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Oxaliplatin pre-, post-surgery extends DFS for patients with advanced rectal cancer
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The addition of oxaliplatin to fluorouracil-based preoperative chemoradiotherapy and postoperative chemotherapy significantly improved DFS among patients with locally advanced rectal cancer, according to results of a phase 3 trial.
The regimens also appeared associated with reduced recurrence rates.
Although the addition of oxaliplatin has been shown to improve DFS and OS among patients who receive fluoropyrimidine-based adjuvant chemotherapy, prior research had not demonstrated clear evidence of its efficacy as part of a combination treatment for patients with locally advanced rectal cancer.
Claus Rödel, MD, professor of radiation oncology in the department of radiotherapy and oncology at Goethe University of Frankfurt in Germany, and colleagues from the German Rectal Cancer Study Group assessed oxaliplatin as an addition to other fluoropyrimidines during preoperative radiotherapy and as adjuvant treatment in phase 1 and 2 trials to establish an active regimen for the phase 3 trial.
Researchers enrolled 1,236 patients with stage III to IV rectal cancer and randomly assigned them to the control group (n = 623) or the investigational group (n = 613).
The control group received the standard fluorouracil-based combination — preoperative radiotherapy of 50.4 Gy in 28 fractions plus infusional fluorouracil (1000 mg/m2 on days 1 through 5 and days 29 through 33), followed by surgery and four cycles of bolus fluorouracil (500 mg/m2 on days 1 through five and day 29).
The investigational regimen consisted of preoperative radiotherapy of 50.4 Gy in 28 fractions plus infusional fluorouracil (250 mg/m2 on days 1 through 14 and days 22 through 35) and oxaliplatin (50 mg/m2 on days 1, 8, 22 and 29), followed by surgery and eight cycles of oxaliplatin (100 mg/m2 on days 1 and 15), leucovorin (400 mg/m2 on days 1 and 15) and infusional fluorouracil (2,400 mg/m2 on days 1 and 2 and on days 15 and 16).
DFS served as the primary endpoint.
After median follow-up of 50 months (interquartile range, 38-61), researchers reported 3-year DFS of 75.9% (95% CI, 72.4-79.5) in the oxaliplatin arm and 71.2% (95% CI, 67.6-74.9) in the control group (HR = 0.79; 95% CI, 0.64-0.98).
At 3 years, patients assigned oxaliplatin had reduced cumulative incidence of local recurrence (2.9% vs. 4.6%) and distanct recurrence (18.5% vs. 22.4%).
Rödel and colleagues observed preoperative grade 3 to grade 4 toxic effects in 24% of patients who received oxaliplatin during chemoradiotherapy and 20% of patients assigned standard chemoradiotherapy.
Researchers reported postoperative grade 3 to grade 4 toxic effects in 36% of patients assigned the adjuvant oxaliplatin regimen and 36% of patients assigned standard adjuvant chemotherapy.
Overall, late grade 3 to grade 4 adverse events occurred in 25% of patient assigned oxaliplatin and 21% of patient assigned standard therapy.
The most frequent grade 3 to grade 4 adverse event was diarrhea (7% in the investigational arm vs. 9% in the control arm).
“The regimen established by [this trial] can be deemed a new treatment option for patients with locally advanced rectal cancer,” Rödel and colleagues wrote. “The multimodal treatment of this disease might be further refined by giving combination chemotherapy as an induction therapy before preoperative chemoradiotherapy and surgery rather than as an adjuvant treatment.”
In an accompanying editorial, Bengt Glimelius, MD, professor in the department of immunology, genetics and pathology at Uppsala University in Sweden, praised the researchers for identifying the statistical significance of adding oxaliplatin to the treatment combination for locally advanced rectal cancer, but emphasized the findings may not be clinically relevant.
“At 3 years, the absolute gain in … DFS was 4.7% and the absolute gain for distant recurrences was 3.9%,” Glimelius wrote. “The target of clinical relevance was to decrease distant recurrences. It is not known if these gains are caused by the addition of preoperative or postoperative oxaliplatin, or by both. The controversial issue of the value of adjuvant chemotherapy in rectal cancer after preoperative chemoradiotherapy has not come closer to a solution.”
The reduction of recurrence associated with oxaliplatin may still be relevant, but the absolute risk of recurrence has been reduced because of better imaging, surgery and pathology since the inception of this trial, Glimelius wrote.
“Many patients are today treated with toxic therapies for gains that are much smaller than in the past,” he wrote. “Adding oxaliplatin … could result in a pronounced overtreatment, risking long-lasting neuropathy in many patients.” – by Anthony SanFilippo
Disclosure: Rödel reports grant funding from German Cancer Aid, as well as grants and personal fees from Merck-KGaA, Roche and Sanofi. Please see the full study for a list of all other researchers’ relevant financial disclosures.
Perspective
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Heather Yeo, MD, MHS
Rödel and colleagues have performed a well-designed multicenter open label randomized phase 3 study of locally advanced rectal cancer. However, caution needs to be exercised when using these results to counsel patients as the demonstrated absolute gain in DFS was low. Toxicity also needs to be considered, especially in light of the fact that the roles of neoadjuvant and adjuvant chemotherapy and chemoradiotherapy are still in evolution.
At 3 years, Rödel and colleagues report an absolute gain in DFS of 4.7% and the absolute reduction in distant recurrences of 3.9%. This absolute benefit of oxaliplatin is real, but should be balanced against the extra toxicity. Although differences may appear less striking than what has been shown in other trials because of the 5-FU schedule selected, still, 22% of those receiving oxaliplatin had a grade 2 neuropathy compared with 1% of those in the 5-FU group, and 11% had a grade 3 to grade 4 neuropathy compared with less than 1% respectively of those in the 5-FU group.
In addition, only 190 (44%) of patients in the oxaliplatin group were able to complete their fully allotted chemotherapy at the doses scheduled compared with 301 (65%) of patients in the FU group alone. There was no statistically significant difference in OS between the two groups, and there was a slight increase in treatment-related cause of death in the investigational group, even though slightly more patients died in the control group. As mentioned, the regimen chosen for the control group was more toxic than that seen in the PETACC-2 trial and other trials, making the toxicity from the control group higher than it might otherwise be.
Current management of rectal cancer is still under debate. There are several questions that still cannot be answered because of the way this study was designed. The benefit of oxaliplatin as a chemoradiosensitizer is still unclear. Several other trials have examined oxaliplatin alongside with 5-FU and radiation, and all others have failed to show a benefit. The neoadjuvant and adjuvant nature of this study make it difficult to know where oxaliplatin is having its effect. However, because the complete response rate was the same in both arms, it is possible that the benefit is more as adjuvant therapy than as a radiosensitizer.
As the researchers point out, due to current surgical technique and treatment options, local regional control is well obtained. The more life-threatening issue for patients is distant spread, an issue several groups are now addressing, in particular with regard to the use of neoadjuvant FOLFOX as opposed to or in addition to neoadjuvant chemoradiotherapy, the need for radiation therapy in the treatment protocol, and ways to identify pathologic complete responders. The trial by Rödel and colleagues was well done, but there are still many questions in the management of rectal cancer.
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