Evolution of FOLFOX Regimens in the Treatment of Advanced Colorectal Cancer

Research inBrief Evolution of FOLFOX Regimens in the Treatment of Advanced Colorectal Cancer Rationale

Figure 1: Schema of FOLFOX Regimens7-12

• The addition of oxaliplatin to 5-fluorouracil (5-FU)/leucovorin (LV) represents a significant advance in the treatment of early-stage and advanced-stage colorectal cancer (CRC).1 Oxaliplatin and 5-FU are associated with side effects that, although not altogether overlapping, can be severe and include neurologic, hematologic, and gastrointestinal adverse events.2 de Gramont et al of the GERCOR (Groupe d’Étude et de Récherche en Cancérologie Onco-Radiothérapic) cooperative in France have developed and successi vely con ducted a series of oxaliplatin/5-FU–based regimens over the past decade. The series of FOLFOX (5-FU/LV/oxaliplatin) regimens, FOLFOX1 to FOLFOX7, were investigated in successive efforts to optimize the therapeutic ratio of 5-FU/LV and oxaliplatin, and these regimens have been tested in the first-line and salvage settings. • The method of 5-FU/LV administration is at the heart of the evolution of the FOLFOX strategies. It has been well established that the incidence of gastrointestinal and hematologic toxicities is highly dependent on the dose and schedule of 5-FU/LV.3-6 Moreover, although neurotoxicity is the primary dose-limiting side effect observed with oxaliplatin, myelosuppression and gastrointestinal toxicities are also observed when it is used in combination with 5-FU/LV.2 The various FOLFOX regimens incorporate bimonthly administration of oxaliplatin with infusional schedules of 5-FU/LV, as outlined schematically in Figure 1.7-12 • de Gramont reviewed the clinical evolution of the FOLFOX regimens and disPrepared by: G. Kesava Reddy, PhD, Angelia D. Gibson, PhD, Nancy Price, PhD Reviewed by: Edward Chu, MD

FOLFOX 17 LV 500 mg/m2

5-FU 1500-2000 mg/m2

LV 500 mg/m2

OX: 130 mg/m2

Day 1

Day 2

5-FU 1500-2000 mg/m2

LV 500 mg/m2

Day 1

Day 2

5-FU 1500-2000 mg/m2

LV 500 mg/m2

Day 1

Day 2

5-FU 1500-2000 mg/m2

FOLFOX 28 LV 500 mg/m2 OX: 100

mg/m2

5-FU 1500-2000 mg/m2

FOLFOX 39 LV 500 mg/m2 mg/m2

OX: 85

FOLFOX 410

5-FU bolus 400 mg/m2

LV 200 mg/m2

5-FU 600 mg/m2

LV 200 mg/m2

OX: 85 mg/m2

Day 1

Day 2

FOLFOX 611 LV 400

5-FU 2400-3000 mg/m2

Day 1

mg/m2

FOLFOX 712

5-FU 600 mg/m2

5-FU bolus 400 mg/m2

mg/m2

OX: 100

5-FU 1500-2000 mg/m2

Day 2

5-FU bolus 400 mg/m2

LV 400 mg/m2 OX: 130 mg/m2

5-FU 2400 mg/m2

Day 1

Day 2

Abbreviation: OX = oxaliplatin

cussed future clinical optimization of the FOLFOX series at the 3rd International Colorectal Congress held in October 2004 in Aventura, FL. The clinical efficacy and toxicity data with these regimens in the salvage setting are presented in Table 1.8,10-12

Summary of the Evolution of FOLFOX Before oxaliplatin was incorporated into 5-FU–based strategies, clinical evaluation showed that different methods of administering 5-FU with LV modulation resulted in differing clinical efficacy as well as different spectrums and severity of toxicities.3-6 Randomized studies comparing bolus 5-FU with infusional schedules have consistently demonstrated higher response rates (RRs) with contin-

296 • Clinical Colorectal Cancer January 2005

uous 5-FU, albeit with minimal impact on overall survival (OS). Administration of the infusional schedules of 5-FU has resulted in a significant reduction in the overall toxicity of this therapy, specifically a marked decrease in the incidence of grade 3/4 neutropenia. However, an increased incidence of hand-foot syndrome as well as gastrointestinal toxicity in the form of diarrhea have been observed with infusional 5-FU. de Gramont et al subsequently developed a hybrid approach combining bolus 5-FU and infusional schedules of 5-FU. This strategy allowed the total administered dose of 5-FU to be increased. In addition, this combination resulted in a substantial improvement in clinical efficacy, with more than a 2-fold increase in overall RR with a reduction in toxicity.10

Table 1: Evolution of FOLFOX Regimen in Patients with Previously Treated CRC8,10-12 Regimen

Grade 3/4 Toxicities* Oxaliplatin ThromboMucositis/ Dose Nausea Diarrhea Neutropenia cytopenia Stomatitis

Efficacy Neurotoxicity

RR

OS PFS (Months) (Months)

FOLFOX28 (N = 46)†

100 mg/m2

4%

9%

13%

39%

11%

9%

46%

17

7

FOLFOX310 (N = 38)

85 mg/m2

5%

5%

17.5%

15%

3%

27.5%

18.4%

10.6

4.6

FOLFOX410 (N = 51)

85 mg/m2

7%

5.2%

5.3%

36.9%

7%

15.8%

23.5%

11.1

5.1

FOLFOX611† (N = 60)

100 mg/m2

7%

7%

5%

24%

2%

16%

27%

10.8

5.3

FOLFOX712† (N = 48)

130 mg/m2

8%

11%

0

9%

11%

15%‡

42%

16.1

6‡

*Toxicity

by World Health Organziation criteria.

†Includes patients previously treated for colorectal cancer but who had not previously received irinotecan. ‡Includes 11% neurotoxicity after chemotherapy.

Varying the Oxaliplatin Dose with an Infusional Regimen of 5-FU/LV: FOLFOX2 and 3 The combination of 5-FU/LV and oxaliplatin was investigated initially using a chronomodulated strategy. Levi et al evaluated 5-FU 700 mg/m2 per day, LV 300 mg/m2 per day, and oxaliplatin 25 mg/m2 per day, infused continuously but with the intensity modulated over the course of each day, for 5 days every 3 weeks in patients who had been previously treated.13 A phase III trial was subsequently conducted in the first-line setting comparing continuous nonchronologic administration directly with the chronomodulated schedule.14 The chronomodulation strategy significantly improved the RR and safety profile of the regimen. A 24-hour continuous infusion of 5FU/LV over 2 days allowed the dose of 5-FU to be increased to 2-fold higher than the dose administered via the chronomodulation schedule (3500 mg/m2 every 3 weeks compared with 3000-4000 mg/m2 every 2 weeks). In an initial feasibility study (FOLFOX1) conducted in pretreated patients, oxaliplatin 135 mg/m2 was given over 2 hours on day 1 with LV 500 mg/m2 followed by a continuous 24-hour infusion of 5-FU 1500-2000 mg/m2 given on days 1 and 2 with cycles repeating biweekly.7 Four of the 10 pretreated

patients had a clinical response. The dose-limiting toxicities of this regimen were mucositis and neutropenia. The FOLFOX3 regimen had reduced doses of oxaliplatin 85 mg/m2 versus FOLFOX2 with oxaliplatin 100 mg/m2 in an effort to reduce the neurotoxicity observed with FOLFOX2.8,9 Although gastrointestinal, hematologic, and neurologic toxicities were reduced with this strategy, the RR decreased from 46% with FOLFOX2 to approximately 20% with FOLFOX3 in similar patient populations.

Introducing Bolus Schedules of 5-FU Within the FOLFOX Regimen: FOLFOX4 The FOLFOX4 regimen was developed in an effort to maintain the lower incidence of toxicity seen with FOLFOX2 and FOLFOX3, but regain the efficacy demonstrated in the earlier trials.9,10 To achieve this goal, boluses of 5-FU were included on days 1 and 2, with a low-dose 5-FU infusion administered over 22 hours on days 1 and 2 in combination with oxaliplatin 85 mg/m2 every 14 days. This regimen was then directly compared with FOLFOX3 in a randomized trial.10 The FOLFOX4 regimen maintained a favorable gastrointestinal toxicity profile but resulted in a higher rate of neutropenia, which was believed to be largely caused by

the 5-FU bolus. Nevertheless, the therapeutic ratio was favorable, with an RR of 23.5% in previously treated patients and median progression-free survival (PFS) and OS of 5.1 months and 11.1 months, respectively. In comparison, the RR in the FOLFOX3 arm was 18.4%, the PFS was 4.6 months, and the OS was 10.6 months. FOLFOX4 was developed further in the first-line setting in phase III trials, in which it was found to be significantly more effective in terms of median OS, time to tumor progression, and overall RR compared with the bolus weekly schedule of IFL (irinotecan/5FU/LV) or the Roswell Park schedule of 5-FU/LV as first-line therapy for advanced CRC.15

Increasing the Oxaliplatin Dose and Simplifying the 5-FU/LV Regimen: FOLFOX6 The FOLFOX6 regimen incorporated a higher dose of oxaliplatin (100 mg/m2) on day 1 with a simplified 5FU/LV administration schedule: a single dose of LV and bolus 5-FU followed by a single continuous 46-hour infusion of 5-FU every 2 weeks.11 In first- and second-line settings, treatment with FOLFOX6 yielded overall RRs of 54% and 27%, respectively, and produced similar OS and PFS compared with previous FOLFOX regimens.

Clinical Colorectal Cancer January 2005

• 297

Figure 2: OPTIMOX 1 Study Design

Patients with CRC

R A N D O M I Z E

FOLFOX4 until disease progression

FOLFOX7 × 6 cycles 5-FU/LV × 12 cycles FOLFOX7 × 6 cycles

Maximizing Dose Intensity of Oxaliplatin: FOLFOX7 The FOLFOX7 regimen was subsequently developed to maximize the dose intensity of oxaliplatin, and, according to de Gramont, this particular combination has emerged as the FOLFOX regimen with the optimal therapeutic ratio.12 FOLFOX7 incorporated the same simplified infusion schedule of 5-FU as was delivered with FOLFOX6 but used a higher dose of oxaliplatin (130 mg/m2). In a phase II study in previously treated patients, FOLFOX7 resulted in a 42% RR and a median OS of 16.1 months, similar to the clinical efficacy observed earlier with high-dose oxaliplatin in FOLFOX2. Because a higher dose of oxaliplatin was used in FOLFOX7, the incidence of gastrointestinal toxicities was slightly higher than had been previously observed with other FOLFOX regimens that used lower oxaliplatin doses. However, the incidence of hematologic toxicity was lower.

A Phase III Comparison of FOLFOX4 and FOLFOX7: OPTIMOX 1 The FOLFOX7 regimen was selected for further testing in the first-line setting in the OPTIMOX 1 trial (Figure 2)17 in which it was compared directly with the FOLFOX4 regimen, which previously had yielded promising results in the first- and second-line settings. To reduce the incidence of oxaliplatin-associated neurotoxicity, patients enrolled in the FOLFOX7 arm of the OPTIMOX trial received intermittent exposure to oxaliplatin: 6 cycles of FOLFOX7 followed by 12 cycles of 5-FU/LV and then reintroduction of oxaliplatin for an additional 6 cycles of FOLFOX7. The modified

Table 2: OPTIMOX 1 Study: Efficacy and Toxicity Data16 FOLFOX7 (N = 264)

FOLFOX4 (N = 262)

P Value

Overall Response Rate

58.3%

58.6%

NS

Complete Response

8.7%

7.4%

NR

Partial Response

49.6%

51.2%

NR

Progression-Free Survival

9.0 Months

9.2 Months

0.47

Overall Survival

21.6 Months

20.0 Months

0.68

Time of Disease Control*

8.7 Months

8.2 Months

0.84

Neutropenia

21.9%

33.2%

0.013

Thrombocytopenia

10.6%

3.1%

0.0006

Nausea

9.4%

5.7%

NS

Diarrhea

11.8%

11.1%

NS

7 Patients

6 Patients

NR

Response

Toxicity

Death within 60 days

Abbreviations: NR = Not reported; NS = not significant *Time of disease control = PFS first FOLFOX + PFS reintroduction if PR or SD.

schedule in FOLFOX7 resulted in lower cumulative doses of oxaliplatin, potentially reducing the development of chronic neurotoxicity. Overall, the intermittent FOLFOX7 regimen appeared to be less toxic compared with FOLFOX4 (Table 2). The incidence of grade 3/4 neutropenia was reduced significantly in patients treated with the FOLFOX7 regimen (21.9%) compared with FOLFOX4 (33.2%; P = 0.013). However, there was a higher incidence of grade 3/4 thrombocytopenia with the FOLFOX7 regimen (10.6%) than with FOLFOX4 (3.1%; P = 0.0006). With respect to clinical efficacy, the median OS at the time of the original analysis was not significantly different between the 2 treatment arms at 20.0 months for patients in the FOLFOX4 arm and 21.6 months for the patients in the FOLFOX7 arm. In addition, the FOLFOX7 and FOLFOX4 regimens achieved comparable response and resection rates in patients with advanced CRC (Table 2), as well as similar total disease control rates. A follow-up analysis has revealed a series of protocol violations relating to the reintroduction of FOLFOX that may have masked differences in outcome be-

298 • Clinical Colorectal Cancer January 2005

tween the 2 regimens. Only 40% of the patients randomized to the FOLFOX7 arm received the scheduled reintroduction of FOLFOX7. Moreover, depending on the particular treatment center, as many of 50% of patients who were randomized to receive FOLFOX4 received additional cycles of oxaliplatin beyond the 6 courses specified by the protocol in the FOLFOX4 treatments. In the multivariate analyses, patients who were reexposed to oxaliplatin had significantly improved median OS compared with those who received only 6 courses of treatment.

Clinical Relevance The combination of oxaliplatin and 5-FU/LV has demonstrated significant clinical activity in patients with advanced CRC in the first-line and salvage settings. The GERCOR cooperative group was instrumental in systematically evaluating several variations of the FOLFOX regimens in phase II/III trials. These regimens all used bimonthly administration of 5-FU/LV and oxaliplatin, but they differed with respect to the oxaliplatin dose (85 mg/m2, 100 mg/m2, or 130 mg/m2), the schedule of infusional 5-FU (two 24hour infusions or one 48-hour infu-

sion), and the inclusion of bolus 5-FU. In the United States, the FOLFOX4 regimen has become the most widely used of these regimens. However, there is growing evidence that the FOLFOX7 regimen, which incorporates high-dose oxaliplatin and a 48-hour infusion of 5-FU with no bolus 5-FU, yields higher RRs and reduced hematologic and neurologic toxicity compared with previous FOLFOX regimens, including FOLFOX4. The OPTIMOX study showed that FOLFOX7 and FOLFOX4 were similar in efficacy for the first-line treatment of advanced CRC.17 The OPTIMOX study also demonstrated that reintroduction of oxaliplatin at the time of disease progression in patients who exhibit stable disease or a response after initial treatment is feasible and does not compromise survival.

References

1. Rothenberg ML, Oza AM, Bigelow RH, et al. Superiority of oxaliplatin and fluorouracil-leucovorin compared with either therapy alone in patients with progressive colorectal cancer after irinotecan and fluorouracil-leucovorin: interim results of a phase III trial. J Clin Oncol 2003; 21:2059-2069. 2. Extra JM, Espie M, Calvo F, et al. Phase I study of oxaliplatin in patients with advanced cancer. Cancer Chemother Pharmacol 1990; 25:299-303. 3. Buroker TR, O’Connell MJ, Wieand HS,

4.

5.

6.

7.

8.

9.

10.

et al. Randomized comparison of two schedules of fluorouracil and leucovorin in the treatment of advanced colorectal cancer. J Clin Oncol 1994;12:14-20. Weinerman B, Shah A, Fields A, et al. Systemic infusion versus bolus chemotherapy with 5-fluorouracil in measurable metastatic colorectal cancer. Am J Clin Oncol 1992; 15:518-523. de Gramont A, Bosset JF, Milan C, et al. Randomized trial comparing monthly low-dose leucovorin and fluorouracil bolus with bimonthly high-dose leucovorin and fluorouracil bolus plus continuous infusion for advanced colorectal cancer: a French intergroup study. J Clin Oncol 1997; 15:808-815. Petrelli N, Herrera L, Rustum Y, et al. A prospective randomized trial of 5-fluorouracil versus 5-fluorouracil and highdose leucovorin versus 5-fluorouracil and methotrexate in previously untreated patients with advanced colorectal carcinoma. J Clin Oncol 1987; 5:1559-1565. de Gramont A, Gastiaburu J, Tournigand C, et al. Oxaliplatin with high-dose folinic acid and 5-fluorouracil 48 hours infusion in pretreated metastatic colorectal cancer. Proc Am Soc Clin Oncol 1994; 13:220 (Abstract #666). de Gramont A, Vignoud J, Tournigand C, et al. Oxaliplatin with high-dose leucovorin and 5-fluorouracil 48-hour continous infusion in pretreated metastatic colorectal cancer. Eur J Cancer 1997; 33:214-219. 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 5fluorouracil regimen. Ann Oncol 1998; 9:1251-1253. Andre T, Bensmaine MA, Louvet C, et al. Multicenter phase II study of bimonthly high-dose leucovorin, fluo-

11.

12.

13.

14.

15.

16.

rouracil infusion, and oxaliplatin for metastatic colorectal cancer resistant to the same leucovorin and fluorouracil regimen. J Clin Oncol 1999; 17:3560-3568. 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 1999; 35:1338-1342. Maindrault-Goebel F, de Gramont A, Louvet C, et al. High-dose intensity oxaliplatin added to the simplified bimonthly leucovorin and 5-fluorouracil regimen as second-line therapy for metastatic colorectal cancer (FOLFOX 7). Eur J Cancer 2001; 37:1000-1005. Levi F, Misset JL, Bienz S, et al. A chronopharmacologic phase II clinical trial with 5-fluorouracil, folinic acid and oxaliplatin using an ambulatory multichannel programmable pump. Cancer 1992; 69:893-900. Levi FA, Zidani R, Vannetzel JM, et al. Chronomodulated versus fixed-infusionrate delivery of ambulatory chemotherapy with oxaliplatin, fluorouracil, and folinic acid (leucovorin) in patients with colorectal cancer metastases: a randomized multi-institutional trial. J Natl Cancer Inst 1994; 86:1608-1617. Goldberg RM, Sargent DJ, Morton RF, et al. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 2004; 22:23-30. de Gramont A, Cervantes A, Andre T, et al. OPTIMOX study: FOLFOX7/ LV5FU2 compared to FOLFOX 4 in patients with advanced colorectal cancer. Proc Am Soc Clin Oncol 2004; 23:251 (Abstract #3525).

Clinical Colorectal Cancer January 2005

• 299