2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

TREATMENT FOR COLORECTAL LIVER METASTASES
that same timing in clinical practice. Delivery of a full 6
months of FOLFOX preoperatively, however, runs the risk
of creating a higher-risk resection because of chemotherapyassociated
steatohepatitis. For this reason, for clearly resectable
patients, our group often favors up-front resection
followed by postoperative FOLFOX for 6 months. No specific
data exist, however, to settle this question.
Resections with Four or More Liver Lesions
The Memorial Sloan-Kettering Cancer Center hepatobiliary
surgical service reviewed the outcome of all patients
with four or more liver lesions resected over a 4-year period
between 1998 and 2002. 7 It should be noted that oxaliplatin
was largely unavailable during that time period, so the
contribution of optimal therapies that are inactive in stage
III adjuvant setting are unlikely to be active in stage IV
adjuvant setting. Of 548 patients who underwent successful
resection, 98 had four or more liver metastases. As is the
case with many such surgical reports, the denominator of
how many patients were taken to the operating room with
the intent of full resection but who would end up having
an R1 or R2 resection is not available. Nevertheless, the
long-term follow-up on these patients does provide useful
insights, especially into the curative compared with noncurative
outcomes and the important difference between overall
survival and cure. Actuarial survival of these 98 patients
was 33% at 5 years. This number was markedly different for
those with four or five lesions (39% actuarial survival at 5
years) compared with 19% 5-year actuarial survival for
those with six or more lesions). These results should be
interpreted within the context of modern imaging and modern
chemotherapy, which make older historic comparisons
moot. It is no longer correct or reasonable to say that the
median survival with systemic therapy is 1 year and that
most patients are dead within 2 years, as was the case 20
years ago. In the N9741 trial of systemic therapy, the 5-year
overall survival in patients treated with frontline FOLFOX
was 9.8% (note that 10% of these 5-year survivors did
ultimately undergo metastasectomy, while 90% did not). 8
Five-year overall survival would be expected to be higher
with systemic treatment for those patients with good performance
status, relatively low volume of disease, and one site
of metastases, so that the population that were candidates
for liver resection would be expected to have a 5-year overall
survival that would be somewhat higher than 10% with
systemic therapy. Thus, the argument that surgery for four
or more lesions improves long-term survival is compelling,
although not airtight. When we look at the cure rate,
however, a different picture emerges. The median diseasefree
survival for these 98 patients was 12 months, with a
range of 10 to 15 months, and the actuarial disease-free
survival was 50% at 1 year, 12% at 3 years, and 0% at 5
years. The intriguing and important question from a medical
oncology perspective is whether or not active systemic
oxaliplatin-containing adjuvant, neoadjuvant, or conversion
chemotherapy could have had a substantial effect on the
likelihood of cure in these patients.
Role of Non-FOLFOX Regimens
It is important to bear in mind that the role of adjuvant (or
neoadjuvant) chemotherapy is to eradicate micrometastases.
This is true for treatment of stage II, stage III, or fully
resected stage IV. As such, there is no compelling argument
for why a micrometastasis in a patient with stage IV disease
should behave any differently from a micrometastasis in
a patient with stage III disease. Numerous studies in the
adjuvant setting of stage III and stage II colon cancer have
demonstrated that irinotecan, bevacizumab, and cetuximab
(and by reasonable extrapolation, panitumumab) are inactive
in the adjuvant setting in stage III, with numerous
large-scale trials showing failure to improve the 3-year or
5-year recurrence-free survival rates or the overall survival
rates. 9-14 Since it is well demonstrated that all of these
agents have activity against macrometastatic disease, it is
clear that we cannot extrapolate this activity to the micrometastatic
setting. On the basis of these data, there is no
compelling argument for why any agents that have been
shown to be inactive in the adjuvant treatment of stage III
colon cancer should be active in the adjuvant or neoadjuvant
treatment of resected stage IV CRC. The only trial that
directly addresses this question is the randomized ACCORD
3 trial of 5-fluorouracil and leucorovin with or without
irinotecan in the adjuvant treatment of resected liver metastases,
which showed no benefit for irinotecan. 15 Note that
this statement regarding irinotecan, bevacizumab, and antiepidermal
growth factor receptor (EGFR) monoclonal antibodies
does not apply to conversion chemotherapy; if the
goal is to shrink a tumor you can see, then irinotecan,
bevacizumab, and the anti-EGFR monoclonal antibodies
are all reasonable considerations. However, if the goal is to
eradicate micrometastatic disease and increase the cure
rate, then in my opinion, they are not.
Role of FOLFOX in Patients with Prior FOLFOX
Adjuvant Treatment
When metachronous liver metastases develop after adjuvant
chemotherapy, it must be recalled that the cells that
gave rise to those metastases were present during that
adjuvant chemotherapy and were therefore, by definition,
resistant to it. It is thus exceedingly unlikely that this same
chemotherapy that failed to eradicate micrometastases in
the first treatment will have activity on residual micrometastases
this second time around after hepatic resection.
Remember, you are not treating the resected metastases;
you are treating residual micrometastases. Thus, adjuvant
or neoadjuvant FOLFOX does not appear to be a reasonable
maneuver in a patient who had previously received adjuvant
FOLFOX and who, by virtue of the development of metastases,
failed that adjuvant therapy. If a patient has received
either no prior therapy or fluorpyrimidine adjuvant only,
then adjuvant or neoadjuvant FOLFOX would be indicated.
It is noteworthy that the EOTRC 40983 trial excluded
patients with prior oxaliplatin adjuvant chemotherapy. In a
patient who has had prior adjuvant FOLFOX (or capecitabine/oxaliplatin
[Cape/Ox]), there unfortunately is not an
active adjuvant or neoadjuvant systemic treatment to offer,
and therefore I do not believe that any adjuvant or neoadjuvant
systemic chemotherapy is indicated in such patients.
Note that FOLFOX and Cape/Ox can be used interchangeably.
There is no evidence to support that one is superior to
the other, that one can rescue the other, or that capecitabine
has activity after failure of an infusional 5-fluorouracilcontaining
regimen.) The fact that FOLFIRI (fluorouracil,
leucovorin, irinotecan) with or without either bevacizumab
or an anti EGFR monoclonal might be able to shrink a tumor
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