2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

tients with stages II and III colorectal cancer after surgery
to a standard 6-month course of FOLFOX or FOLFOX plus
5 mg/kg of bevacizumab every other week followed by 6
months of single-agent bevacizumab. The study accrued
quickly, which reflected enthusiasm for the agent in this
setting. Disappointingly, the primary endpoint of 3-year
DFS did not improve significantly with bevacizumab (HR
0.87, p � 0.08), although there was improvement in DFS at
1 year, suggesting either a biologic effect during bevacizumab
treatment that did not lead to cure or that relapse
was observed later because of later surveillance scanning in
patients on the bevacizumab arm (i.e., median time to first
imaging was earlier in the control arm). Subsequent to this,
the 3,451-patient European AVANT (AVastinAdjuvaNT)
trial, which had a similar design to the NSABP C-08 trial
but included a third capecitabine/oxaliplatin/bevacizumab
arm, reported similarly negative results, including a transient
benefit during the first year. 33 Unlike NSABP C-08,
AVANT actually demonstrated a nonsignificant trend toward
a decrement in survival for patients in both
bevacizumab-containing arms compared with FOLFOX
alone. In neither study did excess toxicity of bevacizumab
appear to be a contributing issue.
So what went wrong with bevacizumab? One question is
whether the scientific rationale for (relatively) short-term
VEGF inhibition was sound. Conceptually, we believe that
adjuvant therapy works by killing tumor cells, something
that bevacizumab is not known to do. If one were to consider
the static effects of VEGF inhibition to be valid, then ideally
bevacizumab would be continued for a long period, with the
expectation of potential relapse whenever one chose to end
therapy. We may never know if prolonged use of bevacizumab
would be of benefit. In some experimental models,
bevacizumab has been shown to work in metastatic tumors
by normalizing aberrant tumor neovasculature, 34 a mechanism
that would not be expected to be of benefit in tumor
micrometastases. At this time, whether further study of
bevacizumab (or other VEGF pathway–targeting strategies)
will be pursued remains unclear.
Antibodies that prevent the binding of ligands to the
epidermal growth factor receptor (EGFR) are the other class
of agent that has recently been studied in the adjuvant
setting. Cetuximab and panitumumab both have clear activity
in subsets of patients with metastatic disease, 35 and both
have been shown to increase response rates by roughly 10%
when added to FOLFOX or FOLFIRI (5-FU/leucovorin/
irinotecan) and when analysis is restricted to patients with
KRAS wild-type tumors. This increase in response rate,
along with single-agent responses that are similar to those
seen with 5-FU, would have suggested that the EGFR
antibodies might cause an increase in tumor-cell killing that
would make them good adjuvant therapy agents. With this
rationale in mind, study N0147 was designed by the North
Central Cancer Treatment Group (NCCTG) and conducted
by multiple U.S. and Canadian cooperative groups. N0147
went through several design iterations before settling as a
study of FOLFOX with or without cetuximab for patients
with resected stage III colorectal cancer. 36,37 An interesting
subgroup of patients randomly assigned to receive FOLFIRI
with or without cetuximab was removed when it became
clear that irinotecan was an ineffective addition to 5-FU in
this setting. 38 Over the course of the N0147 study, the KRAS
story emerged, and the study was amended to include only
226
patients with KRAS wild-type tumors. The final reported
sample size included 1,864 patients with KRAS wild-type
tumors. One issue that became clear was related to toxicity.
A clear signal emerged in patients older than 70 with high
rates of study discontinuation for toxicity, which resulted in
yet another amendment. After all was said and done, the
results of N0147 were again disappointing. Even patients
with KRAS wild-type tumors treated with cetuximab did not
benefit; in fact the trend was toward harm (DFS HR � 1.2,
p � NS). 36 In addition, there was clear harm in patients
with KRAS-mutant cancers. 37 In patients older than 70, the
HR was 1.79 (p � 0.03), significantly favoring the FOLFOXonly
arm. 36
So again, what went wrong with cetuximab? In this case,
unexpected toxicities that could have shortened chemotherapy
contributed to the negative outcome. As with irinotecan,
however, the ultimate cause of failure is unclear. One hint
that this study might have been negative was the relatively
small incremental improvements in outcome in most trials
of patients with metastatic cancer (a disconnect from the
relatively robust increase in radiographic response). Could it
be that micrometastases have not yet become dependent on
EGFR ligands for their growth? Could early-stage tumors
be biologically different and less likely to depend on EGFR
signaling?
Curiously, data from the N0147 study now suggest that
cetuximab might benefit patients when given with the
discontinued irinotecan backbone, although interpreting
these data has to be tempered by the small sample size. 38
In a poster presented at the ASCO Gastrointestinal Cancers
Symposium 2011, N0147 investigators demonstrated a
fairly robust benefit trend in the FOLFIRI subgroup (3-year
DFS HR � 0.4, p � 0.05; 3-year OS HR � 0.3, p � 0.08). 38
Given the irinotecan data, whether this information will be
followed up in larger trials remains to be seen.
Current Adjuvant Therapy Trials
ANDRÉ, O’NEIL, AND MEYERHARDT
To date, adjuvant therapy trials for patients with colon
cancer, as in most other cancers, develop because of promising
data in metastatic disease. Whether this strategy is
optimal is debatable since certain agents might have more
efficacy in a micrometastatic setting, though this remains
the current approach. Hampering the testing of new agents
in adjuvant colon cancer, therefore, has been the recent lack
of new agents with definitive efficacy in metastatic disease.
The last drug to be approved by the FDA was panitumumab
in 2006.
Given the lack of agents to test in the adjuvant setting,
questions have arisen related to the necessary duration of
therapy. In the late 1980s and early 1990s, INT-0089 demonstrated
noninferiority between 6 months of adjuvant chemotherapy
with 5-FU/LV and 12 months with 5-FU/
levamisole. 12 In addition, the GERCOR trial showed that
the LV5FU2 regimen administered for either 6 or 9 months
achieved similar results. 13 Therefore, a 6-month duration of
treatment became the standard. Given the cumulative neuropathy
from oxaliplatin that can remain with patients for
years after completing adjuvant therapy, 18 the question of
needed duration of adjuvant therapy became pertinent.
Further, one small trial by Chau and colleagues demonstrated
noninferiority of a protracted venous infusion regimen
of 5-FU for 3 months compared to the Mayo Clinic
(5-FU/LV) regimen in adjuvant therapy for patients with