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RANDOMIZED CONTROLLED TRIALS

The Conventional Technique Versus the No-touch Isolation Technique for Primary Tumor Resection in Patients With Colon Cancer (JCOG1006)

A Multicenter, Open-label, Randomized, Phase III Trial

Takii, Yasumasa MD; Mizusawa, Junki ME; Kanemitsu, Yukihide MD; Komori, Koji MD§; Shiozawa, Manabu MD; Ohue, Masayuki MD||; Ikeda, Satoshi MD∗∗; Takiguchi, Nobuhiro MD††; Kobatake, Takaya MD‡‡; Ike, Hideyuki MD§§; Sato, Toshihiko MD¶¶; Tomita, Naohiro MD||||; Ota, Mituyoshi MD∗∗∗; Masaki, Tadahiko MD†††; Hamaguchi, Tetsuya MD‡‡‡; Shida, Dai MD; Katayama, Hiroshi MD; Shimada, Yasuhiro MD§§§; Fukuda, Haruhiko MD

Author Information
doi: 10.1097/SLA.0000000000005241
  • Open

Abstract

Surgical resection is the only curative treatment for resectable colorectal cancer, and its goal is to achieve complete removal of the tumor-bearing colon segment, major vascular pedicles, and related lymphatic system.1 There are 2 concepts to achieve this goal. The first concept is based on the extent of resection2–6 and the other is based on the timing of resection. We focused on the latter concept based on the timing of the resection. The conventional uses a standard strategy that prioritizes mobilization of the tumor-bearing colon segment, followed by central vascular ligation (CVL). In contrast, the no touch uses an experimental strategy that was initially proposed in the 1950 s to reduce the risk of recurrence and thereby improve the patient's prognosis.7 This technique prioritizes CVL, thereby reducing the risk of cancer cells spreading to the liver and other organs, which is followed by mobilization of the tumor-bearing colon segment. Two retrospective studies have revealed that this technique was associated with an improved prognosis.8,9 Many basic research have also suggested that the no touch is useful for treating colorectal cancer, as the number of metastases has been shown to increase after surgical manipulation of experimental tumors.10 In addition, the number of circulating tumor cells (CTCs) increased after the radical excision of human colorectal cancers,11 as well as during the resection of liver metastasis from human colorectal cancers.12 Moreover, the no touch decreases the intraoperative detection of CTCs in the portal venous blood.13 However, a randomized, controlled trial (RCT) revealed that the no touch was associated with a non-significant improvement in prognosis.14 Based on the nonsignificant result in prognosis from the trial, the no touch is not considered a standard technique in the current guidelines.1,4,15 However, we reviewed the RCT's protocol and results, which revealed that the non-superiority of the no touch might have been related to insufficient sample size and a large number of patients lost to follow-up. Therefore, we designed a large RCT to evaluate the utility of the no touch in patients with colon cancer. The present study is the first large-scale RCT that aimed to confirm whether the no touch was superior to the conventional technique in patients with colon cancer, and we report the safety and efficacy outcomes from the primary analysis.

METHODS

Study Design and Participants

This open-label, randomized, phase III trial evaluated patients who were treated at 30 Japanese centers that participated in the Colorectal Cancer Study Group (CCSG) of the Japan Clinical Oncology Group (JCOG). The trial complied with the ethical principles of the Declaration of Helsinki and the Ethical Guidelines for Medical and Health. Research Involving Human Subjects in Japan. All patients provided written informed consent before enrollment.

The inclusion criteria were as follows: pathologically proven adenocarcinoma (including mucinous and signet ring cell adenocarcinoma) or adenosquamous carcinoma based on endoscopic biopsy findings; tumor localization to the cecum, ascending colon, transverse colon, descending colon, sigmoid colon, or rectosigmoid junction based on preoperative endoscopic and radiographic imaging findings [barium enema or computed tomography (CT)] without location of the lower border of the tumor at the rectum; clinical tumor depth of T3, T4a or T4b; nodal status of N0–2 based on preoperative endoscopic and radiographic imaging findings; no preoperative findings indicating the presence of M1 disease; age 20 to 80 years; Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; no previous chemotherapy or radiotherapy for any malignancies; sufficient organ function; body mass index of <30 kg/m2; no history of intestinal resection, serious obstruction, or perforation; and no history of familial adenomatous polyposis, ulcerative colitis, or Crohn disease. Tumors were staged according to the Japanese Classification of Colon and Rectal Carcinoma (7th edition) (JSCCR).16

The exclusion criteria were as follows: multiple colorectal cancers; synchronous or metachronous cancers (<5years apart); any infectious disease requiring treatment; a body temperature of ≥38°C; women who were pregnant or breastfeeding; psychiatric disease disturbing participation in the study; continuous use of systemic steroids; myocardial infarction or unstable angina pectoris within the last 6 months; or severe pulmonary emphysema or pulmonary fibrosis.

The study was approved by the JCOG Protocol Review Committee and the institutional review boards of each center.17

Randomization and Masking

Each patient's fulfillment of the inclusion and exclusion criteria was confirmed using telephone evaluations, fax communication, or the web-based system from the JCOG Data Center. Eligible patients were randomly assigned (1:1) to undergo the conventional or the no touch. Randomization was performed using a minimization method with a random component according to institution, tumor location (C, A, T vs D, S, RS), and sex. The investigators or patients did not mask patient allocation. The JCOG Data Center conducted central monitoring of data submission, patient eligibility, protocol compliance, safety, and study progression.

Procedure

In both groups, the Japanese technique for D3 dissection was performed, which involved CVL, intestinal transection, and lymph node dissection. Both study groups received the same extent of intestinal resection and had the same position as the CVL for the lymph node dissection. The procedure for anastomosis to achieve intestinal reconstruction was not specified. The laparoscopic approach was not allowed, as the standard procedure for colorectal cancer in Japan was open surgery when we started this study. Palpation of the intraabdominal organs after laparotomy was not allowed.

In the conventional group, the first step of the operation involved mobilization of the tumor-bearing segment before any vessels were ligated. In the no touch group, the first step of the operation involved CVL, followed by marginal vessel ligation, intestinal transection, and mobilization of the tumor-bearing segment. The quality of the operation was assessed using photographs during every surgery in both groups and then centrally reviewed to confirm complete lymph node dissection and the timing of mobilization of the tumor-bearing segment. Regardless of group assignment, all patients with pathological stage III disease within 56 days after curative resection were recommended to receive adjuvant capecitabine chemotherapy at a dose of 1250 mg/m2 twice daily on days 1 through 14 every 21 days for 6 months.

Outcomes

The primary endpoint was disease-free survival (DFS), which was defined as the time from randomization to the first evidence of relapse, development of a second primary cancer, or death due to any cause. The “relapse” includes both judgment of it based on imaging and judgment of progression due to exacerbation of the condition not based on imaging (clinical relapse). The “relapses” were assessed by local surgeons. The secondary endpoints were overall survival (OS), relapse-free survival (RFS, time to the first evidence of relapse or death), liver relapse-free survival (LRFS, time to the first evidence of liver metastasis or death), mode of recurrence, surgical morbidity, adverse events related to postoperative chemotherapy, serious adverse events (Grade 4 non-hematological toxicities, death within 30 days after the protocol treatment, or treatment-related death), and short-term clinical outcomes (time to first flatus after surgery, postoperative hospital stay). Recurrences were determined based on imaging diagnoses or biopsy findings, and elevated concentrations of tumor marker concentrations were considered insufficient for identifying recurrence in the absence of related imaging findings.

Adverse events were assessed according to the Common Terminology Criteria for Adverse Events (version 3.0). All patients underwent follow-up evaluations every 3 months during the first 3 years, and then every 6 months during years 4 to 6 after surgery. Follow-up evaluations included clinical examinations, namely, CT, to evaluate the thoracic, abdominal, and pelvic areas every 6 months until 6 years after enrollment, and detection of tumor markers [carcinoembryonic antigen (CEA) and cancer antigen 19-9 (CA19-9)] every 3 months until 3 years after enrollment and then every 6 months from year 3 to year 6.

Statistical Analysis

We hypothesized that the 3-year DFS in the no touch group would be 6% higher than that in the conventional group (75%). Based on the methods of Schoenfeld and Richter,18 the required sample size would be 840 patients (420 patients per arm) with a 1-sided alpha level of 5%, power of 80%, accrual period of 3 years and follow-up period of 3 years. A total of 259 events would be expected to occur within the first three years of follow-up. The total target sample size was set as 850 patients to account for patients who would be lost to follow-up.

We planned 2 interim analyses, while taking multiplicity into account, using the Lan-DeMets method with the O’Brien and Fleming-type alpha spending function.19 The Data and Safety Monitoring Committee of the JCOG independently reviewed the interim analysis reports and had the power to prematurely terminate the trial if necessary. In-house monitoring was performed every 6 months by the JCOG Data Center to evaluate and improve the progress of the study.

DFS and OS were analyzed for on an intention-to-treat basis. Survival curves were estimated using the Kaplan-Meier method. DFS was compared using the stratified log-rank test according to tumor location and sex as strata. Hazard ratios (HRs) for DFS were estimated using a stratified Cox regression model according to tumor location and sex as strata. OS was compared using the log-rank test and HR for OS was estimated using a Cox regression model. Preplanned subgroup analyses were performed using Cox regression models according to tumor location (C + A + TvsD + S + RS) and (C + Avs T + DvsS + RS), sex (male vs female), age (≤59 years vs ≥60 years, ≤64 years vs ≥65 years, and ≤69 years vs ≥70 years), PS (0 vs 1), clinical stage (II vs IIIa vs IIIb), clinical T stage (cT3 vs cT4), clinical N stage (cN0 vs cN+), histology (well + moderately differentiated vs others), the number of lymph node metastases (≤3 vs ≥4 and ≤1 vs 2–3 vs 4–6 vs ≥7), JSCCR stage (I + II vs IIIa + IIIb + IV), and UICC TNM stage (I + IIA + IIB + IIC vs IIIA + IIIB + IIIC + IVA + IVB). Adverse events were assessed on a perprotocol basis. The P value for the primary analysis of DFS was onesided, whereas all other P values were 2-sided. Statistical analyses were performed by the JCOG Data Center using SAS software (version 9.4; SAS Institute, Cary, NC).

The present study is registered with UMIN Clinical Trials Registry, number UMIN000004957.

RESULTS

Patients and Treatment

Between January 26, 2011 and November 13, 2015, the study enrolled 853 patients at 30 Japanese hospitals, including 427 patients who were assigned to the conventional group and 426 patients who were assigned to the no touch group. After the randomization, 30 patients (4%) were found to be ineligible, including 12 patients (3%) in the conventional group and 18 patients (4%) in the no touch group. In the conventional group, the exclusion criteria were related to the tumor's lower margin involving the upper rectum (5 patients), other cancers being detected after registration (4 patients), lung metastasis that was confirmed after surgery (1 patient), and other ineligibility factors (2 patients). In the no touch group, the exclusion criteria were related to the tumor's lower margin involving the upper rectum (4 patients), other cancers detected after registration (3 patients), lung metastases that were confirmed after surgery (5 patients), and other ineligibility factors (6 patients). The efficacy analyses included all 426 patients in the no touch group and all 427 patients in the conventional group, based on the intention-to-treat principle (Fig. 1).

F1
FIGURE 1:
Study flowchart.

There were no substantial differences in the baseline characteristics of the two groups (Table 1), and the operative and pathological results are summarized in Tables 2 and 3. The median operation time was similar in both groups {172 minutes [interquartile range (IQR) 146–210] in conventional and 178 minutes [IQR 145–214] in no touch}, although conversion to the conventional strategy was necessary for 5 (1%) of 426 patients in the no touch group. The Japanese D3 dissection technique was performed in 411 (96%) of 427 patients in the conventional group and for 410 (96%) of 426 patients in the no touch group. Among 208 patients with pathological stage III cancer in the conventional group, 130 patients (63%) received per-protocol adjuvant chemotherapy and 71 patients (34%) received adjuvant chemotherapy outside the protocol treatment. Meanwhile, among 194 patients with pathological stage III cancer in the no touch group, 118 patients (61%) received perprotocol adjuvant chemotherapy and 69 patients (36%) received adjuvant chemotherapy outside the protocol treatment. Both groups had similar pathological staging and the same median number of harvested lymph nodes [conventional: 28 nodes, (IQR: 19–41 nodes), no touch: 28 nodes (IQR: 20–40 nodes)].

TABLE 1 - Patient Characteristics
Conventional (n = 427) No Touch (n = 426)
Age, y 66 (60–72) 66 (60–73)
Sex
 Male 211 (49%) 212 (50%)
 Female 216 (51%) 214 (50%)
ECOG PS
 0 407 (95%) 407 (96%)
 1 20 (5%) 19 (4%)
Tumor location
 Right 193 (45%) 191 (45%)
 Left 234 (55%) 235 (55%)
Tumor depth
 cT3 298 (70%) 281 (66%)
 cT4a 113 (26%) 122 (29%)
 cT4b 16 (4%) 23 (5%)
Nodal status
 cN0 174 (41%) 166 (39%)
 cN1 177 (41%) 183 (43%)
 cN2 76 (18%) 76 (18%)
 cN3 0 (0%) 1 (<1%)
Body mass index, kg/m2 22.4 (20.4–24.8) 22.5 (20.4–24.7)
Data are shown as n (%) or median (interquartile range).Conventional indicates conventional technique; no touch, no-touch isolation technique.

TABLE 2 - Operative Results
Conventional (n = 427) No Touch (n = 426)
Operative details
 Time, min 172 (146–210) 178 (145–214)
 Blood loss, mL 69 (24–165) 77 (22–160)
 Conversion 0 (0%) 5 (1%)
Lymph node dissection
 D0–D2 16 (4%) 16 (4%)
 D3 411 (96%) 410 (96%)
Stoma creation
 No 421 (99%) 422 (99%)
 Yes 6 (1%) 4 (1%)
Resection of adjacent organ
 No 374 (88%) 366 (86%)
 Yes 53 (12%) 60 (14%)
Intraoperative organ injury
 No 425 (100%) 425 (100%)
 Yes 2 (G1) (<1%) 1 (G1) (<1%)
Operative morbidity and mortality All grade (CTCAE ver.3)
 Anastomotic leakage 10 (2%) 11 (2%)
 Intraabdominal infection 3 (<1%) 1 (<1%)
 Catheter infection 2 (<1%) 2 (<1%)
 Wound complication 6 (1%) 9 (2%)
 Urinary tract infection 2 (<1%) 3 (<1%)
 Hospital mortality 0 (0%) 0 (0%)
Postoperative results
 Time to first flatus, days 2 (2–3) 2 (2–3)
 Postoperative hospital stay, days 10 (8–14) 10 (8–13)
Data are shown as n (%) or median (interquartile range).Conventional indicates conventional technique; no touch, no-touch isolation technique.

TABLE 3 - Pathological Results
Conventional (n = 427) No Touch (n = 426)
Pathological results
 Tumor size, cm 4.8 (3.8–6.0) 5.0 (4.0–6.0)
 No. of harvested lymph nodes 28 (19–41) 28 (20–40)
Pathological stage
 I 25 (6%) 18 (4%)
 II 181 (42%) 188 (44%)
 III 208 (49%) 194 (46%)
 IV 13 (3%) 25 (6%)
Residual tumor
 R0 421 (99%) 410 (96%)
 R1 1 (<1%) 5 (1%)
 R2 5 (1%) 10 (2%)
Data are shown as n (%) or median (interquartile range).Conventional indicates conventional technique; no touch, no-touch isolation technique.

Regarding follow-up status, there were nine and four censored cases within 3 years in the no touch and conventional groups, respectively. We considered that the accuracy of follow-up was maintained.

Safety

Grade ≥3 operative morbidity (eg, anastomotic leakage, intraabdominal infection, catheter infection, wound complications, and urinary tract infection) was observed in 31 (7%) of 427 patients in the conventional group and in 26 (6%) of 426 patients in the no touch group. No in-hospital deaths occurred in either group.

Central Review of the Procedure

Six members of the evaluation committee evaluated 823 intraoperative photographs of 853 patients regarding the completeness of Japanese D3 dissection and priorities for tumor mobilization and CVL. No case in any of the categories was designated “fail” by all the committee members. The number of cases estimated as “fail” by 1 or 2 committee members was 6, 6, and 9 cases, respectively. Thus, we believe that the quality of the operation was maintained by this central review process.

Efficacy

Among all patients, the median follow-up after randomization was 54.5 months (IQR: 36.1–68.5 months). At the last follow-up (November 28, 2018), secondary cancer, recurrence, or death was observed in 242 patients, including 120 of 427 patients in the conventional group and 122 of 426 patients in the no touch group. The 3-year DFS was 77.3% in the conventional group [95% confidence interval (CI) 73.1%–81.0%] and 76.2% in the no touch group (95% CI 71.9%–80.0%). The analyses revealed that the no touch was not superior to the conventional, based on an HR for DFS of 1.029 (95% C: 0.800–1.324; 1-sided P value = 0.59) (Fig. 2A).

F2
FIGURE 2:
Kaplan-Meier curves for DFS (A), OS (B), RFS (C), and LRFS (D).

The 3-year OS was 94.8% in the conventional group (95% CI 92.2%–96.5%) and 93.4% in the no touch group (95% CI: 90.6%–95.4%), with an HR of 1.006 (95% CI 0.674–1.501) (Fig. 2B). The 3-year RFS was 81.8% in the conventional group (95% CI 77.8%–85.2%) and 79.0% in the no touch group (95% CI 74.8%–82.6%), with the hazard ratio (HR) of 1.220 (95% CI 0.919–1.620) (Fig. 2C). The 3–year LRFS was 89.5% in the conventional group (95% CI 86.2%–92.1%) and 87.0% in the no touch group (95% CI 83.4%–89.8%), with an HR of 1.226 (95% CI 0.877–1.714) (Fig. 2D).

Preplanned subgroup analyses were also performed for DFS. Compared to the conventional group, the no touch group tended to be associated with worse DFS among patients who were ≥70 years’ old, those with tumors in the transverse or descending colon, those with cT4 disease, and those with histology findings of “others” (Fig. 3).

F3
FIGURE 3:
Subgroup analyses of disease-free survival. A indicates ascending;C, cecum;D, descending;moderately, moderately differentiated adenocarcinoma; others, other histology; RS, rectosigmoid; S, sigmoid;T, transverse;well: well-differentiated adenocarcinoma.

DISCUSSION

The JCOG1006 study is the first large-scale RCT to evaluate whether the no touch was superior to the conventional in patients with cT3/T4 colon cancer based on long-term survival outcomes. The efficacy analysis included all 853 patients, based on the intention-to-treat principle, and revealed no significant difference between the 2 groups in the primary endpoint (DFS). Contrary to our expectations, we also did not observe a significant difference in LRFS, despite the fact that the no touch aims to reduce the risk of cancer cell spreading to the liver. Thus, the results failed to confirm that the no touch was significantly more effective than the conventional in this setting. In terms of the short-term results, comparing the conventional and no touch also revealed no differences. The operative morbidity and mortality rate was similar in both groups. These results suggest that the no touch is a simple and reliable technique that does not increase morbidity or mortality.

There are several potential explanations for why the JCOG1006 results failed to reveal an improved prognosis for the no touch. The first possible explanation is that the no touch is not actually a superior option, and we believe this explanation is the most likely based on our findings. The surgical quality in both arms seems to be extremely high, based on the data regarding the total number of retrieved lymph nodes and the margin status. Furthermore, long-term follow-up revealed no significant differences in DFS, OS, or additional oncological outcomes. We are actually quite impressed by a 3-year OS of >90% and a 3-year DFS of >75% in both arms. These results suggest that the no touch did not add additional benefits relative to the conventional based on DFS and OS in the context of already optimized oncologic surgery, which was characterized by complete mesocolic excision (CME), CVL or D3 dissection, R0 resection, and adequate lymph node resection.

A second possible explanation is that postoperative survival has improved markedly in recent years, relative to the outcomes in previous decades. In the 1960 s, Turnbull et al reported that the 5-year OS was 52.5% after standard therapy for Dukes A–C disease,8 which is very similar to Stage I-III disease. In the 1980 s, Wiggers et al reported that the 5-year of DFS was approximate 60% after standard therapy for Dukes A–C disease.14 However, the present study revealed a 5-year OS of 90.5% after standard therapy for cStage II-III disease, even after excluding patients with cStage I disease. In this context, the important prognostic factors include the extent of primary tumor resection (ie, adequate circumferential, proximal, and distal margins) and the integrity of the resection (ie, the involved adjacent tissue/viscera and regional lymph nodes). A retrospective population-based study indicated that the CME with CVL technique is useful for achieving sufficient resection extent and integrity, which may improve the prognosis of patients with colon cancer.3 Improved adjuvant chemotherapy is another potentially important prognostic factor, and regimens involving fluorouracil/leucovorin, uracil-tegafur/leucovorin, and capecitabine have demonstrated efficacy in this setting.20–22 The FOLFOX and CapeOX regimens are considered standard adjuvant chemotherapies,23–25 although capecitabine adjuvant chemotherapy was standard during the study period in our study group. Non-capecitabine adjuvant chemotherapy was only administered to 71 patients in the conventional group and 69 patients in the no touch group, with 34 patients in the conventional group and 32 patients in the no touch group receiving S-1 therapy as participants of JCOG0910.26 Furthermore, 27 patients in the conventional group and 25 patients in the no touch group received other chemotherapies, which mainly involved the FOLFOX or CapeOX regimen. Thus, improvements in prognosis related to surgical techniques and effective adjuvant chemotherapy may have reduced the potential contributions of the no touch.

A third possible explanation for the non-superiority of the no touch may be related to the limitations of the operative procedure used in the JCOG1006 trial. Basic research studies have suggested that the number of metastases increased with greater surgical manipulation of experimental tumors.10 The previous RCT allowed palpation of the intraabdominal organs in the conventional group, although the JCOG1006 technique did not allow palpation of the intra-abdominal organs after laparotomy. Furthermore, Atkin et al have speculated that mesenteric pedicle clamping leads to a shift in blood draining into the systemic circulation.27

Limitations

This study had some limitations. First, the relevance of the surgical steps could be evaluated using preoperative, intraoperative, and postoperative testing for CTCs, although these tests were not performed because of financial limitations. Second, the JCOG1006 protocol did not prioritize ligation of the artery or vein, and this step was not noted in the surgical records because most of the investigators did not consider the timing of the ligation as an important factor. Third, there has been a recent shift toward laparoscopic or robotic surgery for colon cancer, although this trial was performed during an era when open surgery was the standard for colon cancer. We do not have clear data regarding whether our results may be applicable to laparoscopic or robotic surgery, although both techniques use similar principles for the concept and extent of ressection, suggesting that the results may be relevant for patients who are undergoing laparoscopic or robotic surgery. Fourth, this trial excluded patients with a BMI of >30 kg/m2 to secure safety outcomes, and it remains unclear whether our results can be generalized to populations in which obesity commonly occurs with colon cancer.

CONCLUSION

Our findings indicate that the no touch was not superior to the conventional among patients who were undergoing open primary resection of colon cancers, based on the absence of significant differences in DFS, OS, RFS, and LRFS.

ACKNOWLEDGMENTS

The authors thank the participating patients and their families, as well as the investigators, research nurses, study coordinators, operation staff, and the members of the JCOG Data Center and JCOG Operations Office for their support in overseeing the study, managing the data, and preparing the report.

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Keywords:

colon cancer surgery; no-touch isolation technique; randomized controlled trial

Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.