With the exception of surgically
resectable liver or lung metastases, the majority of patients with metastatic
colorectal cancer are treated primarily with systemic chemotherapy. It is now
common for many of these patients to not only receive one, but two or more
chemotherapy regimens during the course of their illness.
In a recently reported randomized trial, 45% of patients
receiving first-line fluorouracil (5-FU) and leucovorin received second-line
irinotecan (CPT- 11, Camptosar). Most of the current available data for
second-line therapy of colorectal cancer comes from phase II trials. These
trials have all the limitations of other phase II trials. In addition, there is
significant heterogeneity in the colorectal cancer population considered for
"second-line" therapy. This group may include patients who first
presented with metastatic disease, patients who have progressed rapidly after
adjuvant therapy, patients who have had more than one resection for disease, and
patients who may have had liver-directed therapy. In addition, as more knowledge
develops on the molecular basis of disease, properties of the cancers themselves
have been identified that may predict chemotherapy effects.
The data regarding the use of oxaliplatin as second-line (or
later-line) chemotherapy will be highlighted herein. The article will
demonstrate that phase II data in this setting are mature and that the time has
come for randomized trials to establish the true role of oxaliplatin in
An important variable in future results of second-line therapy
may be the shifting paradigm for first-line therapy. (Use of oxaliplatin
(Eloxatin) as first-line therapy is discussed elsewhere.) Recently, two clinical
trials compared fluorouracil (5-FU) and leucovorin with 5-FU, leucovorin, and
irinotecan combination therapy. Both trials showed that the addition of
irinotecan increased the response rate, time to progression, and overall
survival compared to 5-FU and leucovorin alone, at the expense of potential
added toxicity.[1-3] Thus, at least in the United States, many patients are now
receiving a combination regimen as first-line therapy.
However, investigators initially assessed irinotecan as
second-line therapy for metastatic colorectal cancer. In that respect, data from
those trials remain the best framework in which to evaluate second-line
oxaliplatin. Single-agent irinotecan as second-line therapy has yielded response
rates of 10% to 22% and median survivals of 8 to 10 months. In two randomized
trials, irinotecan also established a survival benefit over both best supportive
care and second-line infusional 5-FU.[5,6] The trials had different eligibility
criteria and, therefore, patient populations.[7-12]
The activity of single-agent oxaliplatin as second-line therapy
was established in three trials reported in two articles.[7,13] In the trials by
Machover et al, patients received intravenous infusions of oxaliplatin over 2
hours. Doses were repeated every 3 weeks. The study by Levi et al used a
chronomodulated infusion, with the peak dose administered at 4 PM,
over 5 days, also repeated every 3 weeks.
Response rates were 10% to 11%, with stable disease seen in 24%
to 42% of patients. Median time to progression was 4.5 to 6 months and median
survival was 8 to 9 months. These results are comparable to the results achieved
with irinotecan as second-line therapy.[4-6]
The Folfox Regimens
De Gramont and colleagues have pioneered several regimens
combining 5-FU and leucovorin with oxaliplatin.[7-11] The majority of these
regimens are administered every 2 weeks, and contain infusions of leucovorin and
5-FU. Most also contain one or two bolus doses of 5-FU. For example, folfox4
(oxaliplatin, leucovorin, and fluorouracil) administers oxaliplatin at 85 mg/m2
over 2 hours on day 1. Patients then receive leucovorin at 200 mg/m2
over 2 hours on days 1 and 2 followed each day by bolus 5-FU at 400 mg/m2
on days 1 and 2 and 22 hours of infusional 5-FU 600 mg/m2
on days 1 and 2. These cycles are repeated once every 2 weeks, for up to 12
doses of oxaliplatin (Table 1).[7-12]
When combined, the response rate plus stable disease rate is
generally greater than 50% for the folfox regimens. Of particular note, most of
the patients in these trials had progressed while on the same 5-FU and
leucovorin regimen that they later received on trial with the addition of
oxaliplatin, suggesting that the addition of oxaliplatin resulted in the
antitumor effect. Although these data are from phase II trials, response rates
for the folfox regimens were higher than for single-agent oxaliplatin,
suggesting a possible additive effect when combining 5-FU and oxaliplatin.
Differences in the incidence of toxicity were seen among the
folfox regimens with grade 3/4 neutropenia occurring in 20% to 39% of patients
receving folfox2, 3, 4, or 6, and grade 2/3 neuropathy in 16% to 29% of those
receiving folfox2, 3, 4, or 6.
Chronomodulated 5-FU has also been combined with oxaliplatin in
several phase II trials listed in Table 2.[14-18]
Although two trials involved both previously untreated and previously treated
patients, the data are separated when possible for patients with refractory
disease. As with the folfox trials, response rates were high, ranging from 15%
to 58%. In addition, a progression-free survival ranging from 5 to 10 months and
an overall survival as high as 17 months was observed.
Recently, Giacchetti et al reported results that combined
patients from some of the trials listed in Table
3 with other patients being considered for resection of hepatic
metastases. In total, 196 patients had been treated with chronomodulated
5-FU and oxaliplatin. Of these, 60% had received only one previous chemotherapy
regimen and 40% had received greater than or equal to two regimens. Median
progression-free survival was 9 months and overall survival was 17 months.
However, hepatic metastases were resected in 18% of patients.
With chronomodulation, grade 3/4 neutropenia occurred in less
than 5% of patients, while grade 2 or higher neuropathy occurred in up to 32% of
pretreated patients and grade 3/4 mucositis in up to 28% of patients.[14,15]
Other 5-FU Regimens
Several schedules and doses for 5-FU, leucovorin, and
oxaliplatin have been investigated; many of these are listed in Table
3.[20-24] Although some of the bolus schedules for 5-FU appeared to yield
lower response rates, overall survival was similar to that achieved with the
folfox and chronomodulated schedules shown in Table
1 and Table 2. Table
3 is not a comprehensive list of all the trials performed, and more
treatment schedules are likely to be tried. In fact, the Extended Access French
Program (EAFP) allowed the use of over 25 different regimens of oxaliplatin in
combination with 5-FU. This data set incorporated 490 patients from 147
centers, only 18 of whom received single-agent oxaliplatin.
Antitumor effects were reviewed for 370 patients, and 14.6%
responded to therapy with a 9.7-month overall median survival. Response rates
were higher for the biweekly oxaliplatin regimens (36.1%) than for the triweekly
regimens (13.3%) but survivals were similar at 11.1 and 10.0 months,
respectively. The current "compassionate-use trial" in the United
States will accumulate progression and survival data that may help guide a
decision on whether it is worthwhile to explore different regimens in a
A single randomized phase II/III trial has been reported that
compared oxaliplatin plus 5-FU vs one of two other second-line regimens, 5-FU or
irinotecan. The trial was divided into two treatment arms with 49 patients
assigned to the oxaliplatin plus 5-FU arm vs 36 patients in the control arm. The
response rate was 37% for the oxalipatin plus 5-FU arm vs 11% for the control
arm, and progression-free survival was 5.1 months vs 2.2 months for the
oxaliplatin plus 5-FU and control arm, respectively.
The final data from this trial may help to clarify the role of
oxaliplatin plus 5-FU in second-line therapy of colorectal cancer. However,
interpretation may be limited by the inclusion of two different single-arm
regimens in the "control" arm.
Overall, it appears that 5-FU plus oxaliplatin is active in the
second-line therapy of colorectal cancer. A number of regimens have been tested
as listed in Tables 1 to 3. While response rates for combination therapy often
seem higher than response rates for single-agent oxaliplatin, survival does not
appear to differ significantly.
1. Saltz LB, Cox JV, Blanke C, et al: Irinotecan plus
fluorouracil and leucovorin for metastatic colorectal cancer. N Engl J Med
1a. Saltz LB, Douillard J, Pirotta N, et al: Combined analysis
of two phase III randomized trials comparing irinotecan (C), fluorouracil (F),
leucovorin (L) vs F alone as first-line therapy of previously untreated
metastatic colorectal cancer (abstract 938). Proc Am Soc Clin Oncol 19:242a,
2. Saltz LB, Locker PK, Pirotta N, et al: Weekly irinotecan
(CPT-11), leucovorin (LV), and fluorouracil (FU) is superior to daily ´
5 LV/FU in patients with previously untreated metastatic colorectal cancer
(abstract 898). Proc Am Soc Clin Oncol 18:233a, 1999.
3. Douillard JY, Cunningham D, Roth AD, et al: Irinotecan
combined with fluorouracil compared with fluorouracil alone as first-line
treatment for metastatic colorectal cancer: A multicentre randomised trial.
Lancet 355:1041-1047, 2000.
4. Rothenberg ML, Blanke CD: Topoisomerase I inhibitors in the
treatment of colorectal cancer. Semin Oncol 26:632-639, 1999.
5. Rougier P, Van Cutsem E, Bajetta E, et al: Randomised trial
of irinotecan vs fluorouracil by continuous infusion after fluorouracil failure
in patients with metastatic colorectal cancer. Lancet 352:1407-1412, 1998.
6. Machover D, Diaz-Rubio E, de Gramont A, et al: Two
consecutive phase II studies of oxaliplatin (L-OHP) for treatment of patients
with advanced colorectal carcinoma who were resistant to previous treatment with
fluoropyrimidines. Ann Oncol 7:95-98, 1996.
7. De Gramont A, Vignoud J, Tournigand C, et al: Oxaliplatin
with high-dose leucovorin and 5-fluorouracil 48-hour continuous infusion in
pretreated metastatic colorectal cancer. Eur J Cancer 33:214-219, 1997.
8. Andre T, Louvet C, Raymond E, et al: Bimonthly high-dose
leucovorin, 5-fluorouracil infusion, and oxaliplatin (FOLFOX3) for metastatic
colorectal cancer resistant to the same leucovorin and 5-fluorouracil regimen.
Ann Oncol 9:1251-1253, 1998.
9. Andre T, Bensmaine MA, Louvet C, et al: Multicenter phase II
study of bimonthly high-dose leucovorin, fluorouracil infusion, and oxaliplatin
for metastatic colorectal cancer resistant to the same leucovorin and
fluorouracil regimen. J Clin Oncol 17:3560-3568, 1999.
10. Maindrault-Goebel F, Louvet C,Andre T, et al: Oxaliplatin
added to the simplified bimonthly leucovorin and 5-fluorouracil regimen as
second-line therapy for metastatic colorectal cancer (FOLFOX6). GERCOR. Eur J
Cancer 35:1338-1342, 1999.
11. Maindrault-Goebel F, de Gramont A, Louvet C, et al:
High-dose oxaliplatin with the simplified 48h bimonthly leucovorin (LV) and
5-fluorouracil (5-FU) regimen in pretreated metastatic colorectal cancer
(FOLFOX) (abstract 1017). Proc Am Soc Clin Oncol 18:265a, 1999.
12. Beretta GD, Cascinu S, Zaniboni A, et al: Oxaliplatin
(L-OHP) in combination with leucovorin and bolus-continuous infusion
5-fluorouracil (LV5FU2) in advanced colorectal cancer (ACC) pretreated with
5-FU. Eur J Cancer 35(suppl 4):256, 1999.
13. Levi F, Perpoint B, Garufi C, et al: Oxaliplatin activity
against metastatic colorectal cancer: A phase II study of 5-day continuous
venous infusion at circadian rhythm modulated rate. Eur J Cancer 29A:1280-1284,
14. Berheault-Cvitkovic F, Jami A, Ithzaki M, et al: Biweekly
intensified ambulatory chronomodulated chemotherapy with oxaliplatin,
fluorouracil, and leucovorin in patients with metastatic colorectal cancer. J
Clin Oncol 14:2950-2958, 1996.
15. Levi F, Misset J-L, Brienza S, et al: A chronopharmacologic
phase II clinical trial with 5-fluorouracil, folinic acid, and oxaliplatin using
an ambulatory multichannel programmable pump. Cancer 69:893-900, 1992.
16. Guerin-Meyer V, Delva R, Lortholary A, et al: Combination of
oxaliplatin (OXA)/5-FU/FA in 5-FU refractory advanced colorectal cancer (RACRC)
patients treated with 5-FU/FA weekly PK guided regimen (abstract 1001). Proc Am
Soc Clin Oncol 18:260a, 1999.
17. Berheault-Cvitkovic F, Mefti F, Francois E, et al: A phase I
study of bimonthly 48 hours (hrs) chronomodulate 5-FU/folinic (FA) in
combination with oxaliplatin (OXA) in pretreated patients with advanced
colorectal cancer (ACRC) (abstract 997). Proc Am Soc Clin Oncol 18:259a, 1999.
18. Bertheault-Cvitkovic F, Mefti F, Seitz JF, et al:
Chronomodulated (CRM) bimonthly 48 hour (hr) 5-fluorouracil (5-FU), folinic acid
(FA), oxaliplatin (OXA) ‘FOLFOX CRM’ in FU-refractory (FUR) advanced
colorectal cancer (ACRC) patients: Phase II study (abstract 1242). Proc Am Soc
Clin Oncol 19:314a, 2000.
19. Giacchetti S, Zidani R, Chollet P, et al: Chemotherapy of
metastatic colorectal cancer (MCC) with 5-fluorouracil (5-FU)-leucovorin
(LV)-oxaliplatin (L-OHP) as second- to seventh- line treatment (abstract 1255).
Proc Am Soc Clin Oncol 19:318a, 2000.
20. Roca E, Montiel M, Barugel M, et al: 5-FU and leucovorin
(MAYO regimen) plus bimonthly oxaliplatin (OXA) in patients with advanced
colorectal cancer (ACC) (abstract 1144). Proc Am Soc Clin Oncol 18:298a, 1999.
21. Van Cutsem E, Szanto J, Roth A, et al: Evaluation of the
addition of oxaliplatin (OXA) to the same Mayo or German 5-FU regimen in
advanced refractory colorectal cancer (abstract 900). Proc Am Soc Clin Oncol
22. Tassinari D, Panzin I, Pasquini E, et al: Oxaliplatin, 5-FU
and folinic acid (OFFA) as II-line chemotherapy in advanced colorectal cancer.
Eur J Cancer 35 (suppl 4):1999.
23. Janinis J, Fountzilas G, Skarlos DV, et al: Second-line
combination chemotherapy with weekly oxaliplatin (L-OHP) and high-dose
5-fluorouracil (5-FU) with leucovorin (LCV) in metastatic colorectal carcinoma.
A Hellenic Cooperative Oncology Group study (abstract 978). Proc Am Soc Clin
Oncol 18:255a, 1999.
24. Gerard B, Bleiberg H, Van Daele D, et al: Oxaliplatin
combined to 5-fluorouracil and folinic acid: An effective therapy in patients
with advanced colorectal cancer. Anticancer Drugs 9:301-305,1998
25. Bensmaine MA, Marty M, de Gramont A, et al: Extended Access
French Program (EAFP) of oxaliplatin ± 5-FU in 5-FU
refractory colorectal cancer (RACRC) patients (abstract 973). Proc Am Soc Clin
Oncol 18:253a, 1999.
26. Adenis A, Douillard J, Lacroix H, et al: Randomized phase
II-III trial of oxaliplatin (OXA) with 5-fluorouracil (5-FU) continuous infusion
(CI) vs a control arm with either 5-FU or irinotecan (CPT11) in previously
treated metastatic colorectal cancer patients (abstract 1088). Proc Am Soc Clin
Oncol 19:279a, 2000.
27. Kouroussis CH, Mavroudis D, Giannakakis N, et al: Biweekly
oxaliplatin (L-OHP) with high-dose leucovorin (LV) and 5-fluorouracil (5-FU)
48-hour continuous infusion in pretreated patients with advanced colorectal
cancer (abstract 1111). Proc Am Soc Clin Oncol 18:290a, 1999.
28. Tournigand C, Louvet C, André T, et al: FOLFIRI followed by
FOLFOX or FOLFOX followed by FOLFIRI in metastatic colorectal cancer: Which is
the best sequence? Safety and preliminary efficacy results of a randomized phase
III study (abstract 949). Proc Am Soc Clin Oncol 19:245a, 2000.
29. Bleiberg H, Brienza S, Gerard B, et al: Oxaliplatin combined
with a high dose, 24-hour continuous 5-FU infusion and folinic acid based
regimen in patients with advanced colorectal cancer (abstract 1999). Proc Am Soc
Clin Oncol 18:241a, 1999.
30. Giacchetti S, Zidani R, Dogliotti L, et al: Chronotherapy of
metastatic colorectal cancer with 5-fluorouracil (5-FU)-leucovorin
(LV)-oxaliplatin (L-OHP) as second to seventh-line treatment (abstract 1255).
Proc Am Soc Clin Oncol 19:318a, 2000.
31. Scheihauer W, Kornek GV, Roderer M, et al: Combined
irinotecan and oxaliplatin plus granulocyte colony-stimulating factor in
patients with advanced fluoropyrimidine/leucovorin-pretreated colorectal cancer.
J Clin Oncol 17:902-906, 1999
32. Becouam Y, Mousseau M, Gamelin E, et al: CPT-11 and L-OHP
combination vs alternated combination of LV5FU2 +
CPT-11/LV5FU + L-OHP in 5-FU resistant advanced colorectal
cancer: Preliminary results (abstract 219). Eur J Cancer 35(suppl 4):1999.
33. Wasserman E, Kalla S, Misset JL, et al: Oxaliplatin (L-OHP)
and irinotecan (CPT11) phase I/II studies: Results in 5-FU refractory (FR)
colorectal cancer (CRC) patients (abstract 913). Proc Am Soc Clin Oncol 18:238a,
34. Calvo E, Gonzalez-Cao M, Cortes J, et al: Combined
irinotecan, oxaliplatin, 5-FU in patients with metastatic colorectal cancer
(abstract 1008). Proc Am Soc Clin Oncol 19:259a, 2000.