Improving quality of life, through more convenient treatment for patients with rectal cancer and by reducing unnecessary treatment for patients with advanced colorectal cancer, was the subject of two studies presented at the Gastrointestinal Cancers Symposium.
The meeting is cosponsored by the American Gastroenterological Association Institute, the American Society of Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.
“These studies exemplify the type of breakthrough research being released at the 2014 GI Symposium,” said Smitha S. Krishnamurthi, MD, Associate Professor of Medicine at Case Western Reserve University, who moderated a presscast before the meeting that highlighted noteworthy abstracts.
Rectal Cancer—Oral Agent Equivalent to IV Standard of Care
Results of the large National Surgical Adjuvant Breast and Bowel Project R-04 trial of stage III/IV rectal cancer “definitively give patients a more convenient treatment option” as it showed that two neoadjuvant regimens, oral capecitabine and continuous infusional fluorouracil (5-FU), were equivalent when added to neoadjuvant radiotherapy (Abstract 390), she said.
It also adds to data from prior trials that oxaliplatin does not improve tumor response in this setting. The study, with 1,567 patients, “establishes capecitabine as a standard of care in the preoperative rectal setting,” said the lead author, Carmen J. Allegra, MD, Professor of Medicine and Chief of the Division of Hematology & Oncology at the University of Florida, Gainesville.
He noted that while R-04 was focused on the NSABP it was contributed to by virtually all the U.S. cooperative groups. Preliminary results of R-04 focusing on pathologic complete response, sphincter-sparing surgery, surgical downstaging, and toxicity had been presented at the 2011 ASCO Annual Meeting (Roh et al, Abstract 3503).
In the four-arm study, patients with rectal adenocarcinoma less than 12 cm from the rectal verge were randomly assigned to one of four arms of neoadjuvant therapy:
- Continuous infusion 5-FU plus radiotherapy;
- The continuous infusion 5-FU regimen with the addition of weekly oxaliplatin, plus radiotherapy;
- Capecitabine plus radiotherapy; and
- Capecitabine plus oxaliplatin plus radiotherapy.
Allegra reported no difference in three-year locoregional recurrences, which ranged from 87.4 to 88.2 percent. “There was virtually no difference whether one used 5-FU or capecitabine, or whether one used oxaliplatin or not,” he said. Similarly, the rates of overall survival and progression-free survival with either 5-FU or capecitabine were indistinguishable.
Results also were virtually indistinguishable whether or not the regimen included oxaliplatin—added to the regimen ostensibly to enhance the activity of fluoropyrimidine-sensitized radiotherapy.
But there was a significant increase in both overall and grade 3/4 diarrhea with the addition of oxaliplatin to either capecitabine or 5-FU and it did not add to survival.
Three-year rates of locoregional recurrence among patients who underwent R0 resection ranged from two to four percent for stage II patients, and from four to 11 percent for stage III patients. Distant metastases were reported at five years by 16 percent of stage II and 26 percent of stage III patients. But there was no difference in mortality among the four treatment arms, Allegra reported.
Colorectal Cancer: Expanded KRAS Testing Reveals Nonresponders
Testing for the mutational status of KRAS exon-2, -3, and -4 should be the standard of care for certain patients with metastatic colorectal cancer, according to a further analysis of the Phase III 20050181 trial (Abstract LB387).
KRAS exon-2 is already an established predictive biomarker of response to anti-EGFR therapies in this disease, noted Marc Peeters, MD, PhD, Professor of Oncology at Antwerp University Hospital in Belgium.
The new analysis corroborates the need for expanded testing, he said, particularly for patients who might be treated with panitumumab, because patients with mutated tumors in the RAS genes are unlikely to benefit from the addition of panitumumab to FOLFIRI.
“These results clearly support the fact that we need RAS testing when we want to treat patients with panitumumab in the setting of metastatic colorectal cancer,” Peeters said.
In the original study, 1,186 patients were enrolled after first-line treatment failed, and they were randomized to receive panitumumab with FOLFIRI or FOLFIRI alone.
All patients were tested for KRAS exon2 status by routine screening with an investigational kit from Qiagen, and further analysis by Sanger sequencing.
This latest analysis evaluated the treatment effect of FOLFIRI alone versus FOLIO-panitumumab in patients with mutant and wild-type exon2, 3, and 4 of both KRAS and NRAS, on progression-free survival and overall survival.
The expanded RAS testing identified an additional 18 percent of patients who did not benefit from panitumumab in the second-line setting. “We found that we have a very high RAS ascertainment rate in this population, 85 percent, but we also found that 18 percent of patients have wild-type tumors with additional mutation outside the KRAS exon2,” Peeters said. “This had a clear impact on the outcome of these patients—when we did further analysis we saw an improvement in the treatment effect by progression-free survival and overall survival when treatment was based on the wild-type RAS status.”
The objective response rate in patients treated with panitumumab-FOLFIRI based on their KRAS exon2 status was 35 percent, versus 10 percent for FOLFIRI alone.
Krishnamurthi noted that a report of the additional 17 percent of patients identified as RAS mutant with expanded testing in the PRIME study of panitumumab-FOLFOX as first-line setting was presented at the most recent ASCO Annual Meeting (Abstract 3620).
“The new data, as well as data from other studies at this meeting (Abstract 587 and Abstract 493) indicate that expanded RAS testing should become the standard of care in order to best identify patients who benefit from anti-EGFR therapy,” Krishnamurthi said.