Adjuvant Chemotherapy in Colon Cancer Can Be Curative

Nick Mulcahy

February 04, 2009

February 4, 2009 — Does adjuvant chemotherapy in patients with resected stage II and III colon cancer provide higher cure rates, or does it merely delay tumor recurrence?

The answer to this "long-standing question" seems to be yes, adjuvant fluorouracil-based treatment cures some patients. This is the conclusion from a new statistical analysis of 18 randomized clinical trials and more than 20,800 patients published online January 26 in the Journal of Clinical Oncology.

In the analysis, adjuvant therapy resulted in a 7% improvement in 8-year overall survival rate, compared with no treatment after surgery; stage II patients had a 5% improvement and stage III patients had a 10% improvement.

Noting that disease recurrence is unlikely or "minimal" after 8 years and does not exceed 0.5% for both treated and untreated patients, the investigators felt comfortable describing this overall survival as being evidence of a cure.

"After 8 years, the notion of cure is appropriate," write the study authors, led by Daniel Sargent, PhD, from the Divisions of Biostatistics and Medical Oncology of the Mayo Clinic, in Rochester, Minnesota.

After 8 years, the notion of cure is appropriate.

Furthermore, the statistical proof of cure was found in a comparison of the hazard rates of patients treated with chemotherapy and those untreated after surgery.

The hazard rates of overall survival, disease-free survival, and time to recurrence "never exceed the corresponding rates in untreated patients," note the authors about the 8-year follow-up period.

"If therapy merely delayed, as opposed to prevented, recurrences, we would expect the [time to recurrence] hazard rate for treated patients to eventually exceed the rate in the untreated patients," write the authors.

The investigators also emphasized that most relapses in all patients occur in the first 2 years after surgery and that adjuvant therapy is most beneficial during this time. "The clear major benefit of adjuvant therapy is to significantly and meaningfully reduce this risk of early recurrence by approximately 40%," they write.

The clear major benefit of adjuvant therapy is to significantly and meaningfully reduce this risk of early recurrence by approximately 40%.

The authors believe that the new analysis provides some guidance to clinicians. "From a clinical perspective, once a patient has been recurrence-free for 5 years from surgery, continued medical care can focus on other issues beyond the patient's prior colon cancer, such as long-term adverse effects of the adjuvant therapy or secondary cancers," they write.

Most Trials Used Fluorouracil-Based Chemotherapies

The data for this new analysis were assembled by the Adjuvant Colon Cancer Endpoints (ACCENT) Group and come from 18 phase 3 trials conducted from 1978 to 1999. Sixteen of the 18 trials employed either fluorouracil/leucovorin or fluorouracil/levamisole chemotherapy groups.

Fluorouracil with leucovorin became the standard of care for patients with stage III and selected stage II colon cancer in the early 1990s, observe the authors.

In the abundant studies to date, the "clinical demonstration of actual cure of patients by adjuvant therapy is poorly understood," they note, explaining their motives for the analysis, which they also hoped would provide additional insight into the time-related nature of treatment benefit.

Clinical demonstration of actual cure of patients by adjuvant therapy is poorly understood.

For both treated and untreated patients, the risk for death from any cause peaks (7%–8% of patients)at approximately 2 years after surgery and gradually declines over the 8-year estimation period, write the authors.

For both the disease-free-survival (time to recurrence or death) and the time-to-recurrence (recurrence in which deaths without recurrence are censored out) end points in untreated patients, the risk for an event is highest in the first year after surgery, with a rapid reduction until approximately year 4.

The failure rate in treated patients is low at first, increases in years 1 to 3, and then recedes close to the rate in untreated patients by year 4.

The disease-free-survival curves remain slightly separated in years 4 to 8 between treated patients and controls, whereas the time-to-recurrence curves are "virtually superimposable" in that time period.

For all of the end points, note the authors, the failure rate of untreated patients never exceeds that of the treated patients over the 8-year estimation.

The investigators also generated hazard ratios (HR), comparing the treated and untreated patients. The addition of adjuvant chemotherapy provides a "consistent and durable" beneficial effect on overall survival during the 8-year period (HR, 0.74).

However, they also note that while there is a "substantial benefit" of the therapy in reducing the risk for an event in the first 1 to 2 years (HR, 0.61), that benefit diminishes over time and becomes "nonsignificant" after year 4.

In terms of long-term recurrence rates for both groups, after year 5, the rate never exceeds 1.5%, and after 8 years, never exceeds 0.5%, note the authors.

Will This Curative Effect Be Seen With Newer Agents?

The authors note that researchers and clinicians might be tempted to extend the "paradigm" of adjuvant fluorouracil-based chemotherapy providing a cure rate of approximately 10% to newer cytotoxic drugs (oxaliplatin and irinotecan) or to targeted agents (such as bevacizumab or cetuximab).

"Great caution" should be exercised before doing so, they write.

For instance, there are numerous clinical trials underway or recently completed that use oxaliplatin with fluorouracil and leucovorin plus either bevacizumab or cetuximab, note the authors. However, the different mechanism of action of these biologic agents might not allow for a similar analysis. "The unique mechanism of action of these biologic agents may require additional years of follow-up before conclusions regarding a relapse-delaying versus a curative effect of these complex treatments can be reliably ascertained," write the authors.

The researchers have disclosed no relevant financial relationships.

J Clin Oncol. Published online before print January 26, 2009. Abstract

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