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Oxaliplatin in Stage II Colon Cancer: Benefit Questioned


August 29, 2012 — The use of adjuvant chemotherapy in patients with stage II colon cancer remains controversial because many of these patients have a very favorable prognosis after surgery. Even when the decision to use chemotherapy is made, the choice of which drugs to use is a matter of debate.
Oxaliplatin (Eloxatin,sanofi-aventis) has become popular in recent years as part of FOLFOX, the triple-drug chemotherapy regimen of infusional fluorouracil, leucovorin, and oxaliplatin.
Oxaliplatin was added to this regimen after early data from a pair of large randomized trials showed significant improvement in disease-free-survival.
However, as the data from these trials have matured, the hoped-for improvement in overall survival has not materialized. In fact, a new analysis of subgroups from one of these trials has confirmed that adding oxaliplatin does not improve overall survival.
The analysis, published online August 20 in the Journal of Clinical Oncology, was conducted by Christophe Tournigand, MD, from the Hôpital Saint-Antoine in Paris, France, and colleagues. It focused on a subgroup of patients who took part in MOSIAC (Multicenter International Study of Oxaliplatin/Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer).
The team found that the addition of oxaliplatin to infusional fluorouracil and leucovorin did not significantly improve overall survival in patients with stage II colon cancer or in elderly patients.
The use of FOLFOX in these 2 patient groups has been "controversial," the researchers explain. However, their analysis demonstrates that FOLFOX is not "beneficial in stage II patients or for patients between 70 and 75 years."
Dr. Tournigand and colleagues note that adjuvant chemotherapy, even without oxaliplatin, in stage II disease is not well established. "The identification of a patient population for which adjuvant therapy is necessary, safe, and effective continues to be challenging," they write.
An expert not involved in the study voices similar concerns.
It can be questioned whether these patients...merit any adjuvant therapy at all.
In an accompanying editorial, Robert Mayer, MD, from the Dana-Farber Cancer Center in Boston, Massachusetts, writes that "it can be questioned whether these [stage II] patients, whose prognosis is extremely favorable, merit any adjuvant therapy at all."
Dr. Mayer also equivocates about adding oxaliplatin to adjuvant chemotherapy in stage III disease (nonmetastatic disease and positive lymph nodes).
Various data, including from MOSIAC, have shown a "relatively modest" absolute improvement (3% to 5%) in overall survival in stage III patients with the addition of oxaliplatin to adjuvant chemotherapy (either in the form of FOLFOX or FLOX, which is oxaliplatin with a weekly bolus of fluorouracil and leucovorin).
However, this benefit needs to be "balanced" against chronic treatment-related toxic effects associated with oxaliplatin, especially symptomatic neurotoxicity, which was found to occur in 10% to 15% of patients more than 2 years after completion of treatment in MOSIAC and another major trial, C-07.
Both MOSAIC and C-07, which was conducted by the National Surgical Adjuvant Breast and Bowel Project and compared FLOX with fluorouracil plus leucovorin alone, are "high quality" randomized trials that were "carefully designed and meticulously analyzed," Dr. Mayer explains.
Stage II Data From MOSIAC
Although the routine use of oxaliplatin-containing adjuvant chemotherapy in stage III disease is a judgement call, Dr. Mayer suggests that its use in stage II is less so.
In the analysis by Dr. Tournigand's team, there was no "meaningful advantage" of FOLFOX over infusional fluorouracil plus leucovorin alone in stage II disease, he writes.
This was found in the 330 patients with standard-risk stage II disease (5-year disease-free survival hazard ratio [HR], 1.36; P = .305; 6-year overall survival HR, 1.36; P = .399) and in the 569 patients with high-risk stage II disease (5-year disease-free survival HR, 0.72; P = .062; 6-year overall survival HR, 0.91; P = .648).
High-risk disease was defined as having at least 1 of the following: T4 staging, tumor perforation, bowel obstruction, poorly differentiated tumor, venous invasion, and fewer than 10 lymph nodes examined.
For the high-risk group, the absolute difference in 6-year overall survival between FOLFOX and fluorouracil plus leucovorin alone was 1.7% (85.0% vs 83.3%).
The addition of oxaliplatin did not improve disease-free or overall survival in patients 70 to 75 years of age with either stage II or stage III cancer. "This finding is consistent with data from the C-07 study as well as a meta-analysis of the outcomes of more than 12,500 patients enrolled onto various adjuvant trials for colon cancer," Dr. Mayer writes.
Effect on Clinical Practice?
The use of oxaliplatin in adjuvant chemotherapy for stage II patients has become common with clinicians, Dr. Mayer points out.
That evidently happened after the initial publication of data from MOSIAC and the C-07 study, which showed a statistically significant improvement in disease-free survival, he observes.
This spawned hopes of a similar advantage in overall survival, and quickly changed clinical practice, Dr. Mayer notes. However, the data were immature, and definitely did not validate the use of oxaliplatin in the subset of patients with stage II disease, he says.
Nevertheless, the use of oxaliplatin added to fluoropyrimidine for patients with stage II disease jumped from 22.9% in 2004 to 78.8% in 2008, Dr. Mayer points out, citing a recent study (J Clin Oncol. 201129:3255-3262).
He does not find fault with clinicians. He asks: "Is it realistic to expect the oncology community and the patients we serve to ignore early results?"
Nor does Dr. Mayer call on clinicians to stop using oxaliplatin-containing adjuvant chemotherapy in stage II patients.
Instead, he notes that the current guidelines from the National Comprehensive Cancer Network recommend FOLFOX as an adjuvant treatment option for patients with high-risk colon cancer, which includes stage II disease.
"It will be interesting to observe if practice patterns with respect to high-risk, stage II disease change in the near future," he writes.
Overall, Dr. Mayer explains, the use of oxaliplatin as part of adjuvant chemotherapy for colon cancer is "more complicated than once thought."
The study was funded by sanofi-aventis. Dr. Tournigand and some coauthors report relationships with sanofi-aventis, which manufactures oxaliplatin. Dr. Mayer has disclosed no relevant financial relationships.

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