Adjuvant Therapy for Colorectal Cancer:
Adjuvant Therapy for Colorectal Cancer:
Colon cancer remains one of the most common human malignancies, with an annual global incidence of slightly less than 1 million patients per year. While our ultimate goal is to prevent the disease, for the foreseeable future, medical oncologists will continue to see patients with colon cancer, many of whom have undergone potentially curative surgery but are at high risk for recurrence.
As well-outlined by Drs. Beavan and Goldberg, in the past 20 years, the outlook for these patients has gone from pessimism that anything more than surgery was useful to certainty that we can markedly decrease the risk of recurrence. At least some steps have been made in clearly identifying which patients should receive adjuvant therapy. There is general agreement on current effective regimens, alternatives have been developed for patients who are unable to tolerate optimal regimens, and there is promise that future regimens may be more effective.
On the other hand, we are still unable to predict which patients have been cured by operation alone and which require additional therapy; we are unable to choose the optimal regimen for the individual patient; and we do not have adequate predictive markers for minimizing toxicity. In all, we have come a long way but still have a considerable distance to travel.
Drs. Beavan and Goldberg succinctly summarize the state of the art in the mid-1980s. Fluorouracil (5-FU) had already been studied for several decades. It offered modest palliation for patients with advanced disease but had no clear benefit when given as adjuvant therapy. There was considerable debate as to who should be treated and who should not be treated, with some studies still allowing the enrollment of patients with stage I disease. It was known that there were differences in toxicity depending on how 5-FU was given, with some ink-ling as to what might be causing those differences, but the optimal duration of treatment, method of administration, and technique of administration were still controversial.
By the early1990s, the first clear evidence that postoperative adjuvant systemic therapy improved outcome was available. As Drs. Beavan and Goldberg point out, a moderately sized (by current standards) but carefully done controlled study demonstrated that 5-FU plus levamisole (an agent no longer important in colon cancer therapy) clearly decreased the risk of recurrence and reduced the risk of death. This single trial probably played the most important role, at a national consensus conference, in changing the standard of care for stage III colon cancer.
The remainder of the 1990s was spent refining 5-FU-based adjuvant treatment. For patients with stage III disease, 5-FU plus leucovorin given for 6 months became the standard of care. The best method of administering this agent remained controversial, with infusional vs bolus 5-FU studied by a number of investigators.
In the end, a combination of the two routes has become fairly widely used. Despite considerable effort, the use of systemic adjuvant therapy for patients at moderate risk (the majority of stage II patients) was and remains controversial. It is of interest that, as Drs. Beavan and Goldberg point out, several combined analyses have indicated that the additional increase in cure rate for patients with stage II colon cancer using 5-FU/leucovorin-type regimens vs surgery alone is approximately 3% to 5%. Whether or not this is clinically significant has been debated by gastrointestinal oncologists. On the other hand, for women 50 to 69 years of age with early-stage breast cancer, an improvement in outcome with adjuvant cytotoxic chemotherapy is of roughly the same degree (3%-5%) at 15 years. In breast cancer, there is less controversy regarding the use of cytotoxic adjuvant regimens that are at least as toxic as 5-FU and leucovorin.