2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

Table 1. Comparison of Fluoropyrimidines Alone (5-FUl/LV) and Fluoropyrimidines (5-FU/LV)/Oxaliplatin Combination in Patients with
Stage III Colon Cancer: Survival in 3 Phase III Randomized Controlled Trials
ENDPOINTS MOSAIC 61 Stage III MOSAIC 18 Stage III NSABP 07 20 Stage III NO1698 19 Stage III
Disease-Free Survival
Follow-up duration, y 3 5 5 3
DFS without vs. with oxaliplatine, % 65.3 vs. 72.2 58.9 vs. 66.4 57.8 vs. 64.4 66.5 vs. 70.9
Absolute difference in DFS, % � 6.3 � 7.5 � 6.6 � 4.4
HR (95% CI) 0.76 (0.62–0.92) 0.78 (0.65–0.93) 0.78 (0.68–0.90) 0.80 (0.69–0.93)
p value � .005 � .005 � .0007 � .0045
Overall Survival
Follow-up duration, y 3 6 5 4.75
OS without vs. with oxaliplatine, % ND 68.7 vs. 72.9 73.8 vs. 76.5 ND
Absolute difference in OS, % – � 4.2 � 2.7 � 3.4
HR (95% CI) ND 0.80 (0.65–0.97) 0.85 (0.72–1.00) 0.87 (0.72–1.05)
p value – � .023 � .052 � .1486
Abbreviations: 5-FU, 5-fluorouracil; CI, confidence interval; DFS, disease-free survival; HR, hazard ratio; LV, leucovorin; ND, not done; OS: overall survival.
chemotherapy with fluoropyrimidines compared with surgery
alone. 14
Oral Fluoropyrimidines, Capecitabine, and
Uracil/Tegafur (UFT) Are Equivalent to 5-FU/LV
Oral drugs are more convenient than intravenous chemotherapy,
at least when used as single agents. The X-ACT
trial compared bolus 5-FU/LV (the Mayo Clinic regimen)
with oral capecitabine for 6 months in patients with stage III
colon cancer. DFS was at least equivalent (HR � 0.87,
p � 0.001 for noninferiority). 15 In the NSABP C-06 study,
oral uracil and tegafur (UFT) plus LV was compared to the
Roswell Park regimen and the results showed similar DFS
and OS. 16
KEY POINTS
● Adjuvant chemotherapy for patients with stage III
colon cancer has substantially evolved in the past 2
decades, increasing disease-free and overall survival.
● Until the early 1990s, research focused on modulation
and duration of 5-fluorouracil and standard of
care became 5-fluorouracil and leucovorin in 1990.
● The addition of oxaliplatin to 5-fluorouracil/leucovorin
further improved disease-free and overall survival
for patients with stage III disease; however,
additional toxicities during therapy and cumulative
neuropathy require active monitoring and adjustments
in caring for patients with stage III disease.
● Three drugs that have shown benefit in metastatic
colorectal cancer (irinotecan, bevacizumab, and cetuximab)
failed to provide significant additional benefit
in the management of stage III colon cancer, and
the reasons for the discordance between metastatic
disease and adjuvant therapy remains unclear.
● Adjunctive therapies to standard treatment are actively
being considered in colon cancer survivorship,
including physical activity, diet, obesity, vitamin D,
and nonsteroidal anti-inflammatory drugs, and data
are forthcoming to further understand the role these
may play in the outcomes of patients with stage III
colon cancer.
224
ANDRÉ, O’NEIL, AND MEYERHARDT
A 3-Year DFS Is the New Endpoint in Adjuvant Trials
The traditional endpoint for clinical trials of patients
with adjuvant colon cancer treatment was 5-year OS. The
ACCENT meta-analysis of adjuvant studies demonstrated
that 3-year DFS was a predictor of 5-year OS results and
could be an appropriate primary endpoint for adjuvant
studies in colon cancer. The data led to the approval of
3-year DFS as the primary endpoint in adjuvant therapy
studies for patients with stage III colon cancer by the United
States Food and Drug Administration (FDA). 17 Using 3-year
DFS as the main endpoint reduces trial duration, drug
development time, and cost, and as a result, new and better
treatments can be made available to patients more rapidly.
Oxaliplatin Plus Fluoropyrimidines Is Better than
Fluoropyrimidines Alone: The Second Step (2004)
Combined fluoropyrimidines and oxaliplatin led to significant
improvements in survival in three phase III
randomized controlled trials (Table 1). 18-20 The MOSAIC
(Multicenter International Study of Oxaliplatin/5-FU/LV in
the Adjuvant Treatment of Colon Cancer) trial compared the
efficacy of the LV5FU2 regimen and the same regimen plus
oxaliplatin (FOLFOX4) in patients with stage II and III
colon cancer. Patients were randomly assigned to receive
12 biweekly cycles of LV5FU2 or FOLFOX4. 18 For patients
with stage III disease, FOLFOX4 improved DFS by 24%
(HR � 0.76, p � 0.005). On the basis of these results,
FOLFOX4 was approved as adjuvant therapy after surgery
for patients with stage III colon cancer. Updated results
showed 5-year DFS rates of 58.9% and 66.4% for LV5FU2
and FOLFOX4, respectively (HR � 0.78, p � 0.005). A
benefit in OS for patients treated with FOLFOX4 was also
observed: the 6-year OS rates comparing LV5FU2 and
FOLFOX4 were 68.7% and 72.9%, respectively (HR � 0.80,
p � 0.023). 18 The National Surgical Adjuvant Breast and
Bowel Project (NSABP) trial C-07 evaluated the FLOX
regimen (i.e., oxaliplatin added to a weekly bolus of 5-FU/
LV) in patients with stage II and III colon cancer. 20 For both
stages, the benefit provided by oxaliplatin on 3-year DFS
was similar to that reported in the MOSAIC study (HR 0.80,
p � 0.004). A longer follow-up indicated a 6.6% increase in
DFS at 5 years (57.8% vs. 64.4%, p � 0.0007) for patients
with stage III disease, with a nonsignificant benefit in OS:
5-year OS rates with 5-FU/LV and FLOX were 73.8% and
76.5%, respectively (HR � 0.85, p � 0.052).