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SAN FRANCISCO -- Short-course radiotherapy, followed by brief chemotherapy, failed to improve the resection rate in advanced rectal cancer but demonstrated equivalence to conventional chemoradiation with less toxicity, a large randomized trial showed.

Analysis of the primary endpoint showed successful tumor resection occurred in 77% of patients randomized to the alternative regimen versus 71% for conventional treatment. The difference failed to achieve statistical significance (P=0.081).

An early survival analysis revealed a trend favoring the alternative regimen, which deserves consideration as a new therapeutic standard for advanced rectal cancer and warrants investigation in resectable disease, , of the Maria Sklodowska-Curie Memorial Cancer Center in Warsaw, reported at the Gastrointestinal Cancers Symposium.

"Despite the fact that the trial was negative, in that superiority in radical resection rate was not shown, short-course radiotherapy combined with three cycles of chemotherapy can be recognized as a new standard of treatment for advanced rectal cancer with threatened resection margin (fixed cT3 or cT4)," Wyrwicz said during a press briefing that preceded the symposium here. "Lower acute toxicity and a shorter duration of radiotherapy are among advantages of this novel therapy."

Even though the trial turned out negative, Wyrwicz emphasized the positive, noting that "having two standards is better than having one standard. If we say, in 2016, there should be one kind of treatment for rectal cancer, it sounds stupid."

Press briefing moderator , of University Hospitals Case Medical Center in Cleveland, agreed that the results offer patients more than one approach to treatment. She also acknowledged that the two strategies appear to provide similar clinical outcomes and pointed out that alternative regimen improves patient convenience and time requirements and reduces costs.

Neoadjuvant chemoradiation has been standard of care for patients who have rectal cancers with threatened resection margin, defined as fixed clinical stage T3 tumors that have limited mobility on rectal examination, as well as cT4 tumors that have spread to adjacent tissues. Two previous trials demonstrated the equivalence of a chemoradiation protocol lasting about 5.5 weeks and a 5-day hypofractionated radiotherapy protocol for resectable rectal cancer, Wyrwicz said.

Whether a short-course protocol could outperform standard treatment in a high-risk population remained unclear. Wyrwicz reported findings from the randomized, multicenter trial to compare a 5-day radiotherapy protocol followed by three cycles of chemotherapy versus standard chemoradiation.

Investigators randomized 515 patients to a 5-day course of radiotherapy (5 Gy to the pelvis per session) followed a week later by three cycles of chemotherapy (separated by 2 weeks per cycle) or to the standard chemoradiation regimen consisting of a cumulative radiation dose of 50.4 Gy in 28 fractions administered simultaneously with FOLFOX4.

The trial had a primary endpoint of successful radical resection of rectal tumor (R0 postresection status), which the results did not meet. The rate of pathologic complete response also did not differ between treatment groups, 16% with the experimental regimens and 12% with conventional treatment (P=0.17).

The experimental regimen was associated with a reduced acute toxicity burden (75% versus 83%, P=0.006), although grade 3/4 toxicities occurred in a similar proportion of patients in the two treatment groups (23% versus 21%).

A survival analysis performed after a median follow-up of 35 months showed a 3-year overall survival of 73% with the experimental regimen and 65% with the conventional treatment, a difference that did achieve statistical significance (P=0.046). However, Wyrwicz cautioned that survival data remain immature, and additional follow-up will be required to determine whether a true survival difference exists.

Disease-free survival and the incidence of local and distant failure did not differ between the treatment groups.

After the trial began, data emerged to show that the addition of oxaliplatin to 5FU did not improve outcomes but added to toxicity. As a result, investigators were given the option of omitting oxaliplatin from chemotherapy. Wyrwicz said 65% to 70% of patients in both treatment arms received oxaliplatin.

During a discussion that followed Wyrwicz's presentation, Krishnamurthi pointed out a couple of issues that could influence acceptance of the alternative regimen. Use and adoption of short-course radiotherapy varies geographically, being more popular in Europe than in the U.S. Additionally, results of an showed a higher recurrence rate with short-course therapy in the subgroup of patients with distal tumors.

Wyrwicz countered that the recurrence difference in the Australian study did not achieve statistical significance and had won little support in research and clinical circles.

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