FOLFOX4 Arm Research Articles

Oxaliplatin/5FU/LV in the adjuvant treatment of stage II and stage III colon cancer: Efficacy results with a median follow-up of 4 years

3501 Background: MOSAIC trial was designed to demonstrate an increase in Disease Free Survival (DFS) in stage II and III colon cancer. Methods: 2246 patients with completely resected stage II (40%) or III (60%) colon cancer were randomly assigned to receive LV5FU2 or FOLFOX4 every 2 weeks for 12 cycles. Results: Final results of the study have been reported for the overall population, with a median follow-up (mFUP) of 3 years (Andre et Al, NEJM, 2004). With a mFUP of 4 years (48.6 months), a 24% reduction in the relative risk of relapse was observed with the FOLFOX4 combination in the overall population (p=0.0008). For stage III patients, the probability of remaining disease free at 4 years is 61.0% in the LV5FU2 arm and 69.7% in the FOLFOX4 arm, translating into a relative risk reduction of 25% in this subset of patients For stage II patients, 4-year DFS was 81.3% in the LV5FU2 arm versus 85.1% in the FOLFOX4 arm (relative risk reduction of 20%). In the overall population, 84.3% and 82.7% patients are still alive respectively in the FOLFOX4 and LV5FU2 arms. Follow-up is ongoing for a minimum of 5 years for each patient for final survival analysis. After mFUP of 4 years, about 3% (3.4%) of patients presented either with persisting localized paresthesias of moderate intensity (2.7%) or with paresthesias that may interfere with functional activities (0.7%). Conclusions: Based on these results, FOLFOX4 is now a standard treatment for patients with early stage colon cancer. No significant financial relationships to disclose.

N9841: A randomized phase III equivalence trial of irinotecan (CPT-11) versus oxaliplatin/5-fluorouracil (5FU)/leucovorin (FOLFOX4) in patients (pts) with advanced colorectal cancer (CRC) previously treated with 5FU

3506 Background: Single agent CPT-11 is indicated as standard treatment (Rx) for pts with CRC who failed prior 5FU based Rx. FOLFOX4 is active as 1st and 2nd line Rx of CRC. The primary goal of this trial was to determine whether overall survival (OS) of pts treated with 2nd line CPT-11 (Arm A) was equivalent to Rx with 2nd line FOLFOX4 (Arm B). Pts were to cross-over to the other Rx after 2nd line failure. Methods: Eligible pts had failed one prior 5FU based Rx, either for metastatic disease or ≤ 6 months of adjuvant 5FU Rx. Initial protocol Rx (doses in mg/m2) for Arm A: CPT-11 350 d1 q3w (300 for ECOG performance status = 2, age ≥ 70, or prior pelvic radiation) and Arm B: OXAL 85 d1 + LV 200/5FU 400 bolus + 600 as a 22 hour infusion d1, 2 q2w. Final analysis was scheduled after 405 deaths to have 82% power to detect non-equivalence at a hazard ratio of 1.25. Results: 491 pts were randomized to Rx between 10/99 to12/03 (245-A, 246-B). 289 pts (59%) failed previous 5FU for metastatic CRC. 82% of pts have died. 220 pts (45%) received protocol mandated 3rd line therapy (A-57%, B-43%). Efficacy results (including OS, time to progression (TTP), and response rate (RR)) and common grade 3+ toxicities on initial Rx are shown in the table below. 16 pts died < 60 days of study entry (A-5%, B-2%, p = 0.12). 2nd line Rx with CPT-11 was associated with more grade ≥ 3 nausea, vomiting, diarrhea, and febrile neutropenia; FOLFOX4 had more neutropenia and parasthesias. Conclusions: In pts failing prior 5FU Rx for CRC, OS is not significantly different based on whether 2nd line Rx begins with either CPT-11 or FOLFOX4 (HR=1.04, 95% CI 0.9–1.3). 2nd line Rx with FOLFOX4 produces a higher RR and a trend toward longer TTP. Both arms had notable OS in pts who had failed 1st line 5FU Rx. Supported by NIH Grant CA25224 and Sanofi-Synthelabo. Efficacy & Toxicity (≥ Grade 3), by Initial Rx Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca, Genentech, Lilly Oncology, Pfizer, Sanofi Pfizer, Sanofi Pfiizer, Sanofi Sanofi

A comparison of simple single-item measures and the common toxicity criteria in detecting the onset of oxaliplatin-induced peripheral neuropathy in patients with colorectal cancer

8087 Background: Peripheral neuropathy (PN) is a common and intrusive side effect of chemotherapy. The assessment of PN is typically done via the common toxicity criteria (CTC). To date there is no optimal measure of peripheral neuropathy. We developed simple single-item numerical analogue scale (NAS) assessments for the unique oxaliplatin-induced PN. The purpose of this investigation was to asses the relative sensitivity of the CTC and NAS measures in detecting the onset and severity of PN in patients receiving oxaliplatin. Methods: 696 patients randomized to the FOLFOX4 arm of the the practice-changing inter-group/NCCTG study N9741 provided data on the incidence and severity of PN experienced via bi-weekly CTC assessments and NAS measurements taken every 12 weeks. The NAS is a simple measure from 0 representing no PN to 10 representing PN as bad as it can be. A change of 2 points from baseline on the NAS was used as a conservative estimate of a clinically meaningful change in PN. Results: 276 patients (40%) reported a 2 point worsening from baseline in PN via NAS compared to 256 (37%) with a CTC reported grade 2+ PN and 99 (14%) with a CTC reported grade 3+ PN. For those ultimately reporting PN, median dose to onset of a clinically significant worsening of PN via NAS was 424 mg/m2 relative to a dose to grade 2+ (3+) PN of 765 (961) mg/m2 for CTC criteria. This means that patients notice an increase in PN about two or three months earlier via the NAS relative to the CTC. Agreement between CTC grade 2+ (3+) PN and NAS assessment was only 65% (63%) with a Cohen’s Kappa of 0.26 (0.13). The majority of patients reported the 2 point decline in PN via NAS prior to their reported CTC PN event (53% for grade 2+, 83% for grade 3+). Conclusions: The CTC measurement of PN under-reports the incidence and time to onset of PN relative to simple single-item NAS measures. Grade 2 PN via the CTC is a clinically significant problem according to patient ratings on the NAS. In future studies, it is recommended that the CTC be supplemented by patient-reported measures of PN. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Sanofi, sanofi-aventis Sanofi, sanofi-aventis

Randomized Multicenter Phase II Trial of Bolus Plus Infusional Fluorouracil/Leucovorin Compared With Fluorouracil/Leucovorin Plus Oxaliplatin As Third-Line Treatment of Patients With Advanced Colorectal Cancer

The addition of oxaliplatin to fluorouracil (FU) and leucovorin (LV) improves the outcome of patients with colorectal cancer (CRC). This multicenter study evaluated FU/LV with or without oxaliplatin in patients with metastatic CRC after disease progression on sequential fluoropyrimidine and irinotecan. Two hundred fourteen patients were randomly assigned to receive LV 200 mg/m2 intravenously (IV) and FU 400 mg/m2 IV bolus, followed by FU 600 mg/m2 IV over 22 hours on days 1 and 2, every 2 weeks (LV5FU2); or LV and FU as described, plus oxaliplatin 85 mg/m2 IV over 2 hours on day 1 of the schedule (FOLFOX4). The primary end point was overall response. Baseline characteristics were similar in the two treatment arms. Objective response (complete + partial) rates for LV5FU2 versus FOLFOX4 were 2% v 13% (P = .0027), respectively. Median time to disease progression was 2.4 v 4.8 months (P < .0001), and median survival was 11.4 v 9.9 months (P = .20) for LV5FU2 and FOLFOX4, respectively. Among the 72 patients who crossed over from LV5FU2 to FOLFOX4, 6% responded. Symptomatic improvement was significantly better for patients in the FOLFOX4 arm (32% v 18% for LV5FU2, P = .05). Grade 3/4 toxicities for LV5FU2 and FOLFOX4 were neutropenia (13% and 42%, respectively), diarrhea (6% and 16%, respectively), and overall neuropathy (0% and 6%, respectively). In patients with metastatic CRC, the FOLFOX4 regimen was superior to LV5FU2 with a higher response rate and time to disease progression. FOLFOX4 is an effective regimen even after disease progression on two previous chemotherapy regimens with fluoropyrimidines and irinotecan.

5-Fluorouracil, folinic acid and oxaliplatin (FOLFOX) in poor prognosis patients with metastatic colorectal cancer

3565 Background: High alkaline phosphatases (Alk Ph) level is an adverse prognostic factor in patients (pts) with metastatic colo-rectal cancer (CRC). Pts with Alk Ph level over 3-time the upper normal value (UNV) were excluded from previous studies. OPTIMOX trial consisted in a phase III study for pts with conventional inclusion criteria (526 pts), comparing FOLFOX4 to FOLFOX7 x 6 cycles, followed simplified LV5FU2 x 12 cycles and FOLFOX7 reintroduction; and two exploratory studies in pts > 75 yrs (37 pts) and in pts with Alk Ph level > 3-time the UNV (63 pts), treated according to the same regimens. Methods: This report concerns the tolerance and the efficacy observed for the 63 pts with an initial Alk Ph level over 3-time the UNV. 33 pts were treated with FOLFOX4 (arm A), and 30 with FOLFOX7 - sLV5FU2 - FOLFOX7 (arm B). Characteristics of these pts were : PS 0/1–2=26/74%, median age 63 yrs; LDH (normal / > normal) 6%/94%, metastatic site (1/ > 1) 70/30%. Results: 60 pts (766 cycles) and 54 pts are eval...

5-fluorouracil, folinic acid and oxaliplatin (FOLFOX) in very old patients with metastatic colorectal cancer

3571 Background: Pts with age over 75 years are usually excluded from randomised studies. OPTIMOX trial consisted in a phase III study for pts with conventional inclusion criteria (526 pts), comparing FOLFOX4 to FOLFOX7 x 6 cycles, followed simplified LV5FU2 x 12 cycles and FOLFOX7 reintroduction; and two exploratory studies in pts > 75 yrs (37 pts) and in pts with Alk Ph level > 3-time the UNV (63 pts), treated according to the same regimens. Methods: This report concerns the tolerance and the efficacy observed for the 37 pts aged 75 years or older. 20 pts were treated with FOLFOX4 (arm A), and 17 with FOLFOX7 - sLV5FU2 - FOLFOX7 (arm B). Characteristics of these pts were : PS 0/1–2=49/51%, LDH (normal / > normal / unknown) 51%/27%/22%, metastatic site (1/ > 1) 73/27%, alk phosp (nl/elevated/unknown) 59%/35%/6%. Results: 37 pts are evaluable for safety and 35 pts for response. Grade 3–4 toxicities (% of pts, arm A / arm B) were: neutrophils 55/24, platelets 5/0, hemoglobin 5/0, nausea-vomiting 0/12, diarrhea 5/6, neurotoxicity 20/24. Maximal toxicity per patient was grade 3–4 in 80% of arm A pts, and 59% of arm B pts. Response rate (intent-to-treat) was 59.4 % (arm A 65%; arm B 53%). Median PFS was 37 weeks (arm A 33 w; arm B 41 w) and median OS was 79 weeks (arm A 65w and arm B 90w). Moreover, in OPTIMOX study, age does not appear as a prognosis factor in a multivariate analysis. Conclusion: These results indicate that efficacy is maintained with Folfox regimens in patients >75years. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Sanofi

5-fluorouracil, folinic acid and oxaliplatin (FOLFOX) in very old patients with metastatic colorectal cancer

3571 Background: Pts with age over 75 years are usually excluded from randomised studies. OPTIMOX trial consisted in a phase III study for pts with conventional inclusion criteria (526 pts), comparing FOLFOX4 to FOLFOX7 x 6 cycles, followed simplified LV5FU2 x 12 cycles and FOLFOX7 reintroduction; and two exploratory studies in pts > 75 yrs (37 pts) and in pts with Alk Ph level > 3-time the UNV (63 pts), treated according to the same regimens. Methods: This report concerns the tolerance and the efficacy observed for the 37 pts aged 75 years or older. 20 pts were treated with FOLFOX4 (arm A), and 17 with FOLFOX7 - sLV5FU2 - FOLFOX7 (arm B). Characteristics of these pts were : PS 0/1–2=49/51%, LDH (normal / > normal / unknown) 51%/27%/22%, metastatic site (1/ > 1) 73/27%, alk phosp (nl/elevated/unknown) 59%/35%/6%. Results: 37 pts are evaluable for safety and 35 pts for response. Grade 3–4 toxicities (% of pts, arm A / arm B) were: neutrophils 55/24, platelets 5/0, hemoglobin 5/0, nausea-vomiting 0/12, diarrhea 5/6, neurotoxicity 20/24. Maximal toxicity per patient was grade 3–4 in 80% of arm A pts, and 59% of arm B pts. Response rate (intent-to-treat) was 59.4 % (arm A 65%; arm B 53%). Median PFS was 37 weeks (arm A 33 w; arm B 41 w) and median OS was 79 weeks (arm A 65w and arm B 90w). Moreover, in OPTIMOX study, age does not appear as a prognosis factor in a multivariate analysis. Conclusion: These results indicate that efficacy is maintained with Folfox regimens in patients >75years. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Sanofi

5-Fluorouracil, folinic acid and oxaliplatin (FOLFOX) in poor prognosis patients with metastatic colorectal cancer

3565 Background: High alkaline phosphatases (Alk Ph) level is an adverse prognostic factor in patients (pts) with metastatic colo-rectal cancer (CRC). Pts with Alk Ph level over 3-time the upper normal value (UNV) were excluded from previous studies. OPTIMOX trial consisted in a phase III study for pts with conventional inclusion criteria (526 pts), comparing FOLFOX4 to FOLFOX7 x 6 cycles, followed simplified LV5FU2 x 12 cycles and FOLFOX7 reintroduction; and two exploratory studies in pts > 75 yrs (37 pts) and in pts with Alk Ph level > 3-time the UNV (63 pts), treated according to the same regimens. Methods: This report concerns the tolerance and the efficacy observed for the 63 pts with an initial Alk Ph level over 3-time the UNV. 33 pts were treated with FOLFOX4 (arm A), and 30 with FOLFOX7 - sLV5FU2 - FOLFOX7 (arm B). Characteristics of these pts were : PS 0/1–2=26/74%, median age 63 yrs; LDH (normal / > normal) 6%/94%, metastatic site (1/ > 1) 70/30%. Results: 60 pts (766 cycles) and 54 pts are evaluable for safety and response, respectively. 2 pts benefited from metastasis removal. Grade 3–4 toxicities (% of pts, arm A / arm B) were: neutrophils 15.2/10.0, platelets 9.1/3.3, hemoglobin 9.1/3.3, nausea-vomiting 0/10.0, diarrhea 6.1/6.7, neurotoxicity 9.1/10.0. Maximal toxicity per patient was grade 3–4 in 42.4% of arm A pts, and 33.4% of arm B pts. Response rate (intent-to-treat) was 55.6 % (arm A 48.5%; arm B 63.3%). Median PFS was 28 weeks (arm A 29 w; arm B 28 w) and median OS was 50 weeks (arm A 61w and arm B 48 w). Conclusion: These safety and efficacy results incite to propose FOLFOX regimens (either FOLFOX4 or FOLFOX7) in poor prognosis pts with metastatic colorectal cancer. No significant financial relationships to disclose.

FOLFOX4 as adjuvant treatment for stage II colon cancer (CC): Subpopulation data from the MOSAIC trial

3619 Background: Currently, stage II (Dukes B2) CC patients (pts) are included in clinical trials testing adjuvant chemotherapy as benefit of such treatment remains to be confirmed for these pts. Methods: FOLFOX4 [oxaliplatin/5-Fluorouracil (5FU)/leucovorin (LV)] is the first combination which improves 3-year disease free survival (DFS) (78.2%) when compared with 5-FU/LV (LV5FU2) alone (72.9%) in stage II/III CC as demonstrated in a large phase III randomized study (MOSAIC). The decrease in the risk of recurrence (RRR) is 23% in the overall population (p=0.002) (de Gramont, ASCO 2003). Stage II sub population data are presented here. Results: 40% of the 2246 patients were stage II: 451 in FOLFOX4, and 448 in LV5FU2; main characteristics were well balanced between the 2 groups with respectively for FOLFOX4/LV5FU2 (%): Male 57/52, median age (years) 61/60, colon 57/56, sigmoid 32/34, recto-sigmoid 11/9, KPS ≥ 80%: 88/ 90, Bowel obstruction: 16/19, Tumor perforation: 8/10, T4 (%)19/19, venous invasion: 8/10. The observed reduced risk of recurrence with FOLFOX4 was consistent in both stage II and stage III as shown by a non-significant treatment-by-stage interaction (p=0.77). Overall per patient major safety events on study [incidence of SAE, treatment discontinuation and/or death] were less frequent in stage II (19.8%) than in stage III (25.6%). Conclusion: In the FOLFOX4 arm of MOSAIC, stage II patients benefited from a 20% relative reduction in the risk of recurrence versus those of the LV5FU2 arm with a limited incidence of major safety events. This reflects the favorable benefit-risk of FOLFOX4 in this population. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Sanofi-Synthelabo Sanofi-Synthelabo

FOLFOX4 as adjuvant treatment for stage II colon cancer (CC): Subpopulation data from the MOSAIC trial

3619 Background: Currently, stage II (Dukes B2) CC patients (pts) are included in clinical trials testing adjuvant chemotherapy as benefit of such treatment remains to be confirmed for these pts. Methods: FOLFOX4 [oxaliplatin/5-Fluorouracil (5FU)/leucovorin (LV)] is the first combination which improves 3-year disease free survival (DFS) (78.2%) when compared with 5-FU/LV (LV5FU2) alone (72.9%) in stage II/III CC as demonstrated in a large phase III randomized study (MOSAIC). The decrease in the risk of recurrence (RRR) is 23% in the overall population (p=0.002) (de Gramont, ASCO 2003). Stage II sub population data are presented here. Results: 40% of the 2246 patients were stage II: 451 in FOLFOX4, and 448 in LV5FU2; main characteristics were well balanced between the 2 groups with respectively for FOLFOX4/LV5FU2 (%): Male 57/52, median age (years) 61/60, colon 57/56, sigmoid 32/34, recto-sigmoid 11/9, KPS ≥ 80%: 88/ 90, Bowel obstruction: 16/19, Tumor perforation: 8/10, T4 (%)19/19, venous invasion: 8/10. The observed reduced risk of recurrence with FOLFOX4 was consistent in both stage II and stage III as shown by a non-significant treatment-by-stage interaction (p=0.77). Overall per patient major safety events on study [incidence of SAE, treatment discontinuation and/or death] were less frequent in stage II (19.8%) than in stage III (25.6%). Conclusion: In the FOLFOX4 arm of MOSAIC, stage II patients benefited from a 20% relative reduction in the risk of recurrence versus those of the LV5FU2 arm with a limited incidence of major safety events. This reflects the favorable benefit-risk of FOLFOX4 in this population. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Sanofi-Synthelabo Sanofi-Synthelabo