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Adapted from the NCI Cancer Bulletin, vol. 6/no. 1, January 13, 2009 (see the current issue ³).

For several decades, chemotherapy regimens based on the drug fluorouracil (5-FU) have been part of the treatment for high-risk stage II or stage III colon cancer. Many clinical trials have shown that these regimens improve overall survival, but how they affect the risk of recurrence over time has not been clear.

In a study published online January 5, 2009, in the Journal of Clinical Oncology, researchers from the Adjuvant Colon Cancer Endpoints (ACCENT) Group used individual patient data from 18 phase III trials of adjuvant 5-FU-based chemotherapy for colon cancer to show that the regimens provide their survival benefit primarily by reducing the high risk of recurrence within the first two years after surgery (see the journal abstract ⁴).

By five years after treatment with 5-FU-based adjuvant chemotherapy, the risk of recurrence dropped to 1.5 percent, and dropped again to 0.5 percent by eight years after treatment. Instead of delaying recurrence, “5-FU-based chemotherapy truly eradicates the disease and results in long-term cure in some patients,” explained Dr. Daniel Sargent, professor of biostatistics and oncology at the Mayo Clinic and lead author of the study.

Measuring True Risk of Recurrence over Time

The ACCENT investigators reviewed survival data from eight years of follow up for 20,898 patients in the 18 trials. Instead of the Kaplan-Meier method usually used to calculate survival after treatment, the investigators used a system called hazard-rate estimation, which requires a large data set but provides results that are easier to interpret. Hazard-rate estimation “allowed us to estimate and graphically present the true risk of recurrence at any given time” after treatment, said Dr. Sargent.

Out of the 20,898 patients, 35 percent had their cancer recur during eight years of follow up, and 38 percent died from any cause during the same time period. For both patients who did and did not receive chemotherapy, “most relapses [occurred] in the first two years after surgery,” stated the authors. However, the risk of death remained lower during that period of time and during the entire eight years of follow up for patients who had received chemotherapy.

Overall, adjuvant chemotherapy with an 5-FU-based regimen improved eight-year overall survival by 7 percent (5 percent for patients with stage II cancer and 10 percent for patients with stage III cancer).

Implications for Follow-up Care

The authors cautioned against extending these results to newer combinations of chemotherapeutic and biologic drugs that do not contain 5-FU. “Longer-term follow up is likely to be required to establish a long-term survival benefit,” they explained. The ACCENT group plans to update their analysis with data from newer treatment regimens as they become available. Dr. Sargent pointed out that “such analyses are only possible through individual clinical trialists making their data available for such pooled or meta-analyses, which has been made increasingly possible due to improvements in technology and by standardization of clinical trial data elements.” 

The results from the current study have important implications for follow-up care of patients with stage II or III colon cancer, he noted. “The risk of a patient’s disease returning is highest in the first two years, and therefore the patient and their physician have to be very vigilant in their follow up during that period to make sure that if the cancer does come back, it is detected quickly.

“After five years and particularly after eight years, the risk of the patient’s disease coming back is very, very low, and physicians can then turn their attention to other priorities for that patient,” he said.

Glossary Terms

Additional cancer treatment given after the primary treatment to lower the risk that the cancer will come back. Adjuvant therapy may include chemotherapy, radiation therapy, hormone therapy, targeted therapy, or biological therapy.

A type of research study that tests how well new medical approaches work in people. These studies test new methods of screening, prevention, diagnosis, or treatment of a disease. Also called clinical study.

A drug used to treat symptoms of cancer of the colon, breast, stomach, and pancreas. It is also used in a cream to treat certain skin conditions. Fluorouracil stops cells from making DNA and it may kill cancer cells. It is a type of antimetabolite. Also called 5-fluorouracil and 5-FU.

A study to compare the results of people taking a new treatment with the results of people taking the standard treatment (for example, which group has better survival rates or fewer side effects). In most cases, studies move into phase III only after a treatment seems to work in phases I and II. Phase III trials may include hundreds of people.