Adjuvant therapy for colon cancer: 12 months, 9 months, 6 months ... why not 3 months?

A. Sobrero* and S. Sciallero

Medical Oncology, Ospedale San Martino and CBA, Genova, Italy

(* Email: alberto.sobrero{at}hsanmartino.liguria.it)

The article by Chau et al. [1Go] on the adjuvant treatment of 801 stage II and III colorectal cancer patients demonstrates that 3 months of protracted venous infusion (PVI) 5-fluorouracil (5-FU) is as efficacious as 6 months of standard bolus 5-FU–leucovorin (LV) and that it is significantly less toxic. Although the study was designed as a superiority trial, the results allow us to conclude that the chances of the 3-month regimen being inferior to the 6-month treatment plan are extremely low (P <0.005).

 This article is an update and an extension of a previously published report on the first 716 patients [2Go] showing similar results at a much shorter follow-up time point: significantly lower toxicity of the infusional regimen and no difference in overall survival. That preliminary report also indicated that the 3-year disease-free survival was significantly longer and the quality of life better (in the first 6 months) in the PVI 5-FU arm, and that the catheter-related complication rate leading to removal was 9%.

Despite the small number of additional patients since the initial report, the update after 5 years of follow-up is more than welcome because of the scientific and clinical relevance of the major question addressed by this phase III trial: the duration of the adjuvant treatment.

Indirect evidence of its importance is provided by the accrual period: the study was launched in 1993 and completed accrual in 2003. We do not think that this is a pitfall. The very long accrual period is not a sign of little or declining interest of the investigators. Rather, despite the strong competition of drug company-sponsored trials on oral fluoropyrimidines, the doublets (5-FU plus oxaliplatin or irinotecan) and monoclonal antibodies, this independent, ‘academic’ study was able to maintain the interest of the investigators over a 10-year period simply because the major issue addressed was so relevant.

In colon cancer, the initial demonstration of the efficacy of adjuvant 5-FU plus levamisole [3Go] was based upon 12 months of treatment. Thereafter, 6 months of 5-FU–LV proved to be as effective as 12 months of 5-FU–levamisole [4Go]. At the time the present trial was designed, this latter concept was still under study. The rationale was thus based entirely on the results in advanced colorectal cancer, suggesting that PVI 5-FU might be superior to standard bolus 5-FU–LV. This concept was confirmed in Europe in 1998 through a meta-analysis [5Go] indicating a statistically significant benefit of PVI in terms of survival, although the difference was of little relevance clinically (3 weeks). The authors, the ethics committee and the patients must be congratulated for the courage of having designed, approved and accepted this randomized comparison.

Today we have additional data supporting the plausibility of the results reported here.

First, the literature from the advanced colorectal cancer trials indicate that the time to response is very short (~2 months) and that efficacy is not enhanced by prolonged treatment programs beyond 3 months in both first- [6Go] and second-line [7Go]. These data support the general concept that little can be gained from lengthy chemotherapy treatment programs.

Secondly, the use of a hybrid regimen of bolus and infusional 5-FU, the de Gramont regimen, produced equivalent efficacy results when used adjuvantly for 6 versus 9 months in a recent large-scale French randomized comparison [8Go]. This finding extends to infusional 5-FU the observation that it is possible to shorten the treatment duration of bolus 5-FU without compromising the efficacy.

Aside from the present study, so far no other trial has explored the possibility of further reducing the duration of the entire adjuvant program below 6 months. The temptation is strong to take these data for granted and to use this very short regimen as another valuable standard treatment for both colon and rectal cancer (in combination with radiotherapy).

But it is one thing to be interesting, stimulating and innovative, quite another to become standard. The authors in fact are very careful in limiting their conclusions to: ‘therefore shorter duration of adjuvant treatment should be further explored’.

The design and eligibility criteria suggest that this could not be more than an hypothesis-generating trial. In fact, the internal and external validity of these data are far from being impeccable for the following reasons: the limited number of patients planned; the inclusion of both colon and rectal cancer patients, and stage II and III patients; the inclusion of patients with clearly suboptimal surgery (tumor-free margins of just >1 mm); reserving radiotherapy to T4 rectal cancers only, but at the same time leaving the decision about preoperative radiotherapy to the treating physician; and giving more than 4 months of PVI 5-FU (instead of 3 months) in rectal cancer patients receiving radiotherapy. These are the factors limiting the impact on the current standard adjuvant treatment of colorectal cancer.

But there is another concern about these results. The variable discussed so far, i.e. duration of treatment, is not the only one in this trial. Indeed, here the comparison is not between 6 and 3 months of the same treatment, but between two radically different treatments: 3 months of PVI 5-FU versus 6 months of bolus 5-FU–LV. The two variables (duration and scheduling) are so strictly bound in this trial that the study becomes a comparison between two different ‘strategies’, not just 3 versus 6 months of treatment or bolus versus infusional 5-FU. Thus, the effects produced by the different treatment duration, discussed above, are coupled with the effects arising from the different schedules of 5-FU.

Two randomized comparisons of bolus versus infusional 5-FU have been published so far. The French study already mentioned comparing the de Gramont regimen with the standard bolus 5-FU–LV [8Go], showing lower toxicity but equivalent efficacy of the infusional regimen, and the American Intergroup study 0153, published in abstract form only [9Go], comparing the same PVI 5-FU regimen with standard bolus 5-FU–LV. This study was prematurely closed after accrual of 2000 patients, because a planned interim analysis showed the chances of finding significant differences between the treatment arms were too low. A third large-scale randomized comparison of 6 months of infusional 5-FU versus standard bolus 5-FU–LV (the PETACC 2 study) is still ongoing. Therefore, today there is no evidence suggesting that infusional 5-FU is superior to bolus 5-FU in the adjuvant setting. Nevertheless, data from studies in metastatic colorectal cancer strongly suggest that infusional 5-FU is the best way to combine the fluoropyrimidine with either oxaliplatin or irinotecan [10Go]. The majority of currently ongoing large-scale randomized studies use infusional 5-FU in these doublets.

The last consideration about the present trial regards the overall toxicity. In fact, although chemotherapy-related toxic effects were significantly lower in the infusional arm, substantial problems arose from the permanent catheters needed for the PVI. Nine per cent of catheters had to be removed, although the nine participating British centers had strong experience with PVI, a factor minimizing catheter-related complications. When the same schedule was used (for 6 months) in a multicenter study setting, as was the case for the Intergroup 0153 trial, the catheter-related complication rate leading to removal was as high as 20%. This problem must not be underestimated, and that is why other ongoing adjuvant trials with oxaliplatin or irinotecan use capecitabine as the companion fluoropyrimidine.

In summary, this phase III trial does not establish a new standard treatment for radically resected colorectal cancer. However, it does provide evidence that 3 months of adjuvant chemotherapy may be as effective as the current 6-month plans, with two potential immediate consequences on new trial design.

Academic research should further pursue this avenue, particularly with the new oxaliplatin-based doublet that has become another adjuvant standard for colon cancer [11Go]; the cumulative long-term neurotoxicity of this 6-month regimen represents an important limitation that could be overcome by shorter periods of therapy.

In addition, the apparent need for long periods of administration of targeted agents on the horizon of future adjuvant trials strongly encourage the exploration of shorter chemotherapy programs.

Ethics committees should feel more comfortable now approving this type of study, which may be so important for the quality of life of our patients.

Acknowledgements

We thank Associazione Italiana Ricerca Cancro (AIRC) and Consiglio Nazionale Ricerche (CNR) from whom funding was received.

References

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