New Neoadjuvant Regimen Shows Similar Efficacy, Less Toxicity in Rectal Cancer

Preoperative treatment with short-course radiation therapy plus 3 cycles of chemotherapy improved overall survival (OS) and was associated with fewer adverse events compared with standard chemoradiation for patients with locally advanced rectal cancer.

Lucjan Wyrwicz, MD, PhD

Preoperative treatment with short-course radiation therapy plus 3 cycles of chemotherapy improved overall survival (OS) and was associated with fewer adverse events (AEs) compared with standard chemoradiation for patients with locally advanced rectal cancer, according to findings presented ahead of the 2016 Gastrointestinal Cancers Symposium.1

After 3 years of follow-up, 73% of patients treated with short course radiotherapy and chemotherapy remained alive compared with 65% with standard treatment, representing a significant advantage in OS (P = .046). Overall, 75% of patients in the short course arm experienced an AE of any grade compared with 83% with standard chemoradiation (P = .006).

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% of patients had R0 resections compared with 71% with standard chemoradiation (P = .081). The pathologic complete response rate was 16% with short course radiation versus 12% with standard chemoradiation (P = .17).

“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, MD, PhD, 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 3 years, which is an 8% absolute benefit.”

In the study, 515 evaluable patients were randomized to receive short course radiation plus 3 cycles of chemotherapy (n = 261) or standard radiation therapy with chemotherapy (n = 254). 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 5 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 5 to 6 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% of those in the short-course arm and 66% of those in the standard treatment group received oxaliplatin.

“At this point, I wish that 6 or 7 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% versus 52% in the standard arm (P = .85). Local failures were seen in 22% and 21% of those in the short-course and standard radiation arms, respectively (P = .82).

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% versus 21% 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 1 week), early surgery, and adjuvant chemotherapy was similar to longer course chemoradiation. The 3-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,” ASCO Spokesperson Smitha Krishnamurthi, MD, 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.”


  1. Bujko K, Wyrwicz L. Neoadjuvant Chemoradiation for Fixed cT3 or cT4 Rectal Cancer: Results of a Polish II Multicentre Phase III Study. J Clin Oncol. 2016;34 (suppl 4S; abstr 489).
  2. Ngan SY, Burmeister B, Fisher RJ, et al. Randomized Trial of Short-Course Radiotherapy Versus Long-Course Chemoradiation Comparing Rates of Local Recurrence in Patients With T3 Rectal Cancer: Trans-Tasman Radiation Oncology Group Trial 01.04. J Clin Oncol. 2012;30(31):3827-3833


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