"We've shown for the first time that an alternative to standard chemoradiation is well tolerated with lower acute toxicity," said co-author Lucjan Wyrwicz.
Short-course radiation therapy and three cycles of chemotherapy before surgery improved overall survival (OS) for patients with locally advanced rectal cancer. The regimen, compared with standard chemoradiation, was also associated with fewer adverse events (AEs).
These findings were presented ahead of the 2016 Gastrointestinal Cancers Symposium, a meeting of hundreds of oncologists and other oncology professionals in San Francisco in mid-January.1
After three years of follow-up, 73 percent of patients treated with short course radiotherapy and chemotherapy remained alive compared with 65 percent with standard treatment, representing a significant advantage in OS. Overall, 75 percent of patients in the short course arm experienced an AE of any grade compared with 83 percent with standard chemoradiation.
However, despite these advantages, short course radiation plus chemotherapy failed to show a statistically significant advantage for the primary endpoint of R0 resections. In the short course arm, 77 percent of patients had R0 resections compared with 71 percent with standard chemoradiation. The pathologic complete response rate was 16 percent with short course radiation versus 12 percent with standard chemoradiation.
“We've shown for the first time that an alternative to standard chemoradiation is well tolerated with lower acute toxicity,” said co-author Lucjan Wyrwicz, head of Medical Oncology Unit in Department of Gastrointestinal Cancer at the Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology in Warsaw, Poland. “This is an early observation after a median of 35 months of follow-up but we report a survival benefit at three years, which is an 8 percent absolute benefit.”
In the study, 515 evaluable patients were randomized to receive short course radiation plus three cycles of chemotherapy (261 patients) or standard radiation therapy with chemotherapy (254 patients). All patients in the study had resectable cT3 or cT4 rectal cancer without distant metastases.
In the experimental arm, radiation was administered at 5 Gy for five days (total 25 Gy) plus FOLFOX4 (5-FU, leucovorin and oxaliplatin) on weeks 3, 5 and 7. In the standard arm, radiation was administered at 1.8 Gy for 28 fractions (total 50.4 Gy over 5.5 weeks). Chemotherapy included 5-FU plus leucovorin on days 1 to 5 and 29 to 32 plus oxaliplatin at 50 mg/m2 on days 1, 8, 15, 22 and 29.
There was a five- to six-week recovery time between neoadjuvant therapy and surgery. Overall, patients underwent surgery approximately 12 weeks following the initiation of neoadjuvant treatment. During enrollment in the study, the protocol was amended to remove oxaliplatin. Overall, 70 percent of those in the short-course arm and 66 percent of those in the standard treatment group received oxaliplatin.“At this point, I wish that six or seen years back we had not included oxaliplatin as part of standard therapy,” Wyrwicz said. “We wanted to maximize the patients care and activity of the treatment. Looking at the data, there are not substantial [efficacy and toxicity] differences between the early part of the study and the late part of the study.”
After a median follow-up of 35 months, the rates of disease-free survival (DFS), incidence of local failures, and the incidence of metastases were similar between both groups. The DFS in the short-course radiotherapy arm was 53 percent versus 52 percent in the standard arm. Local failures were seen in 22 percent and 21 percent of those in the short-course and standard radiation arms, respectively.
Despite an overall lower rate of acute toxicities with short-term radiation, a statistically significant difference was not seen for grade 3/4 AEs. In the short course arm the rate of grade 3/4 AEs was 23 percent versus 21 percent in the standard chemoradiation arm.
“The new regimen has similar efficacy but causes fewer side effects and is more convenient for patients. It is also less costly compared to standard chemoradiation, so it may be especially valuable in limited-resource settings,” explained Wyrwicz, in a statement.
Earlier studies assessing preoperative short course radiotherapy versus conventional fractionated radiotherapy failed to demonstrate a significant difference between the two treatments. However, these studies did not include oxaliplatin, which may have changed the results, and utilized chemotherapy in different settings.
In a randomized trial of 326 patients with T3 rectal cancer,2 short course radiation (25 Gy in one week), early surgery, and adjuvant chemotherapy was similar to longer course chemoradiation. The three-year local recurrence rates were similar between each arm. Moreover, there were no differences in toxicity or distant recurrence, relapse-free survival, and overall survival.
“We’re trying to fine-tune how we deliver treatment to patients prior to surgery, to maximize efficacy and convenience and minimize side effects,” Smitha Krishnamurthi, an expert from the American Society of Clinical Oncology (ASCO), said in a statement. “No doubt this study will be welcome news for patients with rectal cancer that we can successfully shrink tumors with a shorter course of radiation followed by chemotherapy.”