetic resonance imaging (MRI) guidance allowing for real
time assessment of thermal ablation. Its use is limited in locations that abut critical
organs that could be affected by patient motion during treatment, and can only treat
small tissue volumes at a time.
</p><p id="P10">Data is also accumulating that selective resection of distant lymph
node metastases
may have therapeutic benefit. Patients found to have positive peri-hepatic lymph nodes
have lower 3-year overall survival compared to those with negative peri-hepatic lymph
nodes (25 vs. 75%). Para-aortic lymph nodes exist between the left renal vein and
aortic bifurcation; clearance is associated with a survival advantage in retrospective
series. They are positive in 38% of patients with suspicious pre-operative imaging,
and when positive are associated with survival similar to that of distant metastatic
disease. Similar findings have been reported for lateral pelvic lymph node resections
in rectal cancer. While there is no survival difference between patients with and
without a lateral pelvic lymph node dissection, there is decreased survival for those
who have positive lateral pelvic lymph nodes. Existing data on extended lymphadenectomy
is mostly from Eastern countries, and thus may not be well applied to Western populations.
As such, current recommendations are to perform extended lymph node clearance only
in select patients for prognostic purposes.
</p><p id="P11">Colorectal cancer brain metastases are rarely (<1%) the first metastatic
site. Brain
metastases are most often identified in patients with metastases to 3 or more other
sites, with an average interval from diagnosis of colorectal cancer to detection of
20–40 months. One-year survival after diagnosis is 30%. Patients often present with
headache and gait changes; fewer (24%) present with seizure. Contrast enhanced MRI
is the diagnostic modality of choice. Treatment begins with management of seizures
and cerebral edema if present, but should not be prophylactic. Reviews of patients
treated for colorectal cancer brain metastases consistently show that treatment lengthens
life. This is most true for patients with good performance status; those with no impairment
of performance status have a median survival of 13.5 months. Treatment with surgical
resection via craniotomy is used for more superficial tumors that are larger, and
when tissue is needed to confirm the diagnosis. Stereotactic radiosurgery alternatively
can be used for smaller tumors that are located more deeply in the brain, and can
be used in combination with surgical resection when needed. Whole brain radiation
has been used after open surgery and stereotactic radiosurgery for metastases in the
past, but a recent randomized trial showed no difference in survival with this additional
treatment. In this study, 22% of each group were alive and functionally independent
at 2 years.
</p><p id="P12">To conclude, there are now many accepted effective ways to treat colorectal
cancer
metastases to the liver, lung, peritoneum, bone, distant lymph nodes, and brain. These
treatments can be used to palliate symptoms and also to prolong life. Due to the complexity
and multifactorial nature of the decision making that goes into optimal patient care,
treatment of colorectal cancer metastases should routinely be performed in a multidisciplinary
environment to maximize patient benefit.
</p>