2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

ADJUVANT THERAPY FOR STAGE III COLON CANCER
For both studies, the combination of 5-FU/oxaliplatin,
however, proved substantially more toxic than 5-FU alone,
resulting in a greater risk of severe cytopenia, nausea,
vomiting, diarrhea, and peripheral neuropathy. 18,20
Finally, the superiority of XELOX (i.e., capecitabine/
oxaliplatin) over bolus 5-FU/LV as adjuvant treatment for
patients with stage III colon cancer was shown in the
NO16968 trial. 19 Haller and colleagues reported a 3-year
DFS of 66.5% for 5-FU/LV (Mayo Clinic or Roswell Park
regimens) compared with 70.9% for XELOX (HR � 0.80, p �
0.0045). As anticipated with oxaliplatin, neurosensory toxicity
occurred in the majority of patients in these three
studies, but the frequency of peripheral sensory neuropathy
decreased during the follow-up period. 18 Preliminary
patient-reported outcomes from the NSABP C-07 trial suggest
that symptoms of oxaliplatin-associated neurotoxicity
persisting for 6 years after treatment failed to reach clinical
significance. 21 The total dose of oxaliplatin administered
in NSABP C-07 was approximately 30% lower than in
MOSAIC, yet provided comparable efficacy. The per-protocol
planned oxaliplatin dose was 1,020 mg/m 2 (12 cycles) in
MOSAIC and 765 mg/m 2 (nine cycles) in NSABP C-07,
although the median dose of oxaliplatin received per patient
was 810 mg/m 2 (9.5 cycles) in MOSAIC and 667 mg/m 2 (7.8
cycles) in NSABP C-07. 18,20 Stopping oxaliplatin in cases of
neuropathy at grades 2 (e.g., paresthesia/dysesthesia interfering
with function, but not with activities of daily living
[i.e., permanent dysesthesia]) or 3 (e.g., paresthesia/dysesthesia
with pain or functional impairment) must be done in
clinical practice. If oxaliplatin has to be stopped because of
peripheral neuropathy, 5-FU/LV or capecitabine should be
administered per protocol (i.e., for a total of 6 months).
Could the mFOLFOX6 Regimen Replace FOLFOX4?
The mFOLFOX6 regimen (85 mg/m 2 of intravenous oxaliplatin
with 400 mg/m 2 of LV over 2 hours, followed by 400
mg/m 2 bolus injection of 5-FU, then 2,400 mg/m 2 intravenous
5-FU for 46 hours) is more convenient for patients and
less expensive than the FOLFOX4 regimen (i.e., 1 day
compared with 2 days in the outpatient unit). In addition, no
evidence of further toxicity has resulted from the increased
dose of 5-FU. To date, no study has compared FOLFOX4 to
mFOLFOX6 in the adjuvant setting. However, in the
NSABP C-08 study, 22 which evaluated the mFOLFOX6
regimen with or without bevacizumab in patients with stage
III disease, the 3-year DFS was nearly identical to that
observed in patients treated with FLOX in the oxaliplatin
arms of NSABP C-07 or those treated with FOLFOX4 in the
MOSAIC trial. 18,20
Can Older Patients Benefit from Adjuvant Therapy?
The value and feasibility of 5-FU–based adjuvant chemotherapy
for patients older than age 70 was demonstrated in
a pooled analysis by Sargent and colleagues, 23 who found no
evidence of interaction between age and the efficacy of
chemotherapy. Moreover, except for leucopenia in one study,
the incidence of toxic effects of chemotherapy was not higher
in older patients.
Adjuvant treatment with FOLFOX4 was well tolerated in
patients older than age 70, with higher rates of only neutropenia
and thrombocytopenia compared with younger patients
(49% vs. 43%, p � 0.04%, and 5% vs. 2%, p � 0.04,
respectively). 24 A combined analysis of the two pivotal
adjuvant trials comparing 5-FU/oxaliplatin with 5-FU alone
failed to demonstrate a benefit in DFS and OS in older
patients, despite a positive trend for time to recurrence. 25
On the other hand, the NO1698 trial, 19 and the posthoc
analysis of MOSAIC data 26 showed efficacy in both the
young and the older adult populations. Therefore no formal
recommendation can be offered. From a clinical point of
view, the decision to add oxaliplatin to fluoropyrimidines as
adjuvant treatment should be at least based on performance
status and comorbidities. In addition to these cancer-specific
prognostic factors, the use of a comprehensive geriatric
assessment is strongly recommended to evaluate the appropriateness
of chemotherapy.
Lack of Benefit of Irinotecan in the Adjuvant Setting
As discussed, 5-FU leads to a relatively large improvement
in OS for patients with stage III colon cancer. Interestingly,
this benefit occurs despite a relatively low
radiographic response rate of 15% to 20%. 27 With the addition
of oxaliplatin and irinotecan for patients with metastatic
disease, response rates more than doubled, suggesting
synergy in the cytotoxic effects on colorectal cancer cells. 27
As such, it was anticipated that oxaliplatin would improve
the chance of remaining disease-free longer after surgery
and increase OS when added to 5-FU. 18-20 Perhaps a presaging
event to the current situation, however, was the story
of irinotecan in the adjuvant setting. When compared headto-head
in the metastatic setting, irinotecan has proven
itself to be essentially equivalent to oxaliplatin (i.e., as an
addition to 5-FU). 27 Despite this, four randomized trials of
irinotecan as an adjuvant addition for patients with stages
II and III colorectal cancer failed to demonstrate benefit,
demonstrating that improvements in response and OS in the
metastatic setting might not reliably translate to clear
benefit in the adjuvant setting. 28-30 To this day, the failure
of irinotecan remains a puzzle, but it is also important to
understand that even a doubling of response rate with
oxaliplatin led to a fairly modest improvement in DFS
(HR � 0.78 to 0.8) and OS (HR � 0.8 to 0.85) in the MOSAIC
and NSABP C-07 studies, respectively. 18,20 Perhaps, then,
what we can really conclude about adjuvant therapy for
patients with stage III colorectal cancer is that it is amazing
how large the benefit of 5-FU has been given the very low
response rate in stage IV disease.
Lack of Benefit of Biologics in the Adjuvant Setting:
Where Did We Go Wrong?
The first biologic agent to fail in the adjuvant setting was
bevacizumab. Mouse models of metastasis (tail-vein injection)
performed in the 1990s suggested substantial inhibition
of metastasis by the depletion of vascular endothelial
growth factor (VEGF) that could potentially translate to
benefit in the human adjuvant situation. 31 It is welldocumented
that bevacizumab led to improvements in
progression-free survival and OS in several trials of patients
with metastatic colorectal cancer, with an impressive HR for
death of 0.66 in the pivotal randomized study of bevacizumab.
32 As such, hopes were high for benefit in the adjuvant
setting.
The first published study of adjuvant bevacizumab was
NSABP C-08. 22 This study randomly assigned 2,710 pa-
225