Trial doesn't show clear benefit of oxaliplatin for rectal cancer

Last Updated: 2015-07-22

By Will Boggs MD

NEW YORK (Reuters Health) - Adding oxaliplatin to standard therapy for locally advanced rectal cancer yields slightly better disease-free survival, according to results from the German CAO/ARO/AIO-04 study.

In colon cancer, adding oxaliplatin to adjuvant chemo improves not just disease-free survival but overall survival as well. Given the current study, however, the value of added oxaliplatin for locally advanced rectal cancer is still a matter of debate.

Dr. Claus Rodel from University of Frankfurt, Germany and colleagues compared the established regimen for locally advanced rectal cancer with an investigational protocol in which oxaliplatin was added to chemotherapy both before and after surgery.

In the open-label phase 3 trial of 1265 patients, significantly more patients in the oxaliplatin group achieved a pathological complete response (17% vs 13%). The rate of distant metastases was also lower with oxaliplatin (3% vs 6%).

At three years, the probability of disease-free survival (DFS; the primary endpoint) was significantly higher with oxaliplatin (75.9% vs 71.2%).

Fewer oxaliplatin patients (2.9% vs 4.6%) had local recurrence at three years; distant recurrences were also less common with oxaliplatin (18.5% vs 22.4%).

Overall toxicity did not differ significantly between the groups, and there was no difference in the proportion of patients with complete locoregional resection, the authors reported online July 16 in Lancet Oncology.

Three-year overall survival, however, did not differ significantly between the groups (88.7% and 88.0% in the intervention and control groups, respectively).

The researchers say the regimen tested in their trial "can be deemed a new treatment option for patients with locally advanced rectal cancer."

"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," they add. "This concept of total neoadjuvant treatment is currently being addressed in our CAO/ARO/AIO-12 randomized phase 2 study."

Other experts question the value of adding oxaliplatin.

In an editorial, Dr. Bengt Glimelius from Uppsala University in Sweden writes, "The controversial issue of the value of adjuvant chemotherapy in rectal cancer after preoperative (chemo)radiotherapy has not come closer to a solution. The different fluoropyrimidine schedules in the experimental and control groups prevent an assessment of the efficacy and toxic effects of oxaliplatin."

Also, he writes in the editorial, "The absolute 4-5% benefit should be balanced against the extra toxicity from oxaliplatin."

Furthermore, using oxaliplatin preoperatively and postoperatively as it was in this trial (cT3-4, any N+) "could result in a pronounced overtreatment, risking long-lasting neuropathy in many patients," Dr. Glimelius adds. "Updated results from additional trials will add to the knowledge base and make estimations of the potential gains clearer."

Dr. Jerome C. Landry from Emory University's Winship Cancer Institute in Atlanta, Georgia told Reuters Health by email, "Based on the abundance of evidence both in terms of general lack of efficacy for pre-op oxaliplatin and the increased toxicity demonstrated, I do not believe this is the standard of care, and infusional 5-fluorouracil or daily Xeloda with radiotherapy remains the standard."

"The benefit in three-year DFS seen in the German trial is more likely due to the use of adjuvant FOLFOX chemotherapy rather than pre-op oxaliplatin, since the randomization was regarding the addition of oxaliplatin to both the neoadjuvant and adjuvant phases," Dr. Landry said.

"These findings don't really change standard of care as I see it," Dr. Landry concluded. "Standard of care remains fluoropyrimidine based neoadjuvant radiotherapy followed by total mesorectal excision surgery and adjuvant FOLFOX (at least for patients with residual stage II or III disease)."

Dr. Theodore S. Hong from Massachusetts General Hospital in Boston recommends a middle road. He told Reuters Health by email, "There is likely a role for oxaliplatin in some of these patients. As the authors correctly point out, other data suggest that some patients benefit from the use of oxaliplatin given postoperatively with 5-fluorouracil."

The "greater controversy," he added, involves use of oxaliplatin with chemoradiation before surgery.

"Multiple other randomized trials suggest no benefit but greater toxicity with the addition of oxaliplatin to the preoperative regimen," Dr. Hong said. "This study is difficult because it added oxaliplatin both pre and postoperatively, making (it) impossible to determine where the benefit is derived from. However, the National Comprehensive Cancer Network (NCCN) guidelines recommend no oxaliplatin preoperatively with chemoradiation, but use of oxaliplatin postoperatively."

"Tremendous strides have been made in the outcomes of patients with locally advanced rectal cancer, and currently locally advanced rectal patients are recommended to receive preoperative radiation alone or chemoradiation, followed by chemotherapy with 5-FU and oxaliplatin," Dr. Hong added. "However, when outcomes are greatly improved, there is always the potential of overtreatment. The randomized trials actually have failed to show routine benefit in overall survival with postoperative chemotherapy, and radiation can be associated with long-term side effects. Ongoing trials seek to determine who actually needs this much therapy."

Dr. Rodel did not respond to a request for comments.

SOURCE: http://bit.ly/1gP71k2

Lancet Oncol 2015.