2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

gone forever, no further therapy is needed. “Curative,” when
referring to a treatment strategy—be it medical, surgical, or
combined modality—means that the regimen will result, or
has resulted, in a cure. However, the definition of the term
“curative intent” is a bit more difficult to pin down. First, we
must recognize that long-term survival is not the same as
cure. A patient who is rendered free of known disease but
who then recurs a year later and is alive 5 years after that
has a good long-term survival but has not been cured. It is
true that favorable long-term survival is a highly desirable
outcome, but the degree to which surgery, ablation, and
chemotherapy might or might not improve long-term survival
is a discussion for another day; if the tumor is present,
the patient has not been cured, and if a treatment strategy
does not result in cure in some reasonable percentage of
patients, then we cannot realistically consider that we are
using it with “curative intent.”
There is no agreement on what degree of likelihood of
success constitutes curative intent. If an approach will
result in a cure more than 90% of the time, is that a
treatment given with curative intent? Most of us would say
it is. What about approximately 75% of the time? Fifty
percent? Twenty-five percent? What if a treatment strategy
is curative only 10% or 5% of time? What about 3% or 1%? To
provide some context for this discussion, consider the use of
systemic chemotherapy in patients with surgically unresectable
disease. Dy et al reported the long-term outcome of
patients on intergroup protocol N9741. 4 A total of 1,508
patients with metastatic CRC received one of three first-line
regimens. Of these, 62 patients achieved a clinical complete
response. However, with a median follow-up of 50 months,
only 10 remained disease-free and could be considered
cured. Thus, at first look, systemic chemotherapy would
appear to have a cure rate of 10 out of 1,508, or 0.66%.
However, if we take the group on N9741 who were treated
with folinic acid, fluorouracil, and oxaliplatin (FOLFOX), 43
of 679, or 6.3%, had a clinical complete response, and if we
assume the same 16% cure rate for those achieving a clinical
complete response, then the cure rate for FOLFOX is 1.0%.
But the chance of achieving a complete response (a necessary
first step toward a cure) was increased by having low
tumor burden, a single site of disease, and measurable
rather than evaluable disease, all of which are characteristics
that would be present in the vast majority of patients
who are candidates for resection or ablative therapy. Thus,
for the population that might be considered for curative
resection or ablation, greater than 1% of patients would be
expected to be cured by FOLFOX alone. Clearly we would
KEY POINTS
● “Cure” is easy to define; “curative intent” is not.
● Some, but not all, patients who can undergo resection
or ablation have a realistic chance at cure.
● Adjuvant or neoadjuvant FOLFOX can increase the
likelihood of cure in FOLFOX-naive patients.
● Therapies that are inactive in stage III adjuvant are
unlikely to be active in stage IV adjuvant.
● “Conversion to resectability” chemotherapy and “neoadjuvant”
chemotherapy are not the same thing.
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not regard FOLFOX as being given with curative intent to
an unresectable patient. So the possibility of a rare cure
is not sufficient to allow us to say a regimen has curative
intent.
We are probably more inclined to perceive a regimen as
being given with curative intent if we think of it as curing
10%, rather than if we consider that it fails to cure 90% of
patients. If more than four out of five or more than nine out
of 10 patients treated by a strategy are destined to not
achieve cure, can we say we are treating with curative
intent? The answer to this question will vary from reader to
reader, and this article is not proposing to set a definition;
however, consideration of these points will be useful to the
reader in making his or her own determination.
Defining Curative Resection
LEONARD B. SALTZ
The reason that resection/ablation is an accepted standard
practice without randomized data is that the cure rate with
this approach appears to be substantially higher than what
could realistically be expected from systemic therapy alone.
It should be emphasized that it is the cure rate, and no other
factor, that has led to the universal acceptance of this
approach without a randomized trial. What is the cure rate,
and to what degree does chemotherapy add to that? The
European Organisation for Research and Treatment of Cancer
(EORTC) has conducted one of the few large-scale
randomized trials involving liver resection of hepatic metastases
of CRC. 5 EORTC 40983 was limited to patients with no
more than four liver-only metastases. As it turned out, more
than one-half of the patients had only a solitary liver
metastasis, 14% had three liver lesions, and only 7% had
four liver lesions. Extrapolation to patients with more extensive
disease must be done with caution. The three-year
progression-free survival (effectively recurrence-free survival
in this resected population) was the primary endpoint.
Since the overwhelming majority of recurrences happen
within the first 3 years, 3-year recurrence-free survival is a
reasonable surrogate for cure. In this EORTC trial, of the
patients actually undergoing resection, 3-year disease-free
survival was 33% in patients treated with surgery only
and 42% in patients treated with surgery plus perioperative
FOLFOX (3 months preoperative and 3 months postoperative).
Thus, of the patients with CRC with one to four
(mostly one to two) liver metastases who were able to
successfully undergo resection, approximately one-third
were potentially cured. The administration of perioperative
FOLFOX improved that potential cure rate by an absolute
increase of 9%, or a relative increase of 27% (because 9%
is 27% of the baseline of 33%). This 9% absolute increase
was relatively disappointing, considering that FOLFOX increased
disease-free survival by 7.2% in patients with stage
III A and B disease and 11.5% in patients with stage IIIC
disease in the MOSAIC trial. 6 The reason for this somewhat
disappointing performance by FOLFOX has not been definitively
identified. One possible contributing factor is that
although no patient on the EORTC 40983 trial had received
prior oxaliplatin, 42% had received prior fluoropyrimidinebased
adjuvant chemotherapy for their primary cancer,
thereby selecting for a relatively fluoropyrimidine-resistant
population.
The fact that the clinical trial was done with the FOLFOX
split into 3 months before and 3 months after surgery should
in no way be construed as creating an obligation to follow