Adjuvant chemotherapy for colon cancer: a confusing area!

J. Y. Douillard* and J. Bennouna

Division of Medical Oncology, Centre R. Gauducheau, Bd J. Monod, 44805 St-Herblain, France

* E-mail: jy-douillard{at}nantes.fnclcc.fr

The curability of colon cancer has greatly improved in the past 15 years with the introduction of 5-fluorouracil (5-FU)/leucovorin (LV)-based adjuvant chemotherapy. The last study with a surgery-alone control arm, published by Moertel et al. [1Go] in 1990, showed that surgery alone in stages II and III cured 55% of patients whereas the addition of 6 month 5-FU/levamisole improved 3.5-year survival up to 71%. For stage III, these figures for recurrence-free survival were 47% for surgery alone and 63% with adjuvant chemotherapy (P <0.0001). Various regimens have been evaluated since and the bolus 5-FU/LV known as Mayo Clinic has been a reference treatment for years, along with the weekly bolus 5-FU/LV known as Roswell Park. In 2003, the French cooperative group GERCOR [2Go] demonstrated that an infusional, 48-h regimen, in combination with LV, had a similar efficacy to the bolus Mayo Clinic regimen, but a better safety profile, and the so-called De Gramont regimen gained popularity at least in Europe. New drugs were made available to colon cancer patients in addition to 5-FU. Irinotecan and oxaliplatin are major drugs in metastatic disease, with similar efficacy when combined with 5-FU/LV. Oral fluoropyrimidines also became available and compared favourably to intravenous (IV) bolus 5-FU/LV with a better safety profile and patient preference in advanced disease. More recently, biological targeted therapies have been combined with conventional chemotherapy and provided increased efficacy and survival in metastatic disease. All these newcomers have been or are being tested in adjuvant colon cancer and raise questions for medical practice. Oral fluoropyrimidines such as UFT/LV or capecitabine (Xeloda®) have been compared in randomized trials to IV bolus 5-FU/LV regimen and showed similar efficacy, and even a 3.6% improvement in relapse-free survival (RFS) for capecitabine (Xeloda®) [3Go] in stage III colon cancer. Similarly, UFT (uracil/tegafur)/LV [4Go] was identical to a weekly bolus regimen of 5-FU/LV in NSABP C-06, in a mixed population of stages II (46%) and III. Based on the results of these two large randomized trials there is evidence that oral fluoropyrimidines might be used instead of IV 5-FU/LV, which is not as convenient, more toxic and less preferred by patients.

The addition of oxaliplatin or irinotecan to 5-FU/LV has clearly improved the response rate and median survival in metastatic colorectal cancer. Those drugs have been evaluated in the adjuvant setting. The Mosaïc trial [5Go] compared the combination of oxaliplatin with infusional 5-FU/LV (known as FOLFOX 4) with infusional 5-FU/LV in 2246 patients resected for colon cancer including both stages II (40%) and III. The results were initially published in 2004 and regularly updated at American Society of Clinical Oncology (ASCO) meetings. Overall, FOLFOX 4 provides an improved disease-free survival (DFS) of 6.6% at 4 years (76.4 versus 69.8%) [6Go] over infusional 5-FU/LV with an increased toxicity, mainly peripheral neuropathy, which may be long lasting and affect the quality of life in patients cured of disease for a majority of them, even though this toxic side-effect is always reversible. Keeping in mind these considerations, FOLFOX 4 might be preferred for high-risk patients.

For stage II, in the Moertel et al. trial, the 3.5-year RFS was 77% in the surgery-alone arm and 84% in the adjuvant chemotherapy arm, a non-statistically significant difference. In the IMPACT B2 group [7Go], the 5-year RFS was 73% with surgery alone and 76% with adjuvant 5-FU/LV (not statistically significant). More recently, in the QUASAR1 study [8Go], weekly 5-FU/LV demonstrated an improved 5-year RFS over a surgery-alone group with a statistically significant benefit of 2.6% over surgery. In the stage II subgroup of the Mosaïc trial, the benefit for stage II is 3.5% with FOLFOX, reaching 5.2% in high-risk stage II as compared to 5-FU/LV. According to Moertel et al., IMPACT and QUASAR1, 73–77% of stage II patients are cured with surgery alone at 3.5–5 years. Therefore, out of 100 stage II patients, 3–7% will benefit from additional 5-FU/LV and according to Mosaïc 3.5% will benefit from additional oxaliplatin over 5-FU/LV alone, a non-significant difference. Toxicity, medical cost, inconvenience of the IV route, however, apply to all of them; three-quarters receiving chemotherapy without benefit over surgery alone. In addition to the Mosaïc trial, NSABP C-07 [9Go] combining oxaliplatin with bolus weekly 5-FU/LV (FLOX) also showed an overall 4.9% improvement of 3-year DFS in a mixed population of stages II and III colon cancer, probably driven by the 71% of stage III. Based on the present results of a randomized trial in stage II, only a few patients benefit from adjuvant 5-FU/LV and even fewer from the addition of oxaliplatin, and should therefore be carefully selected on known prognostic factors.

The contribution of irinotecan in the adjuvant setting has so far been disappointing in three consecutive randomized trials for stage III: CALGB using the US IFL regimen [10Go], ACCORD2 in high-risk stage III [11Go] and PETACC-3 using the Douillard regimen [12Go]. ACCORD2 seems definitively negative but suffered from an imbalance in prognostic factor in favour of the control arm. PETACC-3 was negative according to its 3-year DFS primary end-point but was statistically significant on 3-year RFS. PETTAC-3, however, needs more maturation, and a further analysis of the overall population, including patients treated with the German AIO (Arbeitsgemeinschaft für Internistische Onkologie) regimen, before definitive conclusions can be reached. Furthermore, in PETACC-3, as in ACCORD2, there was an imbalance in the patient population with a greater number of patients presenting with T4 tumour in the experimental arm. Statistical analysis after correction for imbalance showed a significant P value for 3-year DFS. One hypothesis to explain the overall negative results of PETACC-3 is an increased incidence of death in the early time of follow-up of the experimental arm due to the greater number of T4 patients, with no benefit from the addition of irinotecan as reported in the ACCORD2 trial. If this holds true, a longer follow-up of the remaining patients may show a late benefit and curves separating further once the negative effect of the imbalance in the experimental arm has been removed out. Cross-comparison among trials is tempting though hazardous. Looking at 3-year DFS for stage III, Mosaïc provides 6.9% benefit and PETACC 3.8% observed, 5.4% after correction of imbalance. Definition parameters (DFS and RFS) were not identical among trials and certainly introduce a bias in cross-comparison. Mosaïc DFS is actually PETACC-3 RFS. These parameters are, however, important to consider. With the benefit of chemotherapy in the adjuvant setting on DFS and RFS, overall survival should improve. Five-year overall survival is the gold standard but is time consuming to wait for and may become irrelevant considering the high rate of 3- and even 4-year DFS. Surrogate evaluation criteria are needed. Sargent et al. [13Go] demonstrated in a meta-analysis that 3-year DFS is a surrogate end-point for overall 5-year survival in the 5-FU/LV adjuvant regimen. This may not be true for combination therapy such as FOLFOX, FLOX or FOLFIRI regimens, however. A first step to be agreed on amongst medical oncologists should be to standardize definitions, so that all clinical trials measure an identical end-point when dealing with DFS or RFS. A consensus should be obtained urgently on this matter. Another difficult issue is who benefits from what? Should all stage II and III patients receive adjuvant chemotherapy, and if no which ones? As emphasized above, only a handful out of 100 stage II patients will benefit from adjuvant chemotherapy. Most of them will receive undue treatment but will have to face toxicity. Similarly, in stage III, overall roughly 50/100 are cured by surgery and do not need adjuvant chemotherapy. An additional 15.3/100 patients would be cured at 3 years by adjuvant 5-FU/LV and 6.9/100 more by FOLFOX. Distant metastasis will develop in 27.8/100 despite adjuvant FOLFOX. Among patients potentially cured by FOLFOX, a majority would have been cured as well with oral capecitabine (Xeloda®) or UFT/LV and would not have experienced neurotoxicity and inconvenience of the IV route. In addition, amongst stage III, sub-stage IIIC benefits the most from adjuvant FOLFOX (11% benefit on 4-year DFS as compared to 7.2% in N1 stage and 8.6% for the overall stage III population). There is an urgent need for prognostic and predictive markers to better decide who should receive adjuvant chemotherapy of which type. Some have already been identified, including 18q-LOH and MSI expression, which will be stratification criteria in NSABP C-O8. Others are being prospectively studied in ongoing clinical trials. Additional ones are known to be valuable for efficacy of 5-FU (e.g. thymidylate (TS), thymidine phosphorylase (TP)), but are not yet established as decision-making markers and are not routinely available. The field of adjuvant chemotherapy in colon cancer has made substantial progress in the past 15 years. Efficient drug availability has rendered the field complex. Addition of targeted therapy in the adjuvant setting, pending the results of ongoing trials, will probably make it even more difficult. In the interest of patients, better indication parameters have to be defined in order to achieve improved unnnecessary without delivering undue chemotherapy.

References

1. Moertel CG, Fleming TR, Macdonald JS et al. Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. N Engl J Med 1990; 322: 352–358.[Abstract]

2. André T, Colin P, Louvet C et al. Semimonthly versus monthly regimen of fluorouracil and leucovorin administered for 24 or 36 weeks as adjuvant therapy in stage II and III colon cancer: results of a randomized trial. J Clin Oncol 2003; 21: 2896–2903.[Abstract/Free Full Text]

3. Twelves C, Wong A, Nowacki MP et al. Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med 2005; 352: 2696–2704.[Abstract/Free Full Text]

4. Wolmark N, Wieand S, Lembersky B, Colangelo L, Smith R, Pazdur R. A phase III trial comparing oral UFT to FULV in stage II and III carcinoma of the colon: results of NSABP Protocol C-06. J Clin Oncol 2004; 22 (July 15 Suppl): 3508.

5. André T, Boni C, Mounedji-Boudiaf L et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med 2004; 350: 2343–2351.[Abstract/Free Full Text]

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. Proc Am Soc Clin Oncol 2005; 23: Abstr 3501.

7. International Multicentre Pooled Analysis of B2 Colon Cancer Trials (IMPACT B2) Investigators. Efficacy of adjuvant fluorouracil and folinic acid in B2 colon cancer. J Clin Oncol 1999; 17: 1356–1363.[Abstract/Free Full Text]

8. Gray RG. QUASAR: a randomized study of adjuvant chemotherapy (CT) vs observation including 3238 colorectal cancer patients. J Clin Oncol 2004; 22 (July 15 Suppl): 3501.

9. Wolmark N, Wieand HS, Kuebler JP, Colangelo L, Smith RE. A phase III trial comparing FULV to FULV + oxaliplatin in stage II or III carcinoma of the colon: results of NSABP Protocol C-07. Proc Am Soc Clin Oncol 2005; 23: Abstr 3500.

10. Saltz LB, Niedzwiecki D, Hollis D et al. Irinotecan plus fluorouracil/leucovorin (IFL) versus fluorouracil/leucovorin alone (FL) in stage III colon cancer (intergroup trial CALGB C89803). J Clin Oncol 2004; 22 (July 15 Suppl): 3500.

11. Ychou M, Raoul J, Douillard J et al. A phase III randomized trial of LV5FU2+CPT-11 vs. LV5FU2 alone in adjuvant high risk colon cancer (FNCLCC Accord02/FFCD9802). Proc Am Soc Clin Oncol 2005; 23: Abstr 3502.

12. Van Cutsem E, Labianca R, Hossfeld D et al. Randomized phase III trial comparing infused irinotecan/5-fluorouracil (5-FU)/folinic acid (IF) versus 5-FU/FA (F) in stage III colon cancer patients (pts). Proc Am Soc Clin Oncol 2005; 23: Abstr 8.

13. Sargent DJ, Wieand S, Benedetti J et al. 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. J Clin Oncol 2004; 22 (July 15 Suppl): 3502.





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