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FOLFOX4: Rationale for use in adjuvant  therapy


FOLFOX4 in metastatic disease


Development of the FOLFOX4 regimen has taken place in patients with metastatic colon cancer. A large Phase III study in patients who had progressed after an IFL regimen  (ironotecan, bolus 5-FU, and leucovorin) showed that the FOLFOX4 regimen was active (1) but more toxic than a 5FU/leucovorin regimen. 


In this study 463 patients from 120 sites in North America were randomized. 



The trial found that FOLFOX4 proved superior to LV5FU2. Objective RRs were 9.9% for FOLFOX4 versus 0% for LV5FU2 (P < 0.0001). Median TTP was 4.6 months for FOLFOX4 versus 2.7 months for LV5FU2 (P < 0.0001). Single-agent oxaliplatin was not superior to LV5FU2 in any measure of efficacy. 



Patients treated with FOLFOX4 experienced a higher incidence of clinically significant toxicities than patients treated with LV5FU2, but these toxicities were predictable and did not result in a higher rate of treatment discontinuation.



Patients treated with FOLFOX4 experienced a higher incidence of clinically significant toxicities than patients treated with LV5FU2, but these toxicities were predictable and did not result in a higher rate of treatment discontinuation and did not lead to a increased rate of treatment related mortality in patients with metastatic colorectal cancer,


Although FOLFOX4 was more toxic than a 5FU/leucovorin regimen, its toxicity when used as frontline therapy for metastatic disease and as assessed versus some CPT-11 based regimens was acceptable (2). 


FOLFOX4 in Adjuvant Therapy


The FOLFOX4 regimen has been compared a standard 5FU/leucovorin regimen in the MOSAIC adjuvant therapy trial reported for safety (3) and for efficacy (4) at 3 years of follow-up at the 2002 and 2003 ASCO meetings. More recently these results have been published (5). An update principally relating to longer term efficacy and toxicity (neutotoxicity) at approximately 56 months of follow-up was presented at the 2005 ASCO meeting (6). 


Patients (n=2246) with Stage 2 (40%)  and Stage 3 (60%) disease were randomized in this trial. Median age was 60.  High risk features such as perforation and obstruction were seen in 7% and 18% of the patients respectively. 54% of the patients were male. Total dose intensity was well maintained in both arms, but there were more dose reductions in the FOLFOX4 arm.  Dose intensities were 81% and 85% for oxaloplatin and 5FU in the FOLFOX4 arm. Dose intensity was 98% for the 5FU in the 5FU leucovorin arm. Fewer patients completed all cycles of therapy on the FOLFOX4 arm than on the 5FU/leucovorin arm (75% vs 86%). 



Overall FOLFOX4 appeared more effective in preventing recurrence than 5FU/ leucovorin. In the clinical trial population as a whole there was a 23% reduction in the hazard rate of recurrence. A 24% hazard rate reduction was seen in the Stage 3 patients. There was a suggestion of benefit in Stage 2 patients (an 18% hazard rate reduction) , but at 56 months of follow-up this was not statistically significant, and the trial is underpowered to make an statements about relative efficacy in Stage II and Stage III patients of FOLFOX4. 


Exploratory analyses were done in patient subsets (by sex, age, T stage, N stage, presence of obstruction, presence of perforation, or histologic grade) and no subgroups were identified that in which benefit was shown not to occur.  For patients with high risk Stage 2 disease (T4 and/or bowel perforation and/or poorly differeniated tumor and/or vascular invasion and/or < 10 examined lymph nodes) the hazard ratio (0.76) improvement was similar to that seen in Stage III patients. 


There was a trend (a 9% hazard rate reduction) for better overall survival for patients getting FOLFOX, but it was statistically significant ovall or in Stage III of Stage II subsets of patients. 




In the adjuvant arena FOLFOX4 was more toxic than 5FU/leucovorin. Overall the toxicity was manageable. 


Although some peripheral neuropathy was present in 92% of patients getting the FOLFOX regimen, in about half of these patients it was Grade 1 (mild), and in about half of the patients it was Grade 2 (moderate). Only 12.4% of the patients experienced more severe neuropathy (Grade 3 ).  The ASCO 2005 presentation showed that this neurotoxicity could be persistant, but did gradually resolve. Of the patients with Grade 3 neurotoxicity the median time to resolution of Grade 2 or less was about 10 weeks. The median time to complete resolution to Grade 0 was about 1 year.  For a few patients the neurotoxicity was very persistent with at 4 years of follow-up 3.4% of the FOLFOX4 treated patients had either with persisting localized paresthesias of moderate intensity (2.7%) or with paresthesias that may interfere with functional activities (0.7%).


Mortality during or within 1 month of treatment occurred in 6 patients in each treatment group (representing less than 1% of the 1108 patients getting FOLFOX and less than 1% of the patients getting the 5FU leucovorin regimen. For the patients getting FOLFOX there were slightly more deaths due to infection (4 deaths) than with the other treatment (1 death) but this was less than 1% not statistically significant. 


4.7 Year Update at ASCO May 2005. 

This clinical trial was updated at the ASCO meeting in May of 2005 at a median follow-up of 56 months. The treatment with FOLFOX4 caused a 23% reduction in the relative risk of relapse (HR 0.77, p<0.001). This was a 6.6% absolute benefit on average (DFS of 76.4 vs 69.85). For stage III patients the FOLFOX arm did better (HR 0.75, 95% CI 0.62-0.89). For stage II patients the hazard ratio also favored FOLFOX but did not reach statistical significance (HR 0.82, 95% CI from 0.60 to 1.13). Although underpowered for statements about statistical confidence, there appeared to be about equal benefit in terms of hazard ratios in the N1 and N2 Stage III patients. 

In the overall population at 4 years of follow-up, 84.9% and 82.8% patients are still alive respectively in the FOLFOX4 and LV5FU2 arms (HR = 0.91, 95% CI 0.75 - 1.11), which was not a statistically significant difference in overall survival. This lack of a clear advantage for 5 year OS for a regimen with a 3 year DFS, is contrary to a statistical analysis based prediction based on 5FU trials that such an OS would be evident at 5 years.(7)  Perhaps part of the reason that the HR's were more effected for DFS than OS was that 43% of the patients who did not recieve oxaliplatin as part of their adjvuant therapy got oxaliplatin containing chemotherapy after relapse. An underpowered exploratory analysis showed no evidence of a survival benefit in Stage II patients, and a trend for a survival benefit in Stage III patients (HR = 0.86, 95% CI 0.69 - 1.08). 

One of the most important aspects of this update was the statement that a median of 4 years of follow-up 3.4% of the FOLFOX4 treated patients presented either with persisting localized paresthesias of moderate intensity (2.7%) or with paresthesias that may interfere with functional activities (0.7%). This update does not really change the efficacy results reported in the 2004 New England Journal of Medicine paper.  The presistance of significant peripheral neuropathy in 0.7% of the patients at 4 years means that this oxaliplatin related problem is probably permanent or at least very long term in some patients. 


Adjuvant!'s Assessment of Efficacy of FOLFOX4.


FOLFOX4 appears to be superior to 5FU/leucovorin based regimens. This is evident both in metastatic disease, and appears to the case in adjuvant regimens as well. FOLFOX4's efficacy estimates in adjuvant therapy at approximately 5 years of follow-up are mature for DFS and unambigously show that an improvement.  The results are underpowered at this time to discern whether there is a difference in effectiveness of FOLFOX4 between Stage 2 and Stage 3 disease. There is a suggestion in the data however that there may be less efficacy in Stage 2 patients. In addition, that the benefit seems particularly great in high risk Stage 2 patients (a subpopulation of Stage 2 enriched in most clinical trials) is troubling because it suggests that there may be little benefit in moderate and low risk Stage 2 patients. 


On the basis of current data Adjuvant estimates that FOLFOX is about 20% superior to 5FU/leucovorin based regimens.  There Adjuvant! estimates that the efficacy of FOLFOX4 over no adjuvant therapy might be inferred to be ~52% [[ 40% (for the 5FU/leucovorin) + 12% (a 20% reduction of the remaining 60% of risk)]]. This estimate might be reasonable estimating the effects on the risk of relapse for Stage 3 disease, with estimates for relapse for Stage 2 disease and on survival still uncertain and controversial (see Source Of Efficacy Estimates). 


(1) 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 ML. Rothenberg, AM. Oza, RH. Bigelow, et al.  J Clin Oncol 21:2059-2069.


(2) N9741: oxaliplatin (oxal) or CPT-11 + 5-fluorouracil (5FU)/leucovorin (LV) or oxal + CPT-11 in advanced colorectal cancer (CRC). Initial toxicity and response data from a GI Intergroup study.  Goldberg RM, Morton RF, Sargent DJ, et al. ASCO 2002. Abstract 511. 


(3) Oxaliplatin/5-FU/LV in adjuvant colon cancer: safety results of the international randomized MOSAIC trial.  de Gramont A, Boni C, Navarro M, et al. ASCO 2002. Abstract 525.


(4) Oxaliplatin/5-FU/LV in adjuvant colon cancer: Results of the international randomized mosaic trial.  de Gramont A, Banzi M, Navarro M, et al. ASCO 2003. Abstract 1015. 


(5) André T, M.D., Boni C, Mounedji-Boudiaf L, et al.  Oxaliplatin, Fluorouracil, and Leucovorin as Adjuvant Treatment for Colon Cancer. New England Journal of Medicine 2004;350:2343-51.


(6) de Gramont A, Boni C, Navarro M, et al. 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. ASCO 2005, Abstract 3501. 


(7) Sargent DJ, Wieand S, Benedetti J, Disease free survival (DFS) vs overall survival (OS) as a primary endpoint for adjuvant colon cancer studies: Individual patient data from 12,915 patients on 15 randomized trials. ASCO 2004. Abstract 3502.


Reviewed 6/2005