Author
Year
Number of patients
Therapy
RR (%)
p-value
PFS (mos)
p-value
OS (mos)
p-value
5–FU and leucovorin vs. capecitabine
de Gramont [43]
1997
216
Bolus 5-FU/LV
14
0.0004
5.5
0.0012
14.2
0.067
217
Bolus + infusional 5-FU/LV
33
6.9
15.5
Hoff [13]
2001
303
Bolus 5-FU/LV
16
0.005
4.7
0.72
13.3
0.974
302
Capecitabine
25
4.3
12.5
Van Cutsem [12]
2001
301
Bolus 5-FU/LV
16
4.7
0.65
12.1
0.33
301
Capecitabine
19
5.2
13.2
Irinotecan–containing regimens
Saltz [44]
2000
231
IFL
39
<0.001
7.0
0.004
14.8
0.04
226
Bolus 5-FU/LV
21
4.3
12.6
226
Irinotecan
18
4.0
12.0
Douillard [45]
2000
188
5FU/LV
31
<0.001
4.4
<0.001
14.1
0.031
199
Irinotecan + 5-FU/LV
49
6.7
17.4
Köhne [46]
2005
216
Infusional 5-FU/FA
62
<0.001
8.5
<0.001
20.1
0.278
214
Irinotecan + infusional 5-FU/FA
34
6.4
16.9
Oxaliplatin–containing regimens
de Gramont [47]
2000
210
Bolus + infusional 5-FU/LV
22
0.0001
6.2
0.0003
14.7
0.12
210
Bolus + infusional 5-FU/LV + oxaliplatin
51
9.0
16.2
Goldberg [48]
2004
264
IFL
31
0.002a
6.9
0.0014a
15
0.0001a
267
FOLFOX
45
8.7
19.5
264
IROX
35
0.03a
6.5
17.4
Porschen [15]
2007
233
FUFOX
54
0.7
8
0.117
18.8
0.26
241
CAPOX
48
7.1
16.8
Cassidy [16]
2008
1,017
FOLFOX
37
NS
8.5
NS
19.8
NS
1,017
CAPOX
37
8
19.6
Ducreux [17]
2011
150
FOLFOX
46
NS
9.3
NS
18.9
NS
156
CAPOX
42
8.9
20.1
Díaz-Rubio [18]
2007
174
FUOX
46
0.539
9.5
0.153
20.8
0.145
174
CAPOX
37
8.9
18.1
Tournigand [49]
2004
109
FOLFIRI → FOLFOX
56
0.26
14.2
0.64
21.5
0.99
111
FOLFOX → FOLFIRI
54
10.9
20.6
Colucci [50]
2005
164
FOLFIRI → FOLFOX
31
0.6
7
0.64
14
0.28
172
FOLFOX → FOLFIRI
34
7
15
Three drug combinations (5–FU, oxaliplatin and irinotecan)
Falcone [51]
2007
122
FOLFIRI
41
0.0002
6.9
0.0006
16.7
0.032
122
FOLFOXIRI
66
9.8
22.6
Souglakos [52]
2006
146
FOLFIRI
37
0.168
6.9
0.17
19.5
0.17
137
FOLFOXIRI
43
8.4
21.5
Table 20.2
Commonly used chemotherapy regimens
Regimen | 5-FU bolus | 5-FU infusion | Leucovorin | Capecitabine | Oxaliplatin | Irinotecan | Cycle length (days) |
|---|---|---|---|---|---|---|---|
Modified de Gramont | 400 mg/m2 | 2,400 mg/m2 over 46 h | 400 mg/m2 | None | None | None | 14 |
mFOLFOX6 | 400 mg/m2 | 2,400 mg/m2 over 46 h | 400 mg/m2 | None | 85 mg/m2 | None | 14 |
mFOLFOX7 | None | 2,400–3,000 mg/m2 over 46 h | 200 mg/m2 | None | 85 mg/m2 | None | 14 |
CAPOX | None | None | None | 850–1,000 mg/m2 for 14 days | 130 mg/m2 | None | 21 |
FOLFIRI | 400 mg/m2 | 2,400 mg/m2 over 46 h | 400 mg/m2 | None | None | 180 mg/m2 | 14 |
FOLFOXIRI | None | 2,400–3,200 mg/m2 over 46 h | 200 mg/m2 | None | 85 mg/m2 | 165 mg/m2 | 14 |
FOLFOX and FOLFIRI can both be considered very appropriate front-line treatments. There are several versions of FOLFOX in use and perhaps the most commonly used one is modified FOLFOX 6 (mFOLFOX6) which consists of 5-FU given as a bolus on day 1 along with leucovorin and oxaliplatin followed by a 46-h continuous infusion of 5-FU with an ambulatory pump. Modified FOLFOX7 (mFOLFOX7) does not contain a 5-FU bolus on day 1 but is otherwise similar. mFOLFOX7 appears to be less likely to cause neutropenia than FOLFOX regimens containing a 5-FU bolus and may therefore be a very suitable regimen for patients with advanced disease receiving palliative chemotherapy.
There is no difference in outcome in terms of survival or response rate between FOLFOX and FOLFIRI assuming patients have access to the other regimen upon progression [49, 50]. The selection of the chemotherapy backbone depends on several factors:
Prior adjuvant therapy: Patients who have a recurrence of a previously resected early-stage colorectal cancer, and received oxaliplatin in the preceding 12 months, should be considered for irinotecan-based therapy, with the intent of reintroducing oxaliplatin at a later time point in the course of the disease.
Comorbidities: Comorbidities may dictate the selection of initial therapy. For example, a patient with underlying neuropathy, such as diabetic neuropathy, may be better served with irinotecan-based regimen (FOLFIRI) instead of oxaliplatin-based regimen (FOLFOX) as initial therapy given its neurotoxicity. Similarly, patients with ileostomy may have difficulties tolerating therapy with irinotecan and capecitabine given the risk of diarrhea. Irinotecan should also be used with great care in patients with liver dysfunction. Oxaliplatin is safe to use even in significant renal and hepatic insufficiency.
Performance status: Patients should undergo a thorough evaluation, including assessment of performance status and comorbidities by a medical oncologist prior to commencing therapy. Performance status is relatively easy to assess and the two most common used tools are the Eastern Cooperative Oncology Group (ECOG) performance scale and the Karnofsky performance score (Tables 20.3 and 20.4) [55, 56]. Patients with impaired performance score may not be candidates for intensive multi-agent systemic therapy but can still derive significant benefit, both in terms of survival improvement and quality of life with fluoropyrimidine monotherapy. (See the section on the elderly and those with impaired performance below)
Table 20.3
Eastern Cooperative Oncology Group (WHO/Zubrod) performance status
Performance status
Description
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work
2
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50 % of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 50 % of waking hours
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
5
Dead
Table 20.4
Karnofsky performance status
Performance status
Description
100
Normal. No complaints. No evidence of disease
90
Able to carry on normal activity. Minor signs or symptoms of disease
80
Normal activity with effort. Some signs or symptoms of disease
70
Care of self. Unable to carry on normal activity or to do active work
60
Requires occasional assistance, but is able to care for most of needs
50
Requires considerable assistance and frequent medical care
40
Disabled. Requires special care and assistance
30
Severely disabled. Hospitalization is indicated although death not imminent
20
Hospitalization necessary, very sick, active supportive treatment necessary
10
Moribund. Fatal processes progressing rapidly
0
Dead
Capecitabine can be safely substituted for 5-FU in oxaliplatin-based regimens in the management of metastatic colorectal cancer [14–17]. The optimal dose of capecitabine is not well defined and there appear to be substantial regional differences in tolerance to capecitabine, likely based on different pharmacogenomics variations in different populations as well as life-style and dietary patterns. Capecitabine has been found to be effective when used in a combination with irinotecan (CAPIRI) [57], but we do not recommend this as a routine option for first line therapy given the risk of complications, especially gastrointestinal toxicity.
Triple cytotoxic drug regimens such as FOLFOXIRI have been evaluated in patients with metastatic colorectal cancer and have been shown to be safe and effective as initial chemotherapy but whether such an aggressive approach improves overall survival remains to be seen [52, 58, 59]. The overall survival of patients in the triple-drug arms does not appear to be superior when compared to recent studies comparing sequential cytotoxic doublet therapy with biologics, especially when maintenance therapy is used. Furthermore, toxicity favors doublet therapy over triple-drug therapy.
The Role of Biologic Drugs
Most newly diagnosed patients treated in the US will receive initial therapy that incorporates biologics, most commonly bevacizumab. Biologic therapy directed against VEGF and EGFR has been extensively studied and found to provide additional benefit when given in conjunction with cytotoxic agents (Table 20.5).
Table 20.5
Key trials of biologic agents in combination with cytotoxic chemotherapy as first line therapy in patients with metastatic colorectal cancer
Author | Year | Number of patients | Therapy | RR (%) | p-value | PFS (mos) | p-value | OS (mos) | p-value |
|---|---|---|---|---|---|---|---|---|---|
Addition of bevacizumab to chemotherapy | |||||||||
Hurwitz [60] | 2004 | 411 | IFL | 35 | 0.004 | 6.2 | <0.001 | 15.6 | <0.001 |
AVF2107 | 402 | IFL + bevacizumab | 45 | 10.6 | 20.3 | ||||
Saltz [61] | 2008 | 701 | FOLFOX/CAPOX | 38 | 0.99 | 8 | 0.0023 | 19.9 | 0.77 |
NO16966 | 699 | FOLFOX/CAPOX + bevacizumab | 38 | 9.4 | 21.3 | ||||
Fuchs [62] | 2007 | 137 | FOLFIRI | 47 | NR | 7.6 | NR | 23.1 | NR |
BICC-C | 57 | FOLFIRI + bev | 58 | 11.2 | 28 | ||||
141 | mIFL | 43 | NR | 5.9 | NR | 17.6 | NR | ||
60 | mIFL – bev | 53 | 8.3 | 19.2 | |||||
Kabbinavar [63] | 2005 | 241 | 5-FU/LV | 34 | 0.019 | 5.6 | <0.0001 | 17.9 | 0.008 |
249 | 5-FU/LV + bev | 25 | 8.8 | 14.6 | |||||
Tebbutt [64] | 2010 | 156 | Capecitabine | 43 | 5.7 | 18.9 | |||
MAX | 157 | Capecitabine + bev | 56 | 8.5 | 0.01c | 18.9 | 0.314c | ||
158 | CBM | 67 | 0.006b | 8.4 | 16.4 | ||||
Cunningham [65] | 2013 | 140 | Capecitabine | 10 | 0.04 | 5.1 | <0.0001 | 16.8 | 0.18 |
AVEX | 140 | Capecitabine + bev | 19 | 9.1 | 20.7 | ||||
Addition of cetuximab to chemotherapy (KRAS wild–type) | |||||||||
Van Cutsem [36] | 2009 | 172 | FOLFIRI | 43 | 8.7 | 0.02 | 24.9 | NS | |
CRYSTAL | 176 | FOLFIRI + cetux | 59 | 9.9 | 21.0 | ||||
Maughan [66] | 2011 | 815 | FOLFOX/CAPOX | 57 | 0.049 | 8.6 | 0.6 | 17.9 | 0.67 |
MRC COIN | 815 | FOLFOX/CAPOX + cetux | 64 | 8.6 | 17.0 | ||||
Tveit [67] | 2012 | 97 | FLOX | 47 | 0.89 | 8.7 | 0.66 | 22.0 | 0.48 |
NORDIC VII | 97 | FLOX + cetux | 46 | 7.9 | 20.1 | ||||
Bokemeyer [68] | 2011 | 97 | FOLFOX | 34 | 0.0027 | 7.2 | 0.0064 | 18.5 | 0.39 |
OPUS | 82 | FOLFOX + cetux | 57 | 8.3 | 22.8 | ||||
Venook [3] | 2014 | 559 | FOLFOX/FOLFIRIa + bev | NR | 10.4 | 0.55 | 29.0 | 0.34 | |
CALGB/SWOG 80405 | 578 | FOLFOX/FOLFIRIa + cetux | NR | 10.8 | 29.0 | ||||
Addition of panitumumab to chemotherapy (KRAS wild–type) | |||||||||
2014 | 331 | FOLFOX | 57 | 0.02 | 8.6 | 0.01 | 19.7 | 0.17 | |
PRIME | 325 | FOLFOX + Pmab | 48 | 10.0 | 23.9 | ||||
All RAS wt | 259 | FOLFOX | 7.9 | 0.004 | 20.2 | 0.009 | |||
253 | FOLFOX + Pmab | 10.1 | 25.8 | ||||||
Schwartzberg [70] | 2014 | 142 | FOLFOX + bev | 54 | 10.1 | 0.353 | 24.3 | 0.009 | |
PEAK | 143 | FOLFOX + Pmab | 58 | 10.9 | 34.2 | ||||
All RAS wt
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