Traditionally, 5-fluorouracil (5-FU) has been used as a radio-sensitizing agent in a neoadjuvant setting for the treatment of patients with rectal cancer. After a new cytotoxic agent, oxaliplatin, showed improved disease control in an adjuvant setting, many trials were conducted to improve the tumor response by adding more cytotoxic agents, or even molecular target agents, during radiation therapy. The results of recent clinical trials are summarized in Table 1. A German trial was the only one that showed statistically significant differences in the pCR rate by adding oxaliplatin to radiation therapy [16]. Other trials, including NSABP R-04, showed an increase in grade 3–4 chemotherapy-related toxicities and a decreased compliance of treatment when oxaliplatin was added [17-26]. Additionally, the NSABP R-04 trial showed that continuous infusion of 5-FU was equivalent to oral capecitabine in terms of pCR rate and downstaging of the tumor [17, 25]. Based on these clinical trials, many other recent trials have adopted oral capecitabine as a radiosensitizer.

The decision to prolong the time interval from 2 weeks to 6 to 8 weeks to achieve a higher pCR is based on the findings of recent clinical trials [27]. More recently, some investigators have tried to delay surgery beyond the classical 6 to 8 weeks from the time of completion of radiation therapy. Petrelli et al. [28] performed a meta-analysis regarding prolonging the time interval and concluded that the pCR rate increased from 13.7% to 19.5% in the longer interval group (>6–8 weeks). However, OS, DFS, R0 resection rate, sphincter preservation and complication rates were similar between the longer interval (>6–8 weeks) and the shorter interval (<6–8 weeks) groups.

Recent studies have suggested an even longer waiting period of up to 12 weeks or more. A UK 6- vs. 12-week trial reported a pCR rate of 6% in the 6-week group compared with 20% in the 12-week group [29]. Conversely, the French GRECCA-6 study reported no differences in pCR rate between the 7-week and the 11-week groups, but postoperative complications (32% vs. 44.5%) were increased and the quality of TME specimens (90% vs. 78.7%) was poor in the 11-week group [30].

An increased waiting period might achieve pCR even in short-course radiation therapy [31]. However, concerns about tumor-cell repopulation during the prolonged waiting period have been expressed, so currently no consensus as to the length of the waiting period exists. Greater, well-designed randomized studies are needed to confirm the efficacy of an increased waiting period in the treatment of patients with rectal cancer.

Although PCRT has shown an improvement in local control, it has not shown improved DFS or OS for patients with LARC (Table 2) [3-9]. Upfront chemotherapies, such as induction or consolidation chemotherapy and total neoadjuvant therapy (TNT), have been introduced to improve and achieve survival benefits and are being actively tested in ongoing trials.

Updated National Comprehensive Cancer Network (NCCN) guidelines suggest induction chemotherapy with FOLFOX or CAPEOX followed by PCRT and transabdominal surgery as treatment options for patients with LARC [2]. Even though induction chemotherapy is not yet approved for coverage by Korean insurance, it has been widely applied in the care of patients with LARC. Gao et al. [32] reported the results of a phase-2 trial using neoadjuvant sandwich treatment with CAPEOX administered prior to and concurrently with flowing radiation therapy for patients with LARC. Among 49 eligible patients, 45 patients underwent optimal surgery, and the pCR rate was 42.2%. When the 4 patients with cCR who refused surgery were considered, the pCR rate rose to 46.9%. The French GRECCA-4 trial tested induction chemotherapy with FOLFIRINOX (5-FU, irinotecan and oxaliplatin) chemotherapy in patients with LAR [33]. Of these patients, 15% showed more than 75% tumor shrinkage 2 weeks after induction chemotherapy. The study was terminated early due to the relatively low treatment efficacy of induction chemotherapy; however, when the inclusion criteria of the patients, such as more than mrT3c or mrT4 tumors or a threatened circumferential resection margin less than 1 mm, were examined, induction chemotherapy might have played some role in the management of patients with LARC.

The main ideas of consolidation chemotherapy are in regard to the potential benefits of improved local and systemic control of LARC when chemotherapy is added during the waiting period between completion of PCRT and surgery. A timing trial reported both short- and long-term outcomes [34, 35]. That study divided patients into 4 groups according to the duration of consolidation chemotherapy. Compared with the no-consolidation group (pCR rate of 18%), adding 2-, 4-, and 6-cycles of FOLFOX consolidation chemotherapy resulted in pCR rates of 25%, 30%, and 38%, respectively. With a median follow-up of 59 months, DFS differed significantly between the no-consolidation group and the consolidation groups. Furthermore, the consolidation groups showed a better compliance to chemotherapy compared to the nonconsolidation group. Other studies, done by Polish and Korean groups used short-course radiation therapy for the treatment of patients with LARC and demonstrated an increased pCR rate with consolidation chemotherapy; however, the improved pCR rate was not statistically significant [31, 36].

Currently, the NCCN guidelines recommend 4 months of adjuvant fluoropyrimidine-based chemotherapy for all patients who receive PCRT and undergo surgical resection, regardless of pathologic findings [2]. These recommendations are not based on direct evidence from randomized trials, but are instead supported by extrapolation from the demonstrated survival benefits in colon cancer adjuvant chemotherapy trials. To date, only 4 randomized clinical trials [37-40] and 1 meta-analysis [41] to test the benefits of adjuvant chemotherapy in the treatment of patients with rectal cancer have been published. Many compounding factors have precluded the finding of evidence in those trials. Of these factors, postoperative complications and resultant poor compliances in adjuvant chemotherapy should be considered. Adopting upfront systemic chemotherapy, which is a growing area of active research on treating patients with LARC, may be a way to overcome these limitations in the effective administration of adjuvant chemotherapy. Recent trials to evaluate the effectiveness of TNT are summarized in Table 3 [42-47]. Many potential benefits, such as early control of micrometastases and improved compliance of chemotherapy, can be achieved by delivering all scheduled systemic chemotherapy before surgery. Moreover, TNT that is effectively delivered before surgery may improve tumor response and increase the probability of successful sphincter-preserving surgery.

The traditional radiation dose for patients with LARC is 5,040 cGy or 2,500 cGy. A recent trial conducted in Denmark proposed increasing the radiation dose to 70 Gy, and this achieved a cCR in 78.4% of the patients [48]. Brachytherapy is also an alternative treatment option for patients that are medically unfit for surgical approaches [49, 50].