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6 Metastatic Colorectal Cancer
95
a
Fig. 6.4 CT Images pre- ( a ) and post- ( b ) chemoradiation therapy demonstrating tumor and lymph node regression
the addition of positron emission testing (PET) may further
substantiate the need for systemic treatment, though the
routine use of PET scan for every patient with a new diagnosis of colon or rectal cancer is not recommended by the
NCCN [ 11 ]. In cases where there is some question about the
diagnosis and the course of action would be altered if metastatic disease were confi rmed, biopsy should be considered.
We would generally recommend image-guided percutaneous
needle biopsy where appropriate. However, for a patient with
a known colorectal malignancy and CT fi ndings strongly
suggestive of malignant disease (and especially if the lesions
are also PET-avid), routine biopsy is not necessary and may
be harmful in terms of complications (e.g., bleeding) or
tumor seeding.
b
(excepting for near obstruction), we will initiate chemotherapy and evaluate for the response to therapy. If the patient
has a favorable or nearly complete clinical response (especially if the metastatic sites respond), we will reevaluate
for resectability (Fig. 6.4 ). If imaging demonstrates resect-
able disease in a good surgical candidate, we will proceed
with attempted resection of both sites. We have also come
across the occasional case where there is a complete clinical
response without any disease activity on PET (i.e., regression
of all lesions) and have resected the primary site (Fig. 6.5 ).
Ensuring the lesion is marked prior to chemotherapy (i.e.,
India ink tattoo, clip) has proved to be benefi cial in this situation. Finally, for patients who continue to have progression,
we must monitor for evidence of impending obstruction and
be prepared to act accordingly.
What Should I Do with the Primary Lesion in the Patient with Extensive Disease?
Key Concept : While some evidence suggests improvement in
outcomes with resection of the primary site , this has not been
substantiated . Focus on the response to treatment and degree
of symptoms .
Considering the primary tumor in the setting of metastatic
disease, there has not been a clear consensus as to what, if
anything, should be done. A recent review has suggested
that there is a survival advantage to resection of the primary tumor [ 12 ]. They did note, however, that selection bias
could in part be used to explain the advantage and, therefore,
recommended further, prospective, studies. A subsequent
Cochrane Review concluded that resection of the primary
tumor is not associated with a survival benefi t nor does it
consistently result in a decrease in the tumor-related complications [ 13 ]. They felt that given the lack of strong evidence
to recommend either for or against resection of the primary
tumor, further clinical trials are warranted. In our practice
What Treatment Modality Should Come First?
Key Concept : The extent of the disease , primary symptoms ,
and ability of the patient to tolerate various options should
be discussed among the multidisciplinary census to determine a unifi ed treatment plan .
Decisions about the order of various treatments (chemotherapy, operation, stenting, radiation therapy in cases of rectal cancer) will depend upon the sites and extent of metastatic
disease as well as symptoms—especially obstruction or
impending obstruction of the primary lesion. Again, multidisciplinary discussions are highly recommended. For
patients without evidence of obstruction, and isolated liver or
lung metastases, up-front chemotherapy would generally be
started, with operation reserved for the metastases and primary lesion after several rounds of chemotherapy, assuming
that the lesions are responding. Subsequently, the surgical
resection(s) can be undertaken, either in one operation or in
staged procedures. The decision is much more diffi cult for
96
a
Fig. 6.5 Pre- ( a ) and post- ( b ) chemoradiation PET-CT images demonstrating absence of PET-positive activity on follow-up imaging
b
S. Mills and M.J. Stamos
patients with multisite metastatic disease. In the past, these
patients were generally felt to be incurable, with the possible
exception of an isolated pulmonary metastasis in concert
with limited liver metastases. Currently, multisite metastases,
including select patients with peritoneal spread, can be considered for aggressive curative intent treatment, but generally only if they show response to up-front chemotherapy.
For surgeons, it is important to take into consideration the
specifi c chemotherapeutic agents the oncologists are planning to use. This is especially important with the increasing
use of bevacizumab, as it has been linked to bowel perforations. There has therefore been some concern about treating
metastatic disease with systemic chemotherapy and bevacizumab, while the primary tumor remains within the colon.
However, McCahill and colleagues demonstrated that the
use of mFOLFOX6 plus bevacizumab did not result in an
increased rate of complications associated to the primary
tumor [ 14 ]. When an operation is planned for a patient on
bevacizumab, it is recommended to wait 6 weeks following
the last dose of bevacizumab prior to operating if possible, in
order to decrease surgical complications that may be attributed to the antiangiogenic effects of bevacizumab [ 15 ]. For
all other chemotherapeutic agents, we typically delay any
operation at least 4 weeks (6–8 weeks for bevacizumab)
when feasible, but one must weigh the risks of operating
with chemotherapeutics circulating versus continued symptoms or progression during the delay.
The Obstructed Patient: What Now?
Key Concept : Several methods exist to deal with an impending obstruction and are at least in part predicated on the
symptoms and location of the lesion .
For patients with a colon or rectal obstruction/near
obstruction, the fi rst step of treatment is generally to relieve
the obstruction. In broad terms this can be performed in three
fashions: resection of the primary lesion, diversion via a
proximal stoma, or utilizing an intraluminal stent. Most
Fig. 6.6 Endoscopic placement of colonic stent
patients, when faced with these options, would choose to
avoid a stoma and would therefore prefer an attempt at intraluminal stenting. Assuming that the lesion is not too low
within the rectum and that the obstruction can be technically
stented, there is a high technical success rate for placement
of a stent [ 16 – 18 ]. The most recent series show both techni-
cal success and clinical success over 90 % of the time
(Fig. 6.6 ). There is relatively low incidence of related mor-
bidity, with migration, and tumor ingrowth being the most
common (Fig. 6.7 ). Fortunately, perforation is uncommon
although Manes et al. did note that the rate of perforation was
considerably higher in patients receiving bevacizumab [ 17 ].
For distal rectal lesions, there may not be enough space
for placement of a stent. The distal end of the stent needs to
be above the pelvic fl oor (levator muscles) to avoid patient
discomfort from the stent (Fig. 6.8 ). When there is no suffi -
cient room for placement of a stent, diversion (proximal
stoma) or primary resection may be needed, depending on
the degree of obstruction. Occasionally, laser recanalization
6 Metastatic Colorectal Cancer
97
Fig. 6.7 Colonic stent perforation
usually to decrease the rates of local (pelvic) recurrence, the
patient with extensive, widespread metastases may not realize this potential benefi t, and often the delay in full systemic
chemotherapy may not be warranted. If the metastatic disease respond to the up-front chemotherapy, there may be a
subsequent role for palliative pelvic radiation or for preoperative radiation (e.g., prior to attempt at cure).
When systemic chemotherapy is chosen as the initial
approach, in some circumstances, the primary tumor shrinks
considerably or even responds completely. What is the role for
resection of the colon or rectum in this circumstance, and is
there still a need/role for radiation in the case of a mid or low
rectal cancer? Is there an indication to remove the primary
source in the setting of metastatic disease? The answers to these
questions are complex and need to be approached on a patientspecifi c basis. Sometimes these decisions are easy, such as for
a patient whose primary tumor shrinks, but less signifi cant
treatment effect on the metastatic disease is observed, or who
develops further metastatic disease despite ongoing chemotherapy. In these cases, there is very little, if any, role for resection of the primary tumor. However, as stated before, in a
patient who has response of their liver/pulmonary disease or
has disease that is resectable after up- front chemotherapy, there
may well be a role in resecting the primary site of disease, especially in cases where the goal of operation is cure. Finally, there
is occasionally a patient who would benefi t from a palliative
resection, especially in a situation where perineal pain from
sphincter invasion has occurred or where the primary tumor
continues to cause obstructive symptoms which are disabling.
Fig. 6.8 Radiograph showing endorectal stent in place to relieve
obstruction
can be effective in avoiding need for a stoma. Given that
most such patients are candidates for pelvic irradiation prior
to operation, we generally observe these patients closely during the fi rst couple of weeks of radiation as long as they do
not have evidence of complete obstruction, or we divert them
with a laparoscopic sigmoid colostomy. Alternatively, for a
patient with widespread metastatic disease, there may not be
a primary role for pelvic radiation. As the goal of radiation is
Specifi c Sites of Disease
Liver
Key Concept : Metastatic disease to the liver is increasingly
resected ( or otherwise treated ), even with bilobar involvement , based on the degree of functioning parenchyma that
will remain after resection .
Colorectal cancer, when it metastasizes, most commonly
spreads to the liver, followed by the lungs. Years ago, it was
felt that any liver metastasis was a death sentence. However,
limited resection for solitary liver metastases was initially
shown to be safe and feasible, and an apparent oncologic
benefi t was demonstrated. Over time, indications expanded
to include multiple metastases. With continued improvement, more aggressive therapy has been undertaken to treat
patients, even with fairly high tumor burden at presentation
(Fig. 6.9 ). The current paradigm in specialized and experi-
enced programs centers around the amount of residual healthy
liver remaining as the main determining factor in treating
patients with liver metastases via resection. The other factor
of importance remains the presence of extrahepatic disease.
98
S. Mills and M.J. Stamos
a
Fig. 6.9 ( a , b ) CT scan images of two patients with varying amounts of bilobar liver disease
As mentioned earlier, even some patients who would have
b
been deemed unresectable (not potentially curable) due to
inadequate normal liver have been able to be downsized to
the point that they are candidates for potentially curative
operation. Progressing from the traditional view that metastatic disease represented a death sentence, more than three
decades of data argue against that view. With hepatectomy,
select patients with colorectal cancer metastasized to the liver
can realize 5-year disease-free survival of 28–58 % [ 19 – 25 ].
The data support treatment of a patient with liver metastases, but prior to embarking on operative therapy, one must
understand the keys to liver resection. Certainly, achieving a
negative margin is among the most important factors. More
than a decade ago, Scheele demonstrated that a negative margin (R0 resection) had a vastly superior median survival
(44 months) compared to those with R1 or R2 margins
(14 months) [ 26 ]. The ability to achieve a negative margin,
along with improved adjuvant therapy, has led surgeons to
broaden indications for hepatectomy. As mentioned above,
the most common limiting factor in liver resective surgery is
the ability to have adequate functioning liver remaining
postoperatively. It is generally felt that adequate liver remnant can be defi ned as 20 % of initial volume, as long as the
remaining liver is normal.
There have also been several technological advancements
Fig. 6.10 Evaluation image of RFA probe in place in the liver
(Courtesy of David Imagawa, MD)
in the past decade for treating liver metastases. Although
surgical resection remains the “gold standard,” alternative techniques to treat liver metastases, such as radiofrequency ablation (RFA) (Fig.
6.10 ), cryotherapy, irreversible
electroporation, microwave ablation, selective internal radiation therapy (SIRT), and chemoembolization, are being
increasingly utilized either as primary treatment or in conjunction with liver resection—especially in the setting of
bilobar disease. RFA (the most commonly performed ablation method in the USA of those listed) can be performed
percutaneously, laparoscopically, or in an open fashion.
6 Metastatic Colorectal Cancer
99
After localization of the metastatic lesion, the RFA probe
is inserted (under image guidance) and then activated. The
tumor is heated, causing coagulation necrosis. Given that
the effect is heat based, vessels located near tumors may
act as a “heat-sink,” potentially explaining the somewhat
higher recurrence rate seen with RFA compared to resection.
However, reasonable results have been obtained in multiple
studies [
27 – 30 ]. Further studies have been advocated [ 31 ].
Lung
Key Concept : Lung lesions are normally treated with chemotherapy primarily . Resection is typically reserved for those
patients able to tolerate a pulmonary resection with isolated
metastases .
Distal rectal cancers, by virtue of the systemic (rather
than portal) venous drainage, are more likely to fi rst spread
to the lungs compared to other primary sites. However, given
that isolated pulmonary metastases are not as commonly
encountered as liver metastases, data supporting resection
are not as compelling. That said, there are studies supporting
resection of pulmonary metastases, with results surprisingly
similar to outcomes for hepatic metastasectomy. For example, Pfannschmidt et al. [ 32 , 33 ] twice reviewed the literature
regarding pulmonary metastasectomy for colorectal metastases and noted that although there were no randomized trials
to evaluate, the retrospective data demonstrated an improved
survival rate for the highly selected group of patients who
underwent pulmonary metastasectomy. Another large review
in 2010 was less convinced [ 34 ]. After reviewing the data,
the authors felt that any connection between increased survival and lung resection was unfounded due to a lack of suffi ciently good data and that a randomized trial was warranted.
With these issues in mind, we approach each patient with
isolated pulmonary metastases on an individual basis. If,
after full staging, the patient still appears to have only isolated lung metastases and the primary lesion is resectable,
we will usually treat with up-front systemic chemotherapy
and then resect the lung lesions fi rst (or resect the primary
lesion simultaneously as able) if response is seen. If the
patient does well and continues to have no other evidence for
disease, we will then tackle the primary lesion either before
or after the addition of further systemic chemotherapy. If, on
the other hand, the patient is found to be unresectable in the
thorax or has other sites of disease, continuation of systemic
chemotherapy, as indicated, is routine.
Peritoneal Metastases
Key Concept: Peritoneal carcinomatosis represents “drop”
metastases that may be approached with combination
therapy in rare instances. The ability to select proper patients
(i.e., healthy, low PCI score) and achieve a complete cytoreduction is imperative .
Carcinomatosis is a dreaded pattern of spread of colorectal
cancer (Fig. 6.11 ). Unfortunately, up to 15 % of patients may
present with carcinomatosis at the time of initial diagnosis
and an even higher rate of carcinomatosis exists with patients
who have recurrent disease [ 35 , 36 ]. Though traditionally felt
to be incurable, carcinomatosis can be treated, and in some
cases, a cure can be achieved, through the use of cytoreductive surgery, peritoneal stripping, and intraperitoneal chemotherapy. There are two general methods of delivering the
chemotherapy, intraoperative hyperthermic intraperitoneal
chemotherapy (HIPEC) (Fig. 6.12 ) and early postoperative
intraperitoneal chemotherapy (EPIC). The use of cytoreductive surgery and intraperitoneal chemotherapy for colorectal
carcinomatosis is based upon the practice championed by
Sugarbaker for treating pseudomyxoma peritonei [ 37 ]. An
intraoperative staging system (PCI) is employed describing
the extent of carcinomatosis on a scale of 1–39 [ 38 ]. For
patients with otherwise surgically treatable disease, HIPEC
should be considered as long as a complete cytoreduction is
possible [ 39 – 41 ]. Outcomes are best for patients with PCI
below 20 at time of exploration and in whom a complete/
near complete cytoreduction is possible [ 42 ].
O v a r y
Key Concept : Only involved ovaries should be resected , and
prophylactic oophorectomy is typically not warranted .
The ovaries can become involved in women with advanced
colorectal cancer. A recent review of 180 cases of colorectal cancer in women demonstrated an overall prevalence
of colorectal cancer metastasis to the ovary of 2.7 %, but
fewer than half that number were isolated metastases to the
ovary [ 43 ]. In the past, it was routine for women to undergo
concomitant bilateral oophorectomy with resection of the
primary colorectal lesion. Currently, only ovaries that are
involved via direct extension or which are morphologically
involved should be removed, when feasible, but prophylactic
oophorectomy is not generally recommended except for suspected/known cases of Lynch syndrome [ 44 ].
Brain
Key Concept : Only in rare instances are brain metastases
addressed and normally as a palliative measure .
Limited data exist on brain metastases, and isolated brain
metastases are extremely rare. Sundermeyer et al. [ 45 ] dem-
onstrated that only 3 % of patients with colorectal cancer
develop brain metastases. They develop more commonly in
100
a
Fig. 6.11 Carcinomatosis leading to bowel obstruction. Image ( a ) demonstrates CT scan fi ndings of extensive carcinomatosis. Image ( b ) (Courtesy
of Alessio Pigazzi, MD) represents surgical specimen of large debulking procedure
Fig. 6.12 Intraoperative
photograph of patient undergoing
HIPEC, with catheters in place
(Courtesy of Alessio Pigazzi,
MD)
b
S. Mills and M.J. Stamos
patients who already have pulmonary metastases. Treatment
is almost always palliative and therefore should be dictated
by symptoms.
Controversial Points
Age of Patient : Should we treat patients differently based
upon their age?
Is there a difference between the Stage 4 patient who is
48 years old versus the patient who is 84? That is, should a
patient be treated differently based primarily upon age alone,
or should we look at something else to determine how aggressive to be, such as comorbidities (ASA) and patient/family
desires? There is no specifi c literature to guide decision making for elderly patients with Stage 4 colorectal cancer; however, there is some related information regarding elderly
patients undergoing colon cancer treatment that can be
extrapolated. In terms of treating the elderly, age alone should
not be a reason to exclude a patient from colon resection or
even from systemic chemotherapy [ 46 ]. It has been shown
that when chemotherapy is appropriately given for Stage 3
patients, despite being older, it is generally well tolerated
with even fewer adverse reactions than younger patients and
6 Metastatic Colorectal Cancer
101
improves overall survival. Older patients receiving chemotherapy have also been reported to have similar disease-specifi c survival as their younger counterparts. Yet, this data was
for Stage 3 patients, not Stage 4, and one must take a realistic
approach to treating the elderly with metastatic disease. In
this more advanced stage, we simply go back to one initial
point regarding treatment indications: the surgeon must evaluate and discuss with the patient and their family about maintaining realistic goals of care and the possibility of futility.
As a patient presents for consideration of resection—any
patient, regardless of age—they arrive with expectations and
desires. Some may have met with other physicians (surgeons
or otherwise) and may have already been told what to expect
to hear from you (rightly or wrongly). When a patient arrives
with set expectations, it is critical to have an open, honest,
and clear discussion about potential outcomes and various
options that are reasonable. Though their expectations and
yours may not be initially aligned, it is imperative that you
leave that meeting united prior to proceeding. Any other way
forward is a setup for failure.
The Patient with a “Near Obstruction”
As stated briefl y earlier, not infrequently a patient will present with an impending obstruction. The endoscopist may or
may not have been able to traverse the lesion with the scope,
and the patient may have varying degrees of symptoms associated with obstruction. When these patients also have metastatic disease on work-up, we generally commence with
systemic chemotherapy. The question of whether or not the
primary “near-obstructing” lesion needs to be addressed fi rst
can be a complicated situation. The surgeon must consider
whether or not the patient is having signifi cant symptoms of
obstruction (smaller stools, diffi culty with BM, loose bowel
movements, obstipation, bloating, etc.) or “simply” a nontraversable lesion on endoscopy. For patients suffering from
symptoms of obstruction (even partial), we would generally
attempt to place an intraluminal stent. Resection and proximal diversion are also options, although you have to weigh
the risks of each of these against other options in light of the
patient (and their overall clinical state) sitting in front of you.
For patients with questionable or intermittent obstructive
symptoms, in general, if it is possible to pass a colonoscope
through the lesion, it is not likely to cause an imminent
obstruction, especially if the patient is being treated with an
effective chemotherapeutic regimen. For these patients we
will continue (or initiate) chemotherapy.
A more diffi cult situation is when, occasionally, a patient
develops an obstruction during chemotherapy. Often these
patients are not ideal candidates for surgical intervention
given the systemic effects of chemotherapy and possibly
of any biologic therapy concurrently employed. When this
Fig. 6.13 End-loop stoma with distal defunctionalized bowel matured
through the same incision
occurs, our fi rst choice would be intraluminal stent placement. Given the high technical and clinical success rates that
we previously highlighted, this typically provides adequate
relief of the obstruction. However, if diversion is required, we
would always recommend creating a loop stoma or mucous
fi stula to avoid a closed-loop obstruction and possible perforation. This is generally obtained via an “end-loop” colostomy [ 47 ], which we generally perform laparoscopically
(Fig. 6.13 ). We create the stoma by stapling off the distal
segment and then opening a corner of the defunctionalized
limb at the inferior aspect of the colostomy, thereby allowing
for the use of a normal colostomy appliance but allowing for
decompression of the distal, obstructed limb.
Role of Radiation for Rectal Cancer in Patients with Stage 4 Disease
Key Concept : Radiation plays a secondary role in patients
with metastatic disease and often for primary palliation of
symptoms .
When treating patients with resectable rectal cancer, the
use of radiation in the “neoadjuvant” setting is primary to
decrease the risk of locoregional recurrence. For a patient
102
S. Mills and M.J. Stamos
with Stage 4 rectal cancer, we will generally start with systemic chemotherapy. This will allow for treatment of the
systemic disease (generally the more important endpoint)
and allow the oncologist to gauge the effectiveness of the
chemotherapeutic regimen. Assuming the systemic disease
responds, and especially if it is surgically amenable to a
curative intent, radiation of the primary would be deferred
until adequate response of the distant metastasis is obtained.
For a patient who does not have curable systemic disease,
but in whom the chemotherapy appears to be controlling the
metastatic disease, the decision about utilization of radiation
therapy for palliative indications should be based upon multidisciplinary response of the primary tumor, overall patient
condition, etc.
Technical Pearls
Salvage Operation
The term “salvage” operation has been used to describe an
extensive resection or aggressive surgical approach with the
aim of cure. Though extensive disease may be present (e.g.,
a primary rectosigmoid cancer and multiple liver metastases)
or a large primary tumor with involvement of other organs or
the abdominal wall, an attempt is planned for an aggressive
surgical approach (salvage) with the hope of providing a
curative (R0) operation. Prior to any attempt at salvage, an
in-depth discussion should be had with the patient. A clear
discussion of goals and possible operative scenarios (such as
what the patient’s wishes are for various potential operative
discoveries) is necessary. The patient should generally be
given a bowel preparation, when feasible.
Prior to any pelvic exenteration or liver resection surgery,
we strongly recommend fi rst performing diagnostic laparoscopy to look for carcinomatosis. If carcinomatosis is encountered, one should calculate the peritoneal cancer index (PCI)
38 ] to determine if the patient would be a candidate for
[
cytoreductive surgery (see above), although this is rarely
done in the presence of signifi cant metastatic disease.
If the decision is made to proceed with resection, one
should fi rst start with adequate exposure. As most of these
cases are performed through a full laparotomy incision, the
use of an abdominal wall retractor (such as a Bookwalter,
Omni, or other retractor system) is essential. In certain situations, as determined by the surgeon’s experience, skill-set,
and needs of the procedure, a laparoscopic or robotic
approach may be feasible. Regardless of approach, we recommend that mobilization be the fi rst step. Prior to committing to resection by performing any step that cannot be
undone (i.e., to “burn a bridge”—to divide the bowel or
devascularize a segment), the surgeon should attempt either
to assure that there is nothing precluding the completion of
the operation or to assure a safe way out of the procedure
(e.g., the ability to create a stoma). Once the resection is
complete, reconstruction is performed.
For extensive pelvic procedures, procedures in reoperative fi elds, or if ureter involvement is suspected, one
should consider the preoperative placement of ureteral catheters. They may aid in identifi cation of the ureter even in a
situation where they are obscured or displaced by tumor or
scar. Further, in the event of ureteral injury, they can help to
identify the injury (visualization of the catheter).
Palliative Care
Some patients are not appropriate for curative treatment. The
question of when to decide to “back off” can be very diffi cult for both the patient and the surgeon. As questions about
futility of care, palliation, and/or hospice arise, involvement
of a palliative care team would be worthwhile. Adding their
input will aid the patient and family member in decision
making regarding myriad end-of-life issues. Some patients
may benefi t from placement of a venting gastrostomy tube
(percutaneous or laparoscopic assisted) to palliate the effects
of bowel obstruction.
Summary Pearls
The management of Stage 4 colorectal cancer is complex.
Given the multimodal therapy options, a multidisciplinary
team approach should be used, primarily a medical oncologist, radiation oncologist (in the case of rectal cancer), and a
surgeon. With the recent advancements of all aspects of cancer treatment, patients with metastatic disease are living longer, and we are extending indications and options for curative
intent. When you are treating a patient with metastatic disease, take a stepwise approach, and treat each of the various
sites of disease. This will allow you to convert some patients
to a potentially curable state. You must be willing to be
aggressive with indications and treatment when appropriate,
but also be realistic. Discussions with the patient and family
are important, and you should be open and genuine. Surgical
and nonsurgical options for palliation are available and
should be utilized as indicated. As a surgeon who treats
colorectal cancer, you should be familiar with all of the various options and treatment scenarios.
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