VIENNA, AustriaThe combination regimen of 5-fluorouracil (5-FU)
and levamisole is one of the National Cancer Institutes
recommendations for adjuvant treatment of stage C colorectal cancer.
However, results from the first 5,000 patients enrolled in the QUASAR
trial suggest that this advice may be open to question. There
is no improvement in survival or recurrence rate with levamisole, and
there is no worthwhile benefit from high-dose folinic acid as
compared with low-dose folinic acid, QUASAR investigator R.G.
Gray, MD, of the University of Birmingham (UK), said at the 10th
European Cancer Conference (ECCO).
QUASAR, the lar-gest chemotherapy trial ever conducted in colorectal
cancer, was designed to compare high-dose with low-dose folinic acid
and levamisole vs placebo in patients with a clear indication for
chemotherapy. The study also compared observation vs chemotherapy in
patients with an uncertain indication for chemotherapy, but this part
of the study is still blinded.
Investigators in 134 centers in five countries randomly assigned
patients who had undergone complete resection and were node positive
but metastasis free to receive one of four adjuvant chemotherapy
5-FU (370 mg/m² or, during radiotherapy, 300 mg/m²) plus
high-dose L-folinic acid (in a fixed dose of 175 mg, equivalent to
about 250 mg/m² of DL-folinic acid) plus levamisole (50 mg three
- 5-FU plus high-dose L-folinic acid (175 mg) plus placebo
- 5-FU plus low-dose L-folinic acid (25 mg) plus levamisole
- 5-FU plus low-dose L-folinic acid (25 mg) plus placebo
The option of whether to give 5-FU and L-folinic acid as six 5-day
courses every 4 weeks or as 30 three-day courses every week was left
up to individual clinicians. Levamisole was administered according to
the Mayo Clinic regimen in 12 3-day courses every 2 weeks.
The first results of QUASAR showed absolutely no differences in
either 5-year recurrence risk or 5-year survival between high-dose
and low-dose folinic acid, Dr. Gray reported. Because of the
large numbers, the possibility of this being a false-negative finding
is very small, he emphasized. Dr. Gray also pointed out that
the use of the high-dose regimen multiplied the cost of treatment 10-fold.
Similarly, the use of levamisole had little impact on outcome. The
5-year rates of recurrence and survival were actually worse among
levamisole-treated patients, although these differences did not reach
statistical significance. Another downside of levamisole was a
doubling in the incidence of dermatologic toxicity.
The contribution of this study is remarkable; it strengthens
what we already know, and, thanks to the inclusion of large numbers
of patients, it will really affect clinical practice, said
discussant Harry Bleiberg, MD, of Jules Bordet Institute, Brussels.
A possible weak point of QUASAR, Dr. Bleiberg said, is that it used
confusing criteria for distinguishing between clear and
uncertain indications for chemotherapy and left the
decision to the treating physician. In addition, because the study
organizers wanted to keep the trial design simple, they omitted
standardized follow-up procedures that, Dr. Bleiberg suggested, could
have jeopardized the evaluation of disease-free survival.
Other unresolved issues, he noted, are the potential impact of
further treatment on outcome and the precise role of adjuvant
chemotherapy in patients with rectal cancer.
Perhaps most important, Dr. Bleiberg said, QUASAR took 6 years to
complete and we are now a step ahead. He cited ongoing
studies that are comparing the Mayo Clinic regimen with either the
thymidylate synthase inhibitor raltitrexed (Tomudex, investigational)
or infusional 5-FU, and assessing the possible benefits of adding
oxaliplatin (an investigational platinum) or irinotecan (Camptosar)
to a 5-FU/folinic acid combination.