Essential advances in surgical and adjuvant therapies for colorectal cancer 2018‐2019

Abstract Surgical resection and adjuvant chemotherapy are the only treatment modalities for localized colorectal cancer that can obtain a “cure.” The goal in surgically treating primary colorectal cancer is complete tumor removal along with dissection of systematic D3 lymph nodes. Adjuvant treatment controls recurrence and improves the prognosis of patients after they undergo R0 resection. Various clinical studies have promoted the gradual spread and clinical use of new surgical approaches such as laparoscopic surgery, robotic surgery, and transanal total mesorectal excision (TaTME). Additionally, the significance of adjuvant chemotherapy has been established and it is now recommended in the JSCCR (the Japanese Society for Cancer of the Colon and Rectum) guideline as a standard treatment. Herein, we review and summarize current surgical treatment and adjuvant chemotherapy for localized colorectal cancer and discuss recent advances in personalized medicine related to adjuvant chemotherapy.


| INTRODUC TI ON
According to the Vital Statistics of Japan, the number of deaths from colorectal cancer in Japan has continued to increase and, in 2016, it exceeded 50 000. 1 The basis of surgical treatment for colorectal cancer has continued to be primary resection with lymph node dissection. However, new approaches such as sphincter preservation surgery, transanal total mesorectal excision (TaTME), robotic surgery, and laparoscopic surgery have been spreading. Important outcomes from the Japan Clinical Oncology Group (JCOG) 0404 trial were published indicating that laparoscopic surgery could be an acceptable option for patients with stage II or III colon cancer. Herein, we review and summarize the results of laparoscopic surgery and new approaches such as robotic surgery and TaTME.
The benefit of adjuvant chemotherapy has been confirmed in curatively resected stage III colon cancer, and it is now a standard treatment strategy in the guidelines of the Japanese Society for Cancer of the Colon and Rectum (JSCCR). 2 The standard adjuvant chemotherapy regimen for colon cancer has been improved based on the findings from several large clinical trials. Ever since the significant benefit of adding oxaliplatin was proved, 3,4 creating other effective regimens has been difficult because several trials showed that no additional benefit was gained by adding bevacizumab or cetuximab. [5][6][7] Thus, the prolonged neuropathy induced by oxaliplatin has emerged as a critical issue, and several prospective trials were conducted to test reductions in the duration of oxaliplatin treatment. 8 A prospective, pre-planned pooled analysis of six concurrently conducted randomized phase III trials (IDEA collaboration), including the ACHIEVE trial, was performed to evaluate the non-inferiority of 3 vs 6 months of adjuvant FOLFOX/ XELOX therapy. Although this study produced negative results, the authors suggested the possibility of adjusting the duration of adjuvant chemotherapy for stage III colon cancer according to the patient's risk and regimen and indicated the increasing importance of personalized medicine.

| G ENER AL PRIN CIPLE S OF RE S EC TI ON FOR COLOREC TAL C AN CER
Surgical resection of primary colon cancer is performed to completely remove the tumor, major vascular pedicles, and lymphatic drainage basin of the affected colonic and rectal segment and is achievable through an open or laparoscopic approach. However, the same principles of resection with lymph node dissection applicable to open surgery are also applicable to the laparoscopic approach.
Although the concept of complete mesocolic excision (CME) has begun to emerge in recent years, 9 Japanese surgeons are already performing D3 lymph node dissection. Japanese D3 dissection and the current standard procedure of CME with central vascular ligation performed in the USA and Europe are almost identical although the resected colon is left slightly shorter following the Japanese D3 procedure. Theoretically, although the procedures should be equivalent because the principles are the same, a 2012 study 9 showed CME with central vascular ligation and Japanese D3 dissection to be superior to the procedure used in previously reported cases.
Additionally, the Japanese specific lymph node dissection is pelvic lateral lymph node dissection, which is considered a distant metastasis in Western countries. Lateral lymph node dissection is indicated when the lower border of the tumor is located distal to the peritoneal reflection and the tumor has invaded beyond the muscularis propria. Prophylactic lateral lymph node dissection has a weak recommendation in the JSCCR guideline. 2

| G U IDELINE S FOR COLOREC TAL C AN CER
The combination of advances in diagnostic methods and the use of many newly developed treatment methods has steadily improved the results of treatment. However, treatment methods vary among the medical institutions in Japan that treat patients with colorectal cancer, and this can lead to differences in treatment results. The rates of macroscopic completeness of resection (88% vs 92%) and positive (<2 mm) circumferential resection margin (10% vs 10%) were similar between the two groups, as were the 3-year rates of locoregional recurrence and survival. 29 In the COREAN South Korean trial, 340 patients with mid-to-low rectal cancer were randomly assigned to undergo laparoscopic or open surgery after preoperative chemoradiation therapy. 30 There were no significant differences in involvement of the circumferential resection margin, macroscopic quality of the total mesorectal excision specimen, number of harvested lymph nodes, or perioperative morbidity between the two groups. These studies are summarized in Table 2.
A systematic review and meta-analysis of randomized trials that including the four above-mentioned studies concluded that, for rectal cancer, a higher rate of "noncomplete" (composite of incomplete and near-complete) total mesorectal excision was achieved with laparoscopic surgery than with open surgery (13.2% vs 10.4%).
However, the rates of circumferential and distal margin involvement, mean numbers of lymph nodes retrieved, and mean distances to radial and distal margins were similar between the two techniques. 35  A systematic review and meta-analysis performed in 2018 of five trials, including ROLARR, comparing robotic-assisted resection for rectal cancer with that of conventional laparoscopy found similar perioperative outcomes regarding mortality, rate of circumferential margin involvement, and number of lymph nodes harvested. 48 Conversion from robotic surgery to open surgery was less likely (7.5% vs 12.9%), but robotic surgery took slightly longer than conventional laparoscopic surgery (mean difference 38 minutes).

| TaTME
In centers with experienced surgeons, TME has also been attempted transanally for distal rectal tumors, particularly in obese men with a narrow pelvis. 49 from the beginning of the procedure, the resection margins can be defined more clearly in TaTME than in standard transabdominal TME. A randomized trial of patients with low rectal cancer (<6 cm from anal verge) that compared TaTME with standard TME showed a lower rate of positive circumferential resection margin for TaTME (4% vs 18%), with other outcomes being comparable between the groups. 52 Other studies following up patients for up to 29 months showed comparable rates of local recurrence and survival between TaTME and standard TME. 50,53 However, long-term oncologic outcomes of TaTME have not been reported yet. Additionally, iatrogenic urethral injury has been reported with TaTME in men. 54   improved therapeutic ratio. 55 The benefit offered by oral fluoropyrimidines was investigated in a meta-analysis of individual data from five Japanese trials comprising 5232 patients with resected stage I, II, or III colon cancer who were randomly assigned to receive adjuvant oral fluoropyrimidines (FU, UFT, or hexacarbonyl FU) or undergo observation only. 56 Overall, oral therapy reduced the risk of recurrence by 11% and death by 15%. However, an absolute survival benefit of only 2.5% was achieved for patients with stage III disease.

| ADJ U VANT CHEMOTHER APY FOR RE S EC TED S TAG E III COLOREC TAL C AN CER
More recent trials suggest that the benefit achievable with either capecitabine or UFT is at least equivalent to that of FU/ LV administered by intravenous bolus. Two randomized trials of oral capecitabine compared with intravenous fluoropyrimidines showed equivalent rates of 6-month DFS. 57,58 In the earlier trial, the European/Canadian Xeloda in Adjuvant Colon Cancer Therapy (X-ACT) study, 1987 patients with resected stage III colon cancer were randomly assigned to 6 months of capecitabine alone. 57 The trial was statistically powered to show therapeutic equivalence, and DFS was the primary endpoint.
Six months of UFT plus LV is a standard approach for adjuvant chemotherapy of stage III colon cancer in Japan. 35 CI, 0.70-1.03), and the rates of adverse events were comparable.
However, S-1 was found to be inferior to capecitabine monotherapy in the JCOG0910 non-inferiority multicenter randomized trial. 63 At present, we should make clinical decision about adjuvant chemotherapy taking into account patient characteristics, values, and preferences, and the potential for benefit and risks of adverse events associated with treatment.

| DUR ATI ON OF ADJ U VANT CHEMOTHER APY
The