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34
Colorectal Cancer: Metastatic (Palliation)
Michael D’Angelica, Kamran Idrees, Philip B. Paty, and Leslie H. Blumgart
Approximately 20% of patients with colorectal cancer present
with established distant metastases.
tases are detectable with noninvasive imaging, and patients
can be assigned to AJCC (American Joint Committee on
Cancer) Stage IV before any surgical intervention. Among
these patients there is enormous heterogeneity with respect to
sites of disease, extent of disease, symptoms, performance
status, and comorbidities. The clinical spectrum at the time of
diagnosis ranges from the asymptomatic patient with a single
metastatic lesion to the rapidly deteriorating patient with
colon obstruction and advanced, multiorgan metastases. It is
therefore difficult to define rigid treatment algorithms that can
be widely applied to all clinical settings.
Despite considerable progress in the treatment of advanced
colorectal cancer, the vast majority of Stage IV patients are
not curable by current treatment protocols. A recent analysis
of data from the SEER (surveillance, epidemiology, and end
results) population-based database estimates that the 5-year
survival rate for Stage IV patients diagnosed between 1991
and 2000 was 8%.
aggressive treatment is indicated for most patients to extend
survival and enhance quality of life. Systemic chemotherapy,
endoscopic treatments to palliate obstruction, surgical diversion, and surgical resection all have important roles in treatment of Stage IV patients. Treatment approaches must be
individualized based on the extent and resectability of local
and distant disease, the presence or absence of bowel obstruction, performance status, and comorbidities. For patients with
good performance status and minimal symptoms from their
primary cancers, standard treatment is systemic chemotherapy, which is well documented to increase survival and quality of life.
when feasible, of the metastatic lesions can provide excellent
palliation and can, in some cases, provide lasting cure.
In the past decade, there has been remarkable improvement
in the efficacy of chemotherapy for colorectal cancer. Firstline therapy with either FOLFOX or FOLFIRI now yields
major responses in up to 50% of previously untreated
3,4
2
However, despite a low overall cure rate,
Surgical resection of the primary tumor and,
1
In most cases, the metas-
patients, and achieves minor responses or stable disease in an
additional 20% of patients.
nations are available as well, and second-line chemotherapy
has become more effective and more likely to impact survival.
Over the past 10 years, the median survival for patients with
metastatic disease who are treated with chemotherapy has
improved from 12–14 months to 21 months.
from chemotherapy alone remains extremely rare, effective
chemotherapy combined with aggressive surgery may be
increasing the overall cure rate. In this setting, the care of
patients with advanced disease has become quite complex.
The goal of this chapter is to provide a reference source for
surgeons managing patients who present with Stage IV colorectal cancer.
5
Multiple, effective drug combi-
6
Although cure
Biology of Metastatic Disease
Metastasis is defined as the spread of malignant cells from a
primary tumor to a distant organ. It is estimated that 90% of
all cancer deaths are a result of metastasis.
metastasis is a continuous and inefficient one that begins early
in tumor formation and increases as tumors grow.
foci themselves can go through the metastatic process and
spread to other organs (i.e., metastases can metastasize).
Numerous clinical and laboratory studies have attempted to
define the complex process of metastasis formation. It is a
multistep process, and failure at any step results in failure of
the overall process. The process relies on properties of the
tumors cells, as well as the microenvironment of the primary
and secondary sites.
(Figure 34-1).
The first step is tumorigenesis, which occurs after the initial malignant transformation. The tumor proliferates into a
small mass of heterogenous cells that are of varying metastatic or malignant potential. These tumor cells undergo multiple
and sequential genetic changes, characterized by the appearance of oncogenes and a decrease in tumor suppressor genes.
9,10
A series of major events must occur
7
The process of
8
Metastatic
462
34. Colorectal Cancer: Metastatic (Palliation) 463
FIGURE 34-1. Schematic illustrating the multistep process involved in the development of metastasis. (Reprinted from DeVita VT Jr, Hellman S,
Rosenberg SA. Cancer: Principles and Practice of Oncology. 6th ed. copyright 2001, with permission of Lippincott Williams & Wilkins.)
As the tumor grows beyond 1 mm in diameter and becomes
relatively hypoxic, angiogenesis is initiated. The process of
tumor angiogenesis is tightly regulated by pro- and antiangiogenic factors secreted by both the tumor and its environment. As tumors successfully grow, suppressors of
angiogenesis are inhibited and pro-angiogenic factors predominate, resulting in neovascularity and further growth of
the tumor.
11
Some tumors may grow by utilizing other exist-
ing blood vessels in nearby tissues.
In the next step, some cells will develop an invasive phenotype. Most researchers believe that there is a selection
process resulting in the clonal expansion of certain cell subpopulations with growth advantages and invasive properties.
Whether this process represents a property of the whole tumor
cell mass or true clonal selection of more invasive cell subpopulations is not known, and is a subject of intense
research.
12
Malignant invasion is characterized by downregulation of cell adhesion, resulting in detachment of the cell
from the primary tumor mass and the extracellular matrix.
Stromal invasion is accomplished through interactions with
the basement membrane, including adhesion, proteolysis, and
migration, ultimately resulting in detachment and invasion
through the basement membrane. This invasive phenotype
also enables these cells to enter thin-walled lymphatics and
vasculature, allowing access to systemic circulation. The neovasculature from tumor-induced angiogenesis seems to be
more susceptible to such invasion. This process of invasion is
critically related to the expression (up-regulated or downregulated) of adhesion molecules and factors influencing cell
migration.
13,14
Once inside the vascular system, cells or cell clumps
(emboli) are circulated, and must survive hemodynamic filtering as well as immune surveillance. They must then arrest
in a distant organ. This probably involves adhesion and/or
trapping, based on size, within small capillary beds. There is
likely a complex interaction between the malignant cell and
the endothelium or exposed basement membrane, allowing
cell arrest. Once arrested in a tissue bed, the cells extravasate
into the tissue, enabling formation of a metastatic focus.
There is debate as to whether proliferation occurs before or
after actual extravasation into the tissue; some experimental
models have shown that extravasation is not a prerequisite for
growth in a secondary organ.
15
Paracrine growth factors, hormones, and the local tissue environment have critical roles in
the ultimate outcome of extravasated cells. These metastatic
cells can become dormant or proliferate; what determines this
464 M. D’Angelica et al.
fate is not fully understood. Growth in the distant organ after
deposition is a major limiting factor in the formation of
metastasis, and some metastatic cells can remain dormant for
years. Once deposited in the distant organ, the metastatic
focus, if proliferating, must again go through tumorigenesis,
angiogenesis, and evasion of the immune system.
16
This complex multistep process of metastasis formation is
related to multiple genetic changes among malignant cells. As
the technology of measuring genetic changes improves, we are
beginning to appreciate the changes that occur during this
process. It seems that there are genes specific to tumorigenesis, invasion, angiogenesis, and other steps. Recently, a number of genes have been identified that suppress metastatic
potential and, by their down-regulation, affect a cell’s ability to
metastasize without affecting tumorigenicity.
17
These discoveries provide a sense of the future challenge in elucidating the
multiple, stepwise, and specific changes that regulate a cell’s
ability to metastasize. Advances in this field will have obvious
and profound implications for the treatment of cancer.
Diagnosis/Staging
The clinical presentation of Stage IV patients is variable. Most
present with symptoms referable to the primary tumor.
However, symptoms from metastatic disease, asymptomatic
metastatic lesions found on imaging studies, abnormalities in
routine blood work, and cancers discovered on endoscopic
screening procedures may also be the first signs of disease.
Initial staging evaluation should include colonoscopy with
biopsy, and imaging of the primary tumor, liver, and lungs.
When feasible, endorectal ultrasound or magnetic resonance
imaging (MRI) is recommended for rectal cancers to document
the initial T and N stage. Spiral computed tomographic (CT)
scanning of the chest/abdomen/pelvis is a highly accurate and
efficient method of detecting metastases. Positron emission
tomography (PET) scanning detects occult disease not seen on
CT scan in 20% of Stage IV patients, and should be considered
if such findings might affect patient management.
Once the extent of disease workup is complete and distant
metastases have been documented, the surgeon must make
three important judgments. First is whether the patient is fit
for aggressive treatment. Patients with poor performance status or serious cardiovascular, pulmonary, renal, neurologic, or
gastrointestinal impairment may not tolerate chemotherapy or
major surgery. Second is whether the primary tumor presents
a clinically significant risk of bowel obstruction. Symptoms,
radiographic findings, and endoscopic findings are important
considerations. If the proximal colon is not dilated on radiographic studies and a colonoscope can traverse the tumor, it
is generally safe to begin treatment with chemotherapy. The
third determination is whether the patient’s metastases can be
surgically resected, and therefore treated with curative intent.
If complete resection of all disease can be expected, then surgical intervention should assume a high priority.
18
Multidisciplinary Evaluation
Management of patients with advanced disease is often complex, and multidisciplinary evaluation can be helpful in determining initial therapy. The surgeon and medical oncologist
should evaluate the patient in consultation with a radiologist
and gastroenterologist. The goals, priorities, and expected
course of treatment should be discussed. For rectal cancers
that are bulky or symptomatic, the advice of a radiation oncologist is often helpful.
Palliative Management of the Primary
Cancer—Stents, Laser
Approximately 8%–29% of patients with colorectal cancer
initially present with symptoms of partial or complete bowel
obstruction.
were left-sided and 23% were right-sided cases.
Furthermore, a majority of obstructing tumors are either
Stage III or Stage IV.
onset, with initial symptoms of mild discomfort and change in
bowel habits. With disease progression, the symptoms can
become worse, ranging from crampy abdominal pain, abdominal distension, nausea, abdominal tenderness, obstipation,
and leukocytosis. Vomiting is a late symptom unless there is
an associated small bowel obstruction. Without treatment, the
process can progress to complete obstruction, ischemia, and
perforation. The risk of cecal perforation is greatest in
patients who have a competent ileocecal valve.
In the setting of metastatic cancer, the critical question is
whether colon obstruction should be considered a contraindication for systemic chemotherapy or radiotherapy. The degree
of symptoms, endoscopic findings, and radiographic findings
are all relevant to this decision. When the cancer can be
traversed with a colonoscope and there is no radiographic evidence for obstruction, many patients with partially obstructing
cancers will tolerate aggressive chemotherapy. Patients must
be instructed to monitor their symptoms closely, and to report
any signs of worsening obstruction immediately. A liquid diet
or pureed diet taken in small portions may help to reduce
obstructive symptoms. For patients with advanced obstruction,
nonresective palliative options include laser therapy, fulguration, colonic self-expanding metal stents, and creation of a
diverting stoma.
Laser therapy has been used for palliation of obstructing
rectal cancers for the past two decades.
272 patients who underwent palliative laser therapy for rectosigmoid cancers, the immediate success rate in treating
obstructive symptoms was 85%.
similar success rates, in the range of 80%–90%.
laser therapy is practical only for treating cancers of the distal colon and rectum, and is rarely used to treat proximal
lesions. In addition, multiple therapy sessions are required to
19
In a review of 713 obstructing carcinomas, 77%
21
Bowel obstruction is insidious in
22–24
In a large series of
25
Other studies have shown
23,24
However,
20
34. Colorectal Cancer: Metastatic (Palliation) 465
achieve lasting relief of symptoms. Serious complications
such as bleeding, perforation, and severe pain have been
reported in 5%–15% of patients, especially those undergoing
multiple treatments.
22,24–26
Surgical fulguration of rectal cancers is another method of
opening the rectal lumen.
27,28
Fulguration, in combination
with endoluminal debulking, can remove a large volume of
tumor; however, unlike laser therapy, this procedure requires
hospital admission and regional or general anesthesia.
Since their introduction in 1991, colonic stents have
become an important method of palliation for obstruction in
colorectal cancer patients, especially those with unresectable metastatic disease. These self-expanding metallic
stents can potentially dilate the lumen to a near-normal
diameter, providing quick relief of symptoms and, in some
cases, allowing endoscopic assessment of the proximal
colon. Stents can be placed in patients using minimal sedation, without need of prior endoscopic dilation and the concomitant increased risk of complications such as perforation
or tumor fracture. Moreover, these stents can be placed
across relatively long lesions by overlapping stents in a
“stent-within-stent” manner.
In a retrospective series of 80 patients who underwent
colonic stent placement for malignant large bowel obstruction, stents were successfully placed in 70 patients (87.5%
overall technical success rate).
29
Satisfactory symptomatic
relief and clinical decompression was achieved in 67 patients
(83.7% overall clinical success rate). Two perforations
occurred in this series, one of which resulted in death. Other
complications included stent migration resulting in expulsion,
reobstruction, and intractable tenesmus. Stenting of cancers in
the mid and low rectum may result in debilitating urgency and
incontinence.
A recent series of 52 patients with malignant obstruction
secondary to either primary or recurrent disease, who underwent stent placement by colorectal surgeons, reported that 50
of 52 were successfully palliated.
30
One patient had a perforation, and in another patient obstruction was not relieved
because of multiple sites of obstruction. The complication
rate in this series was 25%; migration was the most common
complication (15.4%), followed by reobstruction secondary
to tumor ingrowth (3.8%), perforation, colovesical fistula, and
severe tenesmus (2% each). Surgery was required in 17.3%,
mostly because of complications or recurrent obstruction.
Complications reported in the literature on colonic stents
include stent malpositioning, migration, tumor ingrowth
(through the stent interstices), tumor overgrowth (beyond the
ends of a stent), perforation, stool impaction, bleeding, tenesmus, and postprocedure pain.
Laser therapy has also been used in certain situations, in
conjunction with colonic stents, to recanalize and decompress large bowel. Overall, as more experience is gained,
these endoscopic palliation therapies increasingly provide
effective and durable palliation for patients with malignant
obstruction.
Surgical Management of the Primary
Cancer—Resection
The role of bowel resection in patients with unresectable
metastases is controversial. It is important to recognize that
there are no randomized data demonstrating a survival benefit for bowel resection in Stage IV patients. However, palliative resection of the primary tumor does provide durable local
control, is generally well tolerated, and can benefit many
Stage IV patients.
rouracil (5-FU)-based chemotherapy versus best supportive
care, conducted in the 1990s, have shown that Stage IV
patients receiving systemic chemotherapy have increased
length and quality of life.
regimens, the beneficial impact of chemotherapy continues to
increase.
5,6
unresectable metastatic colorectal cancer is systemic
chemotherapy. The proper use of elective colon/rectal resection in nonobstructed patients is a source of continuing
debate. Oncologists properly cite loss of performance status,
risk of surgical complications, and delay in chemotherapy as
major downsides to palliative resection. Surgeons, however,
understand that elective operations have a far lower morbidity
than emergency surgery and fear having to operate on patients
who obstruct while receiving chemotherapy or who present
with more advanced disease after multiple cycles of ineffective chemotherapy.
Four retrospective studies have evaluated nonoperative
management of Stage IV colorectal cancer by comparing
patients who did and did not undergo colorectal resection
(Table 34-1). The data come from the 1990s, when 5-FUbased chemotherapy was the standard systemic therapy. In all
four studies, a strong majority of patients were treated by
upfront bowel resection. Patients who were not initially
resected were more likely to have rectal cancers, to have more
extensive metastatic disease, and to be older. Operative mortality for the patients having upfront resection ranged from
1.6% to 9%. Patients who did not have initial bowel resection
underwent a subsequent colorectal operation in 9.3%–32% of
cases, although the indications for subsequent operation were
often not specified. From these limited data, it is clear that
upfront colon resection is frequently practiced, particularly
for patients with colon primaries and with less extensive
metastatic disease. However, it is not possible to assess the
impact of colon resection on symptom control, tolerance to
subsequent chemotherapy, quality of life, or survival.
A prospective study of 24 patients with unresectable Stage
IV colorectal cancer and minimally symptomatic primary
cancers treated by 5-FU-based chemotherapy was reported by
Sarela and colleagues.
ited to the liver (six with greater than 50% replacement of the
liver), 10 patients had lung metastases, and six patients had
peritoneal metastases. In the follow-up period, four patients
with sigmoid colon cancer developed bowel obstruction,
31
However, randomized trials of 5-fluo-
3,4
Moreover, with modern multidrug
Thus, standard management for patients with
32–35
36
Eleven patients had metastases lim-
466 M. D’Angelica et al.
TABLE 34-1 Retrospective analysis of bowel resection for patients with unresectable Stage IV colorectal cancer
Study Surgical group N Group features mortality (%) surgery (%) survival (mo)
34
Vander bilt
33
MSKCC
35
Medicare
32
SEER
*
Resection group includes both initial and delayed bowel resection.
NR, not reported.
Resection 66 Proximal cancers 4.6 — 14.5
No resection 23 Rectal cancers — 9 16.6
Resection 127 Proximal cancers, fewer metastases 1.6 — 16
Resection 6,469 Proximal cancers, younger age 9 10
No resection 2,542 Rectal cancers 32 3
Resection
No resection 9,096 Rectal primary, older age NR Colon 2, rectum 6
*
103 Rectal cancers, more metastases — 29 9
17,658 Proximal cancers, younger age NR Colon 11, rectum 16
Operative Subsequent colon Median
which was treated by operation in two cases and by endoluminal stenting in two cases. Three patients underwent right
colectomy for abdominal pain with poor symptom relief. One
patient underwent potentially curative resection after disease
downstaging by chemotherapy. From this small study, it was
concluded that a policy to defer resection of minimally symptomatic primary colorectal cancer is acceptable. However, it is
noteworthy that 25% of the primary cancers (and 35% of the
colon primaries) were ultimately resected.
Several retrospective studies have specifically examined
the impact of rectal resection on patients with Stage IV rectal
37–40
cancer.
The goals of radical surgery in this setting are to
eliminate bleeding and obstruction, prevent local tumor progression, and prepare the patient for systemic chemotherapy.
Moran et al.
37
reported that, among 95 patients undergoing
rectal resection, local symptom control was excellent, and
only one required subsequent reoperation for local recurrence. Longo et al.
38
reported that, among 103 patients, pelvic
pain and sepsis were more common in the nonresected group
(15%, 14%) than in the resected group (4%, 9%). Chu and
colleagues
39
reported on 21 Stage IV patients treated by
abdominoperineal resection. Perioperative morbidity (33%)
and mortality (0%) were acceptable, and 20 of 21 patients had
complete and durable resolution of local symptoms. Nash and
colleagues
40
reported results for 80 patients treated by rectal
resection without radiotherapy. There was only one perioperative death, and median hospital stay was 9 days. Only five
patients developed local failure. Median survival was
25 months, with greatest survival seen in patients who
received and responded to systemic chemotherapy. These
studies document that surgical resection can achieve excellent
palliation of local symptoms.
There are few published data evaluating the effectiveness
of radiotherapy in palliative management of Stage IV rectal
cancer. Crane et al.
41
reported on 55 patients who received
chemoradiotherapy and 25 patients who received chemoradiotherapy followed by surgery. Both groups received systemic therapy (78% of patients). Pelvic symptom control was
high (81%) in the chemoradiotherapy group, but not as
high as in the chemoradiotherapy plus surgery group (91%).
There were limited data on the durability of symptom control
over time.
To summarize the treatment options for Stage IV patients
with unresectable metastases, treatment algorithms are
shown for patients with Stage IV colon cancer (Figure 34-2)
and Stage IV rectal cancer (Figure 34-3). The algorithms
show multiple treatment options, reflecting the heterogeneity
of disease presentation. The major variables to consider are
location of the primary tumor, degree of colon/rectal obstruction, extent of metastatic disease, and fitness of the patient
for surgery. For patents with nonobstructing primary tumors,
upfront treatment with chemotherapy is favored because, in
this era of increasingly effective chemotherapy, it is important that patients be given the full benefit of aggressive systemic therapy. However, it should be remembered that the
goal of therapy is effective palliation, and surgical resection
remains the most effective and durable local treatment
option.
Liver Metastasis
Of the 150,000 new cases of primary colorectal cancer diagnosed in the United States each year, approximately 60% of
these patients will develop liver metastases and about onethird will have disease limited to the liver.
been estimated that about 10% of all patients with colorectal
liver metastases are candidates for potentially curative hepatic
surgery.
42
Of those able to undergo complete hepatic resection, 25%–35% achieve long-term survival.
a small percentage of the overall number of patients with
metastatic colorectal cancer are cured by liver surgery; this
underlines the paramount importance of patient selection in
determining optimal treatment. These statistics also highlight
the fact that the majority of patients with liver metastases have
unresectable disease, and require evaluation for chemotherapy or supportive care. It should be noted, however, that with
improvements in chemotherapy, surgical technique, and ablative techniques, the number of patients eligible for hepatic
surgery is on the rise.
44,45
1
Overall, it has
43
Therefore, only
34. Colorectal Cancer: Metastatic (Palliation) 467
FIGURE 34-2. Treatment algorithms for patients with Stage IV colon cancer: use of palliative colon resection.
FIGURE 34-3. Treatment algorithms for patients with Stage IV rectal cancer: use of palliative rectal resection.
Natural History of Untreated Liver Metastases
To understand the impact of any therapy on outcome for
patients with hepatic colorectal metastases, the natural history
of untreated disease must be reviewed. This is especially relevant in understanding the impact of surgery for hepatic
metastases, because there has never been a randomized trial
comparing any therapy to surgery (nor is there ever likely to
be). Before the 1980s, most hepatic metastases were left
untreated. Several investigators have retrospectively studied
untreated patients, documenting median survivals of 5–10
months; long-term survival was rarely seen.
these patients, however, had extensive disease, and most had
46
The majority of
their primary tumor in place, making comparison to modern
surgical series irrelevant. Nonetheless, some investigators retrospectively identified patients with isolated, potentially
resectable hepatic metastases who were left untreated. In
these patients with limited metastases isolated to the liver,
who would otherwise be potential candidates for surgery,
3-year survival was 14%–23% and 5-year survival was
47,48
2%–8%.
Whereas these studies were instrumental in
demonstrating the relationship between bulk of disease and
survival, they also clearly showed that, even in the best of circumstances, 5-year survival of patients with untreated liver
metastases is distinctly uncommon.
468 M. D’Angelica et al.
Diagnosis and Patient Evaluation
In the patient who presents with liver metastases, the first consideration must be whether he or she is a potential surgical
candidate, because resection remains the only potentially curative modality. A careful extent of disease workup should be
initiated. First, a complete evaluation of the colon via
colonoscopy should be performed within a year of presentation; this addresses the issue of synchronous and metachronous colonic neoplasms, as well as the issue of local
recurrence (especially in rectal cancers). Complete crosssectional imaging of the abdomen and pelvis with high-quality
CT is also essential, to rule out extrahepatic disease. The additional advantage of routine chest CT is low compared with that
of a plain chest X-ray, but should be considered in high-risk
49 18
cases.
routinely performed because of early prospective data documenting its utility. The information obtained from PET scanning changes management decisions in patients with recurrent
colorectal carcinoma 20%–50% of the time. The major
strength of PET scanning seems to be the detection of occult
extrahepatic disease.
more clearly define the benefits of PET. A baseline serum carcinoembryonic antigen (CEA) level should also be drawn, as it
is of prognostic value (see below), and serves as a baseline to
follow after the conclusion of therapeutic interventions.
Once the issue of extrahepatic disease has been addressed,
high-quality imaging of the liver is essential in determining
bulk of disease and resectability. CT scans are the most common modality used to address liver disease and, with modern
dynamic helical scanning techniques, this remains the mainstay of hepatic imaging. Routine CT scans can now evaluate
the liver in combination with CT angiography or triphasic
imaging of the parenchyma through various phases of intravenous contrast circulation. The most sensitive CT technique
is CT portography, which is a CT scan performed after injection of contrast into the superior mesenteric artery. Because
liver metastases derive their blood supply from the hepatic
artery, when injected contrast enters the portal circulation,
metastases appear like filling defects. Although this technique
is considered the most sensitive method for evaluating the
number of hepatic tumors, it often fails to define the anatomic
relationships of tumor to hepatic vasculature, it requires an
invasive procedure, and it is costly.
modern standard CT techniques, the marginal benefit is probably smaller than it once was.
Ultrasound and MRI are additional imaging techniques that
can be useful in specific circumstances. Ultrasound is not an
accurate method for addressing extrahepatic disease and,
indeed, often cannot visualize the entire liver. However, in
experienced hands, ultrasound is excellent at distinguishing
neoplastic tumors from benign lesions such as cysts, focal
nodular hyperplasia, or hemangiomata. Additionally, ultrasound can specifically evaluate the relationship of specific
lesions to major vascular structures and the biliary tree. MRI
F-FDG (Fluoro-deoxy-glucose) PET scanning is
18
Ongoing larger prospective studies will
50,51
Additionally, with
is an excellent method for characterizing liver lesions.
Particularly if there are multiple hepatic lesions, not all of
which are suspected to be metastatic tumors, MRI can help
distinguish malignant lesions from cysts, hemangiomata, and
other benign lesions. MRI is also an excellent modality for
evaluating relationships of tumor to the biliary tree (via magnetic resonance cholangiopancreatography—MRCP) and to
hepatic vasculature. High-quality MRI and CT are probably
equivalent for evaluating extent of liver disease, and as aids in
52
surgical planning.
In any patient being considered for
hepatic resection, a complete medical workup should be performed to assess the patient’s fitness for undergoing a major
abdominal operation. Any potential for liver dysfunction,
such as alcohol abuse or chronic hepatitis, must be carefully
evaluated. Pulmonary function should also be specifically
evaluated, because patients undergoing major hepatectomy
are at special risk for developing pulmonary complications,
because of the upper abdominal transverse incision that is
often necessary and the inevitable sympathetic pleural effusion. Likewise, any patient with a history of cardiac disease
should be evaluated (as for any major abdominal surgery). We
do not use chronologic age as a contraindication to hepatic
surgery. We have previously reported that patients older
than age 70 did as well as younger patients after hepatec-
53
tomy.
This reflects careful patient selection and emphasizes
the fact that physiologic age is more important than chronologic age.
Treatment Options
Chemotherapy
Until recently, chemotherapy was considered largely ineffective as treatment of unresectable metastatic colorectal cancer.
However, with the development of irinotecan, oxaliplatin,
hepatic arterial infusional chemotherapy with fluorodeoxyuridine (FUDR), and newer molecular-based therapies, there are
now more effective chemotherapeutic options for these
patients. For nearly 50 years, 5-FU was the only effective
chemotherapeutic regimen for metastatic colorectal cancer.
Despite many attempts to modify 5-FU with other agents,
response rates generally ranged from 15% to 20%, and survival beyond 1 year was uncommon. The addition of leucovorin (5-FU/LV) and the use of infusional dosing techniques
are associated with an increased response rate, and are frequently used despite no improvement in survival.
Irinotecan (CPT-11) in conjunction with 5-FU/LV has been
recently shown to be more effective than 5-FU/LV alone for
treatment of metastatic colorectal cancer. Two randomized trials established the superiority of single-agent irinotecan over
5-FU/LV alone or best supportive care as second-line ther-
55,56
apy.
Additionally, two randomized trials utilizing combined irinotecan/5-FU/LV as first-line chemotherapy have
shown response rates of 40%, with modestly improved survival (median 15–17 months versus 12–14 months).
54
57,58
The
34. Colorectal Cancer: Metastatic (Palliation) 469
addition of oxaliplatin has been particularly exciting because
of the in vitro sensitivity seen in cisplatin-resistant cell lines,
as well as its synergy with 5-FU.
58,59
In a trial comparing
oxaliplatin/5-FU/LV (FOLFOX) to 5-FU/LV, response rates
for FOLFOX were in excess of 50% (compared with 22% for
5-FU/LV). There was no difference in survival, but this is
likely attributable to a 37% crossover from 5-FU/LV to FOLFOX during the trial.
60
Early analyses of comparisons of
irinotecan/5-FU/LV to FOLFOX have so far shown FOLFOX
to yield superior response rates.
61
Ongoing trials continue to
define optimal timing, dosing, and sequence of various combination regimens. As these trials mature, and modern systemic chemotherapy regimens are refined, we are now seeing
median survivals in excess of 20 months.
59,62
Regional hepatic therapy via hepatic artery infusional
(HAI) chemotherapy has been studied since the 1970s. This
treatment takes advantage of the fact that hepatic metastases
derive their blood supply from hepatic arterial branches.
Additionally, only a small proportion of systemically administered chemotherapy reaches the liver. The most frequently
used agent for HAI is FUDR, which has a 90% hepatic extraction ratio. This permits maximal treatment of liver metastases
and minimization of systemic side effects. However, HAI
with FUDR limits treatment of occult extrahepatic disease.
This can be addressed by giving additional systemic agents,
or by using 5-FU via the hepatic artery with a higher
“spillover” effect into the systemic circulation.
Early phase II trials of HAI FUDR or 5-FU for unresectable colorectal hepatic metastases demonstrated remarkable response rates ranging from 29% to 88%.
Subsequently, 10 randomized phase III trials comparing HAI
chemotherapy to systemic chemotherapy have been completed (Table 34-2). From 1987 through 1990, five trials were
done comparing HAI FUDR to intravenous FUDR or intravenous 5-FU/LV. All of these trials showed significantly
increased response rates, but only trials comparing HAI
chemotherapy to best supportive care showed improved survival. Most of these trials were underpowered and most
allowed crossover, making conclusions about survival difficult. Two metaanalyses of the first seven trials have been performed on the assumption that each was underpowered, in an
attempt to detect significant survival differences.
clearly confirmed the increased response rates, and both
showed a modest survival benefit.
63
Since reporting of these seven trials, three more have been
performed. The German Cooperative Group compared HAI
FUDR to HAI 5-FU/LV to systemic 5-FU/LV. Response rates
were significantly higher in patients receiving HAI
chemotherapy (43% and 45% versus 20%), but there was no
improvement in time to progression or overall survival.
Similar to many of the previous trials, this study is difficult to
interpret because only 70% of the HAI patients received the
intended therapy and 51% of patients crossed over to other
70
groups.
Another trial performed by the Medical Research
68,69
64–67
Both
TABLE 34-2. Randomized trials comparing HAI to systemic chemotherapy for unresectable liver metastases
Study group Year Arms n assigned treatment Crossover allowed (% CR + PR) survival (mo)
161
MSKCC
162
NCI
163
NCOG
City of Hope
165
NCCTG
166
French
167
English
70
German
MRC/EORTC
168
CALGB
Source: Adapted from Cohen and Kemeny.
Note: Response rate calculations are based on patients who received assigned treatment. Survival based on intent-to-treat calculation.
NCI, National Cancer Institute; NCOG, Northern California Oncology Group; NCCTG, North Central Cancer Treatment Group; MRC/EORTC, Medical
Research Group/European Organization for Research and Treatment of Cancer; CR, complete response; PR, partial response.
*
Statistically significant (P < .05)
1987 HAI FUDR 48 94 Yes 50
1987 HAI FUDR 32 66 No 62
1989 HAI FUDR 67 75 Yes 42
164
1990 HAI FUDR 31 100 Yes 55
1990 HAI FUDR 39 85 No 48 13
1992 HAI FUDR 81 87 No 44
1994 HAI FUDR 51 96 No — 14
2000 HAI FUDR 54 69 Yes 43
71
2003 HAI 5-FU/LV 95 66 No 22 15
2003 HAI FUDR 59 87 No 48
IV FUDR 51 94 20 12
IV FUDR 32 92 17 12
IV FUDR 76 86 10 16
IV 5-FU 10 100 20 12
IV 5-FU/LV 35 100 12 11
BSC or IV5-FU 82 50 got 5-FU 9 11
BSC or IV5-FU 49 20 got 5-FU — 8
HAI 5-FU/LV 57 70 45
IV 5-FU/LV 57 91 20 18
IV 5-FU/LV 126 87 19 15
IV 5-FU/LV 58 87 25 20
169
Percentage receiving Response rate Median
*
*
*
*
*
*
*
*
17
17
17
14
*
15
13
19
*
23
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