Could neoadjuvant radiation dose escalation increase tumor response and recurrence-free survival in patients with locally advanced rectal cancer?

Neoadjuvant chemoradiotherapy (CRT), followed by total mesorectal excision, is recommended for patients with locally advanced rectal cancer [1,2]. Neoadjuvant radiotherapy can improve the local control and sphincter preservation rates in patients with rectal cancer. The advantages of neoadjuvant radiotherapy were recognized by the Swedish Rectal Cancer Study Group, which demonstrated a significant reduction in locoregional recurrence rates in 1,168 enrolled patients [3]. Standard long-course neoadjuvant radiotherapy for rectal cancer consists of a total dose of 45–50.4 Gy delivered in 25–28 daily fractions [2,4]. The clinical outcome after neoadjuvant CRT is mainly dependent on the tumor response and 10–15% of patients with rectal cancer experience a pathological complete response (ypCR) after CRT with a standard radiation dose of 45–50.4 Gy [4–6]. A meta-analysis showed that a higher radiation dose delivered to a rectal tumor was associated with a better tumor response rate [7]. However, this often leads to an increased risk of adverse effects and surgical complications [8].

In the previous issue of the Radiation Oncology Journal, the study entitled "Clinical outcomes of neoadjuvant chemoradiotherapy followed by total mesorectal excision in locally advanced rectal cancer with mesorectal fascia involvement" by Lee et al. [9] analyzed the clinical outcomes and efficacy of dose-escalated neoadjuvant concurrent CRT for patients with locally advanced rectal cancer involving mesorectal fascia. Patients who received radiation doses of ≤50.4 Gy were defined as the non-boost group, whereas those receiving ≥54.0 Gy as the boost group. After a median follow-up of 32.4 months, the 5-year intrapelvic recurrence-free survival (RFS) rates were 90.3% and 87.0% (p = 0.242), the 5-year distant metastasis-free survival rates were 82.0% and 71.3% (p = 0.105), and the 5-year overall survival rates were 93.0% and 80.6% (p = 0.439). Treatment-related toxicity was comparable between the two groups (p = 0.211). Although the boost group included patients with more advanced clinical T4 stages (21.1% vs. 32.9%; p = 0.021) and increased carcinoembryonic antigen level of ≥10 ng/mL (14.5% vs. 26.8%; p = 0.008) as compared to the non-boost group, this retrospective study failed to confirm the efficacy of dose-escalated radiotherapy in recurrence and survival for patients with rectal cancer.

Another clinically relevant covariate for tumor response is surgical interval (<6 vs. ≥6 weeks) after the end of preoperative radiotherapy. Longer surgical intervals were associated with higher rates of ypCR and lower rates of local recurrence [10]. However, in the recent GRECCAR-6 trial [11], extending the waiting period by 4 weeks (7- vs. 11-week waiting period) following preoperative CRT had no significant influence on ypCR and RFS of patients with locally advanced rectal cancer. In the RECTAL-BOOST trial [12], compared with standard CRT, dose-escalated CRT resulted in a transient deterioration in global health and increased fatigue and diarrhea at 3 months after the start of radiotherapy without increasing the tumor response. Further research is required to identify the dose-response relationship in the regression analysis of tumor response after radiotherapy in rectal cancer [13].

An optimal radiation-dosing schedule, taking into account the radiation toxicity and postoperative surgical complication could improve the long-term oncologic outcomes for patients with rectal cancer who received preoperative CRT and curative surgery.