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are here: Home: CCU 3 | 2003: John
Zalcberg, MB, BS, PhD, FRACP
Edited comments by Professor Zalcberg
MOSAIC adjuvant trial: FOLFOX4 versus the DeGramont
regimen
The MOSAIC adjuvant trial was a well-designed and well-conducted,
multinational study comparing FOLFOX4 to the DeGramont regimen.
The primary endpoint was three-year, disease-free survival.
In planning the study, the investigators calculated the expected disease-free
survival to be 73 percent in the control group and 79 percent in the
experimental arm — a 25 percent reduction in the risk of recurrence.
Amazingly,
the actual three-year, disease-free survival was 73 percent and 78 percent,
respectively.
The reduction was not statistically significant for patients with Stage II
disease,
but there were fewer events in those patients, and it may still be too early
to
develop firm conclusions about that subset.
NSABP adjuvant trial C-08 in Stage II and III colon cancer
NSABP-C-08 is essentially a three-by-two factorial design. Patients with Stage
II
and III colon cancer will be randomized to bolus 5-FU/leucovorin and
oxaliplatin 85 mg (FLOX) or FOLFOX6 or capecitabine/oxaliplatin (CAPOX). In
each arm, patients are further randomized to bevacizumab or not.
The C-08 trial will also involve very interesting correlative science studies
on
the tumor. It’s not possible to utilize fresh tissue in adjuvant studies,
but the
NSABP has devised a way to perform gene arrays using paraffin-embedded
blocks.
This will be a powerful research tool, because the sample can be processed
normally, patients can be entered into the study postoperatively, and it won’t
interfere with surgical practice.
Utilization of irinotecan combinations versus oxaliplatin
combinations
There are several considerations in deciding whether to utilize an irinotecancontaining
regimen or an oxaliplatin-containing regimen as first-line therapy for
metastatic disease. The recent NCCTG-N9741 data presented by Rich Goldberg,
comparing FOLFOX, IFL and IROX, is compelling. Although there are issues
with the study in regard to the use of infusional versus bolus 5-FU and
crossover regimens, FOLFOX was clearly superior to IFL. Another consideration
is the data presented by Tournigand at ASCO a couple of years ago, which
suggested using either regimen up front — as long as they were infusional —
and ultimately resulted in equivalent survival.
Clinically, my decision is based upon individual preferences and values, such
as
concerns about hair loss, neuropathy, etcetera, but most of my patients will
receive both regimens. I tend to utilize oxaliplatin-containing regimens prior
to
irinotecan.
Improved survival with IFL/bevacizumab versus IFL alone in
patients with metastatic colorectal cancer
Although we’ve been discussing angiogenesis for as long as Judah Folkman
has
been working in the area — about 30 years — we have not had clear
evidence
that antiangiogenics were effective in controlling cancer.
Data from a randomized Phase II trial, recently reported in the Journal of
Clinical
Oncology, demonstrated a benefit when bevacizumab was combined with IFL
compared to IFL alone. At ASCO this year, results of a Phase III study in
patients with metastatic colorectal cancer demonstrated IFL/bevacizumab
improved median survival by five months when compared to IFL alone. The
magnitude of this improvement should not be discounted; the increase in
median survival used to justify the substitution of IFL for 5-FU/LV was only
1.5 months.
An important issue being addressed by several cooperative group trials is
whether the addition of bevacizumab to other chemotherapy regimens will
result in similar improvements seen when added to IFL. It’s a reasonable
assumption that it will be as effective, and cooperative groups are launching
additional trials incorporating bevacizumab.
Management of patients with asymptomatic, advanced colorectal
cancer
Only two studies have addressed the management of patients with
asymptomatic colon cancer. The Nordic study, done a number of years ago,
suggested that early chemotherapy was preferred for asymptomatic patients;
however, that study had limitations. Another trial was conducted by a Canadian
group and the Australian GI Trialists’ Group. Patients with asymptomatic
advanced colorectal cancer were randomized to immediate chemotherapy or delay
of chemotherapy until they were symptomatic. This study is being
prepared for publication, and it demonstrated no apparent benefit in starting
chemotherapy before onset of symptoms.
It’s important to recognize that these results are based on 5-FU/leucovorin
regimens. Would the results be different with the newer agents, such as
oxaliplatin and irinotecan? I suspect we will never know the answer because
those trials will never be performed. In clinical practice, the issue is decided
by
patient and physician preference. I tell patients either choice is a reasonable
alternative. I would prefer to treat them earlier, but there are certainly
opportunities to delay treatment based on lifestyle decisions.
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