(1) Following the recent introduction of several new
cytotoxic agents, a new look at the role of
chemotherapy in metastatic
colorectal cancer is needed. (2) In one clinical trial of first-line treatment,
fluorouracil +
folinic acid infusion, after an initial bolus (LV-5FU2 protocol), was more effective and better tolerated than bolus administration alone (Mayo Clinic protocol). (3) Five comparative trials failed to show that
raltitrexed was more effective than
fluorouracil +
folinic acid in first-line treatment, and it has more serious adverse effects. (4) There are no comparative trials of
capecitabine or
tegafur +
uracil versus
fluorouracil +
folinic acid (LV-5FU2 protocol) in first-line treatment. (5) In three comparative randomised trials involving previously untreated patients, adjunction of
oxaliplatin to the
fluorouracil +
folinic acid combination (
FOLFOX protocol) increased both tumour response rate and progression-free survival (by about 2 months), but it also caused more neuropathies, severe
diarrhea and severe
neutropenia. (6) In two comparative trials of first-line treatment, adjunction of
irinotecan to
fluorouracil +
folinic acid (
FOLFIRI protocol) increased the median survival time by about 3 months, to 15-17 months, but increased the incidence of
diarrhea,
neutropenia, serious cardiovascular disorders and severe
thrombosis. (7) In second-line treatment,
irinotecan is the only properly assessed
drug with a positive impact, prolonging survival compared with appropriate
palliative care (34 months after diagnosis, versus 27 months). (8) In one comparative trial, first-line treatment with the
FOLFOX protocol, followed by the
FOLFIRI protocol, resulted in the same median survival time (21 months) as the reverse sequence. (9) In practice, the first-line treatment for metastatic
colorectal cancer appears to be the
fluorouracil +
folinic acid combination (LV-5FU2 protocol) plus either
oxaliplatin (
FOLFOX protocol) or
irinotecan (
FOLFIRI protocol). The reference second-line treatment is the
FOLFIRI protocol (or the
FOLFOX protocol if the
FOLFIRI protocol has already been used). These treatments were associated with the longest survival in one trial.