Anything in modulation?

R. Gray*, R. Hills and R. Stowe

University of Birmingham Clinical Trials Unit, Birmingham B15 2RR, UK

*E-mail: r.gray@bham.ac.uk

This issue of Annals of Oncology sees a report of a trial by the Italian INTACC intergroup comparing folinic acid-modulated fluorouracil, combined with levamisole, with fluorouracil and levamisole alone [1]. This large trial (n = 1703) adds importantly to our knowledge of the value of folinic acid in the fluorouracil/folinic acid (FUFA) chemotherapy combination, which is now widely accepted as the standard regimen in colorectal cancer [2]. No statistically significant differences in terms of disease-free survival or overall survival were found from modulating the action of fluorouracil with folinic acid. However, the absence of a statistically significant difference does not of course establish lack of benefit. There were fewer deaths (32% versus 35%) and fewer recurrences (33% versus 34%) seen in the folinic acid arm, and so it remains plausible that adding folinic acid to fluorouracil does in fact produce a moderate improvement in survival. Even with 1700 patients randomised, the INTACC trial has insufficient statistical power to detect a 3% or 4% improvement in outcome.

Moreover, as with a number of similar trials, the study design is ‘confounded’ by the use of different doses of fluorouracil in the two arms (450 mg/m2 in the absence compared with 370 mg/m2 in the presence of folinic acid) and so, in effect, the study compares two approximately equitoxic regimens. It would perhaps have been more scientifically informative to address the cleaner question of whether adding folinic acid to the same dose of fluorouracil produces improvements in outcome sufficient to outweigh the extra toxicity. With the INTACC study design, it may be that a small benefit from the use of a higher dose of fluorouracil in the comparator arm partly counterbalanced the benefits derived from adding folinic acid.

The imbalance in study design must explain the different patterns of toxicity seen in the two groups. There was significantly more gastrointestinal (GI) toxicity [19% (152/859) versus 9% (70/844), grade >=3 (WHO grading system)] in the folinic acid group, indicating that the addition of folinic acid to fluorouracil—at least in a 5-day, 4-weekly regimen—substantially increases diarrhoea, stomatitis, nausea and vomiting. However, haematological toxicity was higher in the no folinic acid arm [3% (24) versus 1% (six), grade >=3 leukopenias] and this can only be explained by the higher dose of fluorouracil, which may well also explain the higher fatal toxicity (six versus one deaths) as most fatalities were among neutropenic patients. The chemotherapy-related mortality with FUFA was very low in the INTACC study as it has been in previous studies of this regimen [3, 4], averaging ~0.1% overall. Since safety is paramount in adjuvant studies, particularly for lower risk patients, FUFA may therefore be the regimen of choice on toxicity grounds despite greater GI toxicity.

So, what is now known and what is not known about the optimal use of fluorouracil-based chemotherapy for colorectal cancer? First, levamisole can be taken out of the equation. The INTACC study did not evaluate levamisole—using the same dose and schedule in each group—but results from other studies establish beyond reasonable doubt that adding levamisole to fluorouracil—with or without folinic acid—does not improve outcome [47]. Secondly, the dose of folinic acid appears unimportant with no difference in outcome or toxicity seen in the large QUASAR study comparing high with low-dose folinic acid [4]. The three important considerations with fluorouracil-based chemotherapy are, therefore, whether or not to use low-dose folinic acid, the choice of schedule (once-weekly or 5-day, 4-weekly), and the choice of dose of fluorouracil (between 370 mg/m2 and 500 mg/m2).

We believe that folinic acid should be used to modulate the action of fluorouracil. Although none of five large studies evaluating the addition of folinic acid to fluorouracil-based adjuvant treatment have shown statistically significant benefits, there has been a consistent trend towards greater benefit in the folinic acid containing arms [1, 69]. There may, therefore, be a small survival benefit that has not been picked up in individual studies because of inadequate statistical power. The meta-analysis of individual patient data from these studies, being undertaken by the Colorectal Cancer Collaborative Group, will help clarify this.

Another consideration is that that the toxicity of FUFA can be greatly reduced by using the once-weekly rather than 5-day, 4-weekly schedule of delivery. There are concerns that less pain will also mean less gain. Although generally true with chemotherapy, this may not be the case with cell-cycle specific drugs such as fluorouracil, when the probability of hitting a dividing cell is much the same with 30 once-weekly shots as six 5-day salvos. The QUASAR study provides some evidence to support this theory. Clinicians were free to choose either the once-weekly or the 5-day, 4-weekly FUFA schedule and, mostly by institutional choice, approximately half the patients received each schedule. Comparison of the two groups suggests that the once-weekly schedule is just as effective as the 5 day, 4-weekly regimen of FUFA but with much less toxicity [10]. This comparison was not randomised—and so needs to be confirmed—but there was no indication of selection bias and large numbers of patients were included.

Despite their apparently favourable efficacy/toxicity ratio, once-weekly FUFA schedules, such as QUASAR or ‘Roswell Park’, are used less often than 5-day, 4-weekly regimens such as the ‘Machover’ or ‘Mayo’. The fluorouracil dose in these regimens varies from 370 mg/m2 (Machover and QUASAR) to 425 mg/m2 in the Mayo and 500 mg/m2 in the Roswell Park regimens. Survival benefits have been reported at all three dose levels, but there is little comparative evidence to guide choice between these different FUFA regimens. There is accumulating evidence to suggest increasing efficacy with increasing dose of fluorouracil: striking survival benefits have been seen with Roswell Park compared with an active MOF chemotherapy control in both colon and rectal cancer [11, 12], and the high dose of fluorouracil used must explain the efficacy of the fluorouracil/levamisole combination [13, 14]. The once-weekly QUASAR regimen (FU 370 mg/m2 plus FA 20 mg/m2) has become standard chemotherapy in the UK. It would be interesting to investigate whether results might be improved by escalating the dose of fluorouracil to 500 mg/ m2 as in the Roswell Park regimen. There are safety concerns about escalating the dose of fluorouracil because of the steeply increasing toxicity with increasing dose, and the large heterogeneity between patients regarding sensitivity to toxic effects. However, higher doses might be delivered more safely by use of a progressive ‘dose escalation if acceptable toxicity’ schedule rather than the usual ‘dose reduction if unacceptable toxicity’ schedules. It does remain important to find out what dose and schedule of fluorouracil and folinic acid provides the best efficacy to toxicity ratio so that the appropriate comparator regimen can be used in trials of new, more expensive drugs.

R. Gray*, R. Hills & R. Stowe

University of Birmingham Clinical Trials Unit, Birmingham B15 2RR, UK (*E-mail: r.gray@bham.ac.uk)

References

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