Challenges and shifting treatment strategies in the surgical treatment of locally advanced rectal cancer

Abstract The current standard treatment for locally advanced rectal cancer (LARC) in Korea and Western countries is a multimodal approach incorporating preoperative long‐course chemoradiotherapy (LCRT) followed by total mesorectal excision (TME) and adjuvant chemotherapy. This approach has significantly improved local control and reduced recurrence rates; however, the overall survival benefit has not been established. Although LCRT is a good option, there remain challenging unresolved problems for colorectal surgeons. We focused on four challenging issues in this review article. The first is LARC with resectable liver metastases, for which there has been no consensus regarding optimal management and practice thus far. The second is cancer progression at the time of restaging after completion of preoperative LCRT. To date, there have been few reports on this issue. The third is early recurrence after TME following preoperative LCRT, the reason for which is thought to be the delayed systemic chemotherapy in the preoperative LCRT protocol. The fourth is cost‐effectiveness. The preoperative LCRT protocol takes 5 weeks. After a 6‐8‐week waiting period, surgery is performed. Therefore, it is more time‐consuming than short‐course chemoradiotherapy. To overcome these issues, total neoadjuvant treatment (TNT) modalities, performed using various protocols, have been conducted globally based on cumulative experience. We also attempted to discuss previous TNT protocols in this article. One treatment strategy is not sufficient for patients with varying clinical characteristics. Therefore, we should revisit current treatment strategies based on recent clinical experience.


Abstract
The current standard treatment for locally advanced rectal cancer (LARC) in Korea and Western countries is a multimodal approach incorporating preoperative longcourse chemoradiotherapy (LCRT) followed by total mesorectal excision (TME) and adjuvant chemotherapy. This approach has significantly improved local control and reduced recurrence rates; however, the overall survival benefit has not been established. Although LCRT is a good option, there remain challenging unresolved problems for colorectal surgeons. We focused on four challenging issues in this review article. The first is LARC with resectable liver metastases, for which there has been no consensus regarding optimal management and practice thus far. The second is cancer progression at the time of restaging after completion of preoperative LCRT.
To date, there have been few reports on this issue. The third is early recurrence after TME following preoperative LCRT, the reason for which is thought to be the delayed systemic chemotherapy in the preoperative LCRT protocol. The fourth is cost-effectiveness. The preoperative LCRT protocol takes 5 weeks. After a 6-8-week waiting period, surgery is performed. Therefore, it is more time-consuming than short-course chemoradiotherapy. To overcome these issues, total neoadjuvant treatment (TNT) modalities, performed using various protocols, have been conducted globally based on cumulative experience. We also attempted to discuss previous TNT protocols in this article. One treatment strategy is not sufficient for patients with varying clinical characteristics. Therefore, we should revisit current treatment strategies based on recent clinical experience.

| CURRENT TRE ATMENT S TR ATEG IE S FOR LO C ALLY ADVAN CED REC TAL C AN CER
Before discussing the treatment of locally advanced rectal cancer (LARC), we should define the rectum. In Japan, the rectum is divided into the rectosigmoid (the sacral promontory to the inferior border of the second sacral vertebra), upper rectum (the second sacral vertebra to the peritoneal reflection), and lower rectum (the peritoneal reflection to the superior border of the puborectal sling). 1 However, the definition of the rectum is different in Japan from those in Western countries and Korea. Moreover, the definition differs even among Western countries. In the national comprehensive cancer network (NCCN) guidelines, the rectum is defined as the portion of the bowel located below the pelvic inlet (an imaginary line drawn from the sacral promontory to the top of the pubic symphysis) as determined by dedicated magnetic resonance imaging (MRI) of the pelvis. The rectum is divided into the upper rectum (above the anterior peritoneal reflection), mid-rectum (at the anterior peritoneal reflection), and lower rectum (below the anterior peritoneal reflection). 2 In the European Society for Medical Oncology (ESMO) guideline, tumors with 15-cm distal extension from the anal margin (as measured by rigid sigmoidoscopy) are classified as rectal cancers. Cancers are categorized as low (up to 5 cm), middle (>5-10 cm), or high (>10 up to 15 cm). 3 In Korea, we use a definition similar to that in the ESMO guideline, in which the rectum is divided into the upper, mid, and lower rectum by 4-5 cm.
In this review article, we used the definition from the Western guideline, as most of the introduced studies and treatment strategies were from Western countries.
Traditionally, preoperative long-course chemoradiotherapy (LCRT) combined with radiosensitizing chemotherapy followed by total mesorectal excision (TME) and postoperative adjuvant chemotherapy has been used for LARC in Western countries and Korea.
In the German CAO/ARO/AIO-94 trial, neoadjuvant treatment, consisting of 50.4-Gy radiation in 28 fractions, with concurrent chemotherapy and continuous 5-fluorouracil (FU) infusion, resulted in significantly better outcomes than adjuvant treatment in terms of lower local recurrence (LR) (6% vs 13%, P = .006) and lower toxicity rate (27% vs 40%, P = .001). 4 Neoadjuvant CRT is better tolerated than postoperative CRT, allows curative resection after downstaging, and results in improved sphincter preservation rates. The German trial established preoperative LCRT as the preferred concurrent option for LARC.
Several European studies have looked at the efficacy of preoperative short-course radiotherapy (SCRT) (25 Gy over 5 days). The results of the Swedish Rectal Cancer Trial, evaluating the use of SCRT administered preoperatively for resectable rectal cancer, showed a survival advantage and a decreased rate of LR compared with the use of surgery alone. 5 The Dutch TME trial on SCRT reported that 10-year survival was significantly improved in patients with stage III disease and a negative circumference resection margin (CRM) in the RT plus surgery group compared to the surgery-only groups (50% vs 40%, P = .032). 6 Along with RT, adjuvant chemotherapy is a matter of debate. Currently, total neoadjuvant therapy (TNT) has been highlighted as the treatment modality for LARC. TNT is defined as chemotherapy using cycles of induction or consolidation in conjunction with standard CRT prior to surgery. The rationale for TNT includes early introduction of systemic treatment to address micrometastases, earlier reversal of diverting ileostomy, decreased toxicity rates, and increased tumor regression that can enhance complete (R0) resection rates and optimize adaptive strategies and patient selection for organ preservation. 9 In a recent systemic review and meta-analysis, TNT increased the risk of pathologic complete response (pCR) by 39% (P = .01). Moreover, patients who received TNT and surgery had a better DFS (Hazard ratio [HR] = 0.75, 95% confidence interval [CI] 0.52-1.07, P = .1) and OS (overall survival) (HR = 0.73, 95% CI 0.59-0.9, P = .004) than those who received standard CRT. 10 In this review, based on accumulated clinical experience, we would like to address a couple of issues that have proven very challenging in the treatment of patients with LARC.

| LARC with resectable liver metastases
In guidelines on colorectal cancer, if both distant metastases and the primary tumor are resectable, curative resection of the primary tumor is performed and resection of the distant metastases is considered. 2,3,11 The NCCN guideline also recommends upfront chemotherapy as the primary treatment even in resectable synchronous liver metastases (LM). 2 However, currently, there is no consensus regarding optimal management and practice.
In rectal cancer with synchronous LM, a more complex procedure for the determination of optimal treatment strategies is required, particularly when patients present with LARC. This is because local treatment with RT is definitely needed for tumor regression of the primary tumor. Delay of administration of systemic therapy has become a great concern because of the potential progression of LM beyond resectability during preoperative LCRT. Accordingly, there is a need for early administration of preoperative systemic chemotherapy and shortened duration of RT owing to the metastatic condition. 12 Chemotherapeutic agents used in LCRT include 5-FU regimens that are used as radiosensitizers. 13 The dose is too small for systemic control of LM.
For systemic and local treatment simultaneously, we instituted our own "sandwich" protocol in our institution ( Figure 1). This aimed to systemically control first LM; then, SCRT with delayed surgery was adopted for LARC. We administer four cycles of systemic chemotherapy as induction chemotherapy, followed by SCRT for 5 days.
Subsequently, additional chemotherapy of the same regimen can be administered during the waiting period to allow tumor regression.
After restaging, simultaneous resection for primary rectal cancer and LM was performed. This protocol allows systemic chemotherapy to be administered earlier, and surgery can be planned after the evaluation of tumor response at least 6 weeks after completion of SCRT. A case series of six patients with LARC with synchronous and potentially resectable distant metastases was reported in 2011. 14 The investigators reported that R0 resection was achieved, except for a primary tumor in one patient. Neither LR nor mortality was observed, and there were acceptable adverse events. This protocol can also be adopted in LARC with LM, even though they are unresectable. A phase II single-arm study for LARC with synchronous liver-only metastases was conducted. 15 This study was focused on LARC with synchronous liver-only metastases (no number or size limitation of LM). Among 32 patients, surgical resection was performed in 25 patients (78%), and an R0 resection rate of 63% for both sites was recorded. The tumor downstaging rate was 54%. We are still waiting for long-term outcomes in these patients.
In addition to a primary tumor-first approach, a liver-first approach was first described in 2006 in an effort to overcome progression of LM. 16 The liver-first approach consists of upfront chemotherapy followed by liver resection and subsequent CRT and

| Early recurrence after TME following preoperative LCRT
Early recurrence occurring within one year after surgery for primary rectal cancer has been linked to systemic failure and poor survival. 19 Early recurrence reflects aggressive biologic behavior. This is the reason early systemic chemotherapy is necessary. Delayed systemic chemotherapy in the preoperative LCRT protocol can be the reason F I G U R E 1 Sandwich protocol for no benefit on OS, despite the fact that local control may have been obtained. 20 Recently, EMVI has been studied in detail ( Figure 2). EMVI is defined as tumor cells invading the veins beyond the muscularis propria; it is relatively common in T3-4 tumors. 21 EMVI is closely associated with local and systemic recurrence. 22 Studies have shown the advantages of high-resolution MRI in detecting EMVI. 23 When we compared patients with and without mrEMVI after preoperative LCRT, significant differences were observed in terms of 5-year DFS (80.8% vs 57.8% P = .005) and 5-year systemic recurrence-free survival rates (86.9% vs 64.3%, P = .007). Furthermore, mrEMVI was a significant independent prognostic factor for systemic recurrence (HR: 3.321, 95% CI: 1.185-9.309, P = .022). 24 For patients who show poor response to LCRT, consolidation chemotherapy consisting of systemic chemotherapy after LCRT before TME can be an option. The current treatment strategy for LARC is preoperative LCRT followed by TME, regardless of tumor regres-  26 The ongoing RAPIDO trial (NCT01558921) 27 will report results soon. The RAPIDO trial compared two groups; the standard arm consists of LCRT preoperatively, followed by selective postoperative adjuvant chemotherapy.
Postoperative chemotherapy is optional. The experimental arm consists of SCRT followed by full-dose chemotherapy before surgery. In the experimental arm, no postoperative chemotherapy is prescribed.
The hypothesis is that SCRT with neoadjuvant chemotherapy will increase DFS and OS without compromising local control. The primary end-point is DFS at 3 years.
When we consider that most early recurrences after preoperative LCRT followed by TME are systemic failures, systemic chemotherapy rather than radiation therapy should be adopted earlier.

| Cost-effectiveness
The preoperative LCRT protocol takes 5 weeks with treatment administered for 5 days per week. After 6 to 8 weeks of the waiting period, surgery is performed. By contrast, SCRT requires only 5 days and a restaging period. There have been many reports comparing outcomes between LCRT and SCRT. However, there have been no reports on cost-effectiveness among treatment modalities.
Polish and Australian randomized studies have compared preoperative SCRT and immediate surgery with LCRT and delayed surgery in resectable rectal cancer. 26,28 Ngan et al compared SCRT followed by early surgery and LCRT with delayed surgery. 28 They found no difference in long-term outcomes (3-year LR 7.5% vs 4.4%, P = .24; 5-year distant recurrence 27% vs 30%. P = .92; 5-year OS 74% vs 70% P = .62). The Stockholm III randomized study compared preoperative SCRT and immediate surgery with SCRT and delayed surgery. 29 Surgical complications were more common in SCRT and immediate surgery (36% vs 28% HR: 0.70 CI: 0.51-0.96, P = .03). However, there was no difference in long-term outcomes. They suggested that SCRT with delayed surgery would be a useful alternative to conventional SCRT with immediate surgery. They also compared the SCRT regimen with LCRT with delay. The cumulative incidence of LR was not different among the groups. They concluded that LCRT with delay is similar to both SCRT regimens; however, it substantially prolongs the treatment time.
Recently, we started a prospective study called the ESCORT  Table 1 displays various TNT protocols discussed in this article.

| S HIF TING TRE ATMENT S TR ATEGY TO TOTAL NEOADJ U VANT TRE ATMENT
Several TNT protocols have been studied worldwide. Some protocols comprising full doses of chemotherapy for 3-4 months followed by standard CRT and surgery as well as other courses of treatment, including SCRT after chemotherapy (induction chemotherapy), have been studied. Alternatively, some researchers have delivered chemotherapy immediately (consolidation chemotherapy) before surgery and after RT. Another group tried to omit RT according to the response to induction chemotherapy. Target agents were also studied with various treatment strategies. 10 In the Spanish GCR-3 randomized phase II trial, 32 patients were randomized to receive CapeOX either before CRT or after surgery (induction chemotherapy group vs adjuvant chemotherapy group).
Similar pathologic complete response rates were seen, and induction chemotherapy appeared to be less toxic and better tolerated. A single-institution retrospective cohort analysis of patients with LARC compared traditional neoadjuvant CRT followed by resection with the TNT approach of induction chemotherapy followed by CRT before resection. Patients in the TNT group received a greater percentage of  35 Group B (CRT followed by consolidated chemotherapy) resulted in better compliance with CRT but worse compliance with chemotherapy than group A (induction chemotherapy). A better pCR rate was seen in group B. To adopt the TNT protocol as the primary treatment modality, well-designed randomized controlled studies including molecular biomarkers will be necessary to determine the optimal treatment strategies according to patient characteristics. Nevertheless, TNT may be the preferred option in patients with LARC who have high risk factors for poor prognosis.

| CON CLUS ION
For the past decade, preoperative LCRT for LARC has been the standard treatment protocol for improving oncologic outcomes.
With the accumulation of treatment experience, we identified groups of patients who did not show good tumor responses, with disease progression and early systemic failure as well. These findings suggest that one treatment plan cannot achieve all the oncological outcomes we desire.
Four robust consensus molecular subtypes (CMSs) were identified: CMS1, enriched for inflammatory/immune genes; CMS2, canonical; CMS3, metabolic; and CMS4, mesenchymal. 36  should be encouraged. 38 The rapid evolution of knowledge in cancer biology should be integrated at the individual level. 39 Advances in technologies such as imaging and molecular typing, combined with updated TNT protocols, may result in better oncological outcomes than current treatment strategies based on individual risk factors.