Comparability of D2 vs D3 lymph node dissection for RIght COloN most cancers (RICON): research protocol for a global multicenter open-label randomized managed trial | Trials

Examine setting

Sufferers will probably be recruited from the Departments of Colorectal Most cancers Surgical procedure #1 and #2, in addition to the Division of Laparoscopic and Minimally Invasive Surgical procedure on the G.V. Bondar Republican Most cancers Middle in Donetsk, Ukraine. Further recruitment areas embody the Clinic of Coloproctology and Minimally Invasive Surgical procedure at Sechenov College, Moscow Metropolis Oncology Hospital No. 62 in Moscow, Russia, and St. Luke’s Medical Hospital in St. Petersburg, Russia (Fig. 2). All sufferers who meet the eligible standards are proposed to be recruited in all facilities. This research protocol is documented in accordance with the SPIRIT reporting pointers [17]. The outcomes of the trial will probably be reported within the subsequent publications.

Reference to the clinic the place the checklist of research websites may be obtained

Randomization and blinding

A easy 1:1 randomization was used on this research. A random quantity checklist was construct utilizing R studio software program by an unbiased statistician and downloaded to digital case report type (eCRF) with an allocation ratio 1:1 (D2 and D3 teams). After rigorously choosing sufferers based mostly on the inclusion and exclusion standards, knowledgeable consent will probably be obtained by the corresponding investigators and the sufferers will probably be assigned to the corresponding intervention group. The trial is open-label, the surgeons are unblinded, and sufferers are clearly knowledgeable in regards to the procedures they’ll endure, as required by the healthcare techniques of all facilities in each nations. Within the D2 lymph node dissection group, in case of intraoperative macroscopically suspicious apical lymph nodes are noticed, the surgeon ought to take away them for moral causes. The affected person is not going to be transferred to the D3 lymph node dissection group and can proceed with follow-up as per the D2 group.

Examine inhabitants and eligible standards

Inclusion standards

1. 1.

   Provision of signed knowledgeable consent by sufferers

2. 2.

   Affirmation of adenocarcinoma of the best colon (cecum, ascending, hepatic flexure, and proximal transverse colon) verified by colonoscopy

3. 3.

   Tumor staging as cT_3-4a,bN₀M₀ (stage II) or cT_1-4a,bN_1-2M₀ (stage III) on CT

4. 4.

   Demonstrated tolerability of chemotherapy medicine

5. 5.

   Age starting from 18 to 75 years

6. 6.

   American Society of Anesthesiologists (ASA) bodily standing classification of 1–3

Exclusion standards

1. 1.

   Presence of distant metastases (cM1)

2. 2.

   Tumor staging as cT_is–cT₂N₀ (stage I) and cT4_b (involving the liver, kidney, head of the pancreas and duodenum, vena cava, aorta, or superior mesenteric vessels)

3. 3.

   Emergent circumstances (restricted to tumor perforation and acute bowel obstruction)

4. 4.

   Historical past of earlier chemotherapy or radiation remedy

5. 5.

   Presence of synchronous or metachronous most cancers

6. 6.

   Being pregnant or breastfeeding

7. 7.

   Refusal to take part in trial

Withdrawal standards

Exploratory laparotomy/laparoscopy or different causes for refusing resection.

Standards for research facilities and intervention performers

1. 1.

   The hospital should concentrate on colorectal most cancers surgical procedure.

2. 2.

   Surgeons concerned within the research ought to have expertise in conducting a minimal of fifty elective colon most cancers resections.

3. 3.

   They need to show a dedication to totally complying with the protocol necessities of this research.

Interventions

Knowledgeable consent

Medical doctors will current the trial to sufferers and supply them with info playing cards. They’ll then talk about the small print of the trial as outlined on the playing cards with the sufferers. Following these discussions, medical doctors will search written consent from sufferers who comply with take part within the trial.

Laboratory analysis

1. 1.

   Full blood rely (CBC) and urine exams

2. 2.

   Biochemical blood exams (urea, creatinine, bilirubin, blood sugar, ALT, AST, α-amylase, whole protein)

3. 3.

   Coagulogram

4. 4.

   Tumor markers: CEA, CA19-9

Instrumental research

1. 1.

   Colonoscopy with biopsy for analysis verification

2. 2.

   Computed tomography of the belly and thoracic cavity with intravenous bolus distinction

3. 3.

   Esophagogastroduodenoscopy

4. 4.

   Electrocardiogram, echocardiography if obligatory

Surgical procedure

The surgical procedures embody two varieties: proper hemicolectomy and prolonged proper hemicolectomy. The excellence lies within the degree of center colic artery ligation and the removing of various parts of the transverse colon. In proper hemicolectomy, solely the best department of the center colic artery is transected, together with division of the proximal transverse colon. Prolonged proper hemicolectomy includes ligation of the center colic artery at its origin and transection of the mid transverse colon.

Strategies for the best colon mobilization

The surgical approach for the best colon mobilization consists of 4 steps: cranial, caudal, medial, and lateral. The cranial strategy initiates from entry into the lesser sac and continues distally to the extent of ileocolic pedicle. The caudal mobilization begins from the embryonic aircraft underneath the ileum and progresses proximally to the extent of the Henle’s trunk. The medial strategy includes motion into the embryonic aircraft beneath the ileocolic artery and continues within the proximal, distal, and lateral instructions to the degrees of transverse colon and ileum transection. Lateral strategy is carried out by dissecting Toldt’s line between the mesocolic fascia and Gerota’s fascia, persevering with till the extent of superior mesenteric vessels. Full-length mobilization consists of the preservation of mesocolic fascia, besides the circumstances of regionally superior most cancers, the place excision past the embryological planes is required.

The boundaries of D2 and D3 lymph node dissection

The proximal boundary of D2 lymph node dissection is outlined by the situation of mesocolon fixation to the Gerota’s fascia and the descending duodenum. In D3 lymph node dissection, the extra boundary extends to the top of the pancreas, as much as the gastroepiploic vein and the decrease fringe of the pancreatic neck.

The distal boundary for D2 lymph node dissection begins from the ileum, 10 cm from the cecum, persevering with 1 cm under the projection of ileocolic vessels till 1 cm laterally from the superior mesenteric vein (SMV). For D3 lymph node dissection, the distal resection margin moreover consists of the opening of the anterior floor of the SMV, 1 cm under the origin of ileocolic vein. Paracolic lymph nodes needs to be eliminated at a minimal distance of 10 cm from the tumor in each the proximal and distal route.

The lateral border for D2 and D3 lymph node dissection is outlined by the white line of Toldt.

The surgical trunk (medial boundary) for D2 lymph node dissection is about at 1 cm from the lateral fringe of the SMV on the degree of the ileocolic artery and vein, extending proximally to the anterior floor of the duodenum. The top of the pancreas and origin of the feeding arteries aren’t visualized, together with the superior mesenteric vein and Henle’s trunk.

The surgical trunk (medial boundary) for D3 lymph node dissection is the medial facet of the SMV from the decrease border of the pancreatic neck to 1 cm under the origin of the ileocolic vein (Figs. 3, 4, 5, and 6). The anterior floor of the SMV, origin of the feeding vessels, and ligation of the intestinal tributary of Henle’s trunk function anatomical landmarks of full D3 lymph node dissection. When the ileocolic artery and/or proper colic artery go behind the SMV, the ligation of those arteries is carried out on the lateral facet of the SMV.

Schematic illustration for proper hemicolectomy with D2 and D3 lymph node dissection. The inexperienced space signifies the mesentery that underwent removing

Schematic depiction for prolonged proper hemicolectomy with D2 and D3 lymph node dissection. The inexperienced space signifies the mesentery subjected to removing

Intraoperative view for open D2 and D3 lymph node dissection

Intraoperative view for laparoscopic D2 and D3 lymph node dissection

For hepatic flexure or proximal transverse colon most cancers and suspicious infrapyloric and/or larger curvature lymph nodes, D3 lymph node dissection might embody its removing.

Concomitant care

Routine concomitant care is constant between the 2 teams. No particular or prohibited interventions or necessities have been recognized for this trial.

Photographic recording and high quality evaluation of the eliminated specimen

Following the appliance of the clips and earlier than crossing the vessels, a photograph of the surgical discipline is captured to evaluate the compliance of the carried out lymph dissection with the declared process.

Photographic recordings of the specimen are taken on either side (intraperitoneal and retroperitoneal) to evaluate the preservation of the mesocolic fascia (Figs. 7 and 8).

{Photograph} of the specimen after D2 and D3 lymph node dissection (intraperitoneal view)

{Photograph} of the specimen after D2 and D3 lymph node dissection (extraperitoneal view)

The standard of the specimen is set in line with West classification [18], and this analysis is carried out independently by a collaboration of the surgeons and pathologists.

Specimen preparation for pathologists

Lymph node extraction from the contemporary specimen is carried out by surgeons after photographic recording of the specimen on either side (Fig. 9). All mesentery is meticulously separated into teams of lymph nodes. An exception is made for the realm of the paracolic mesentery, which is proscribed by the dimensions of the tumor. This exception is meant to find out tumor invasion into the mesentery, in addition to extramural invasion, tumor deposits, tumor budding, and round resection margin (CRM).

Extraction of lymph nodes from the specimen

The mesentery of the colon is dissected, and all seen lymph nodes are properly remoted. Separate containers with chosen lymph nodes, distributed by every group, together with the mesentery from which they had been extracted (for extra detection of lymph nodes and different findings), will probably be despatched to the pathologist (Fig. 10).

Last view for the pathologist after lymph node extraction

Specimen controlling course of

The fabric was mounted for 12 h in 10% impartial formalin, after which the fabric was minimize out by a pathologist in line with the usual protocol. Chosen fragments endure commonplace dehydration course of within the pathological departments from all facilities. A number of sections (2–4) with a thickness of 5–6 μm had been shaped from the paraffin blocks. Hematoxylin and eosin had been used for staining. The ready slides had been examined by a pathologist underneath a microscope.

All macroscopic specimens collected will probably be saved in a ten% answer of impartial formaldehyde till the trial completed.

After ending of the trial, sealed disposable containers with all collected specimens are utilized in settlement with the State Sanitary Inspection Regulation for medical establishments or in a centralized means (thermal neutralization—cremation).

Adjuvant chemotherapy

Adjuvant chemotherapy is not going to be administered for stage I of the illness or stage II with out danger elements similar to poor tumor differentiation, extramural invasion, intestinal obstruction, tumor perforation throughout surgical procedure, lower than 12 examined lymph nodes, or involvement of resection margins. In all different circumstances, a fluoropyrimidine and/or oxaliplatin routine will probably be employed.

Comply with-up

Your entire follow-up course of will probably be meticulously monitored by the investigators concerned. Common contact with sufferers will probably be established to implement the mandatory follow-up methods.

1. 1.

   Stomach ultrasound each 3 months for the primary 2 years, then each 6 months till the fifth yr

2. 2.

   CEA monitoring each 3 months for the preliminary 2 years, then each 6 months till the fifth yr

3. 3.

   Chest and stomach CT scans each 6 months throughout the first 2 years, then yearly till the fifth yr

4. 4.

   Colonoscopy yearly for five years postoperatively

End result parameters

Major endpoint

A 15% enhance in 5-year general survival (OS) using D3 lymph node dissection.

Secondary endpoint

1. 1.

   5-year disease-free survival (DFS)

2. 2.

   Incidence of apical lymph node involvement

3. 3.

   Intraoperative problems

4. 4.

   Postoperative morbidity

5. 5.

   Mortality

Definition of endpoints

OS and DFS

OS is the proportion of people in a research (in every group) who’re alive 5 years after receiving the intervention. OS is outlined by any-cause mortality.

DFS is the proportion of people in a research (in every group) who’re alive 5 years after receiving the intervention, with out experiencing native or distant recurrence or loss of life from any trigger. For DFS, an occasion is outlined as native or distant recurrence or loss of life. Contributors who’re misplaced to follow-up throughout the 5-year interval post-procedure will probably be labeled as censored. The survival evaluation will probably be carried out utilizing Kaplan–Meier curves, with comparisons made utilizing the log-rank check.

Incidence of apical lymph node involvement

The incidence of apical lymph node involvement is the histologically confirmed share of sufferers who underwent D3 lymph node dissection with optimistic lymph nodes.

Intraoperative problems

All intraoperative problems will probably be recognized throughout the operation.

1. 1.

   Vascular damage: An unintentional full-thickness defect of the vessel (arteries and veins) wall brought on by surgical manipulations. Arterial vessels embody the ileocolic, proper colic, center colic, accent center colic, gastroepiploic, superior mesenteric, and aorta. Venous vessels embody the ileocolic, proper colic, gastrocolic trunk and its tributaries, center colic, superior mesenteric, and cava.

2. 2.

   Tumor rupture/perforation: An unintentional partial or full-thickness defect of the colon wall the place the tumor is positioned, brought on by surgical manipulations.

3. 3.

   Abscess perforation: An unintentional defect within the abscess capsule accompanied by the discharge of pus into the belly cavity.

The strategy of aggregation for all intraoperative problems will contain calculating the proportion of sufferers who expertise problems throughout the operation relative to the whole variety of sufferers. Group comparisons will probably be carried out utilizing the chi-square or Fisher’s actual check.

Postoperative morbidity

All postoperative morbidity will probably be recognized inside 30 days after the process, aside from postoperative diarrhea.

1. 1.

   Postoperative lymphatic leakage: Consists of lymphatic fistula, lymphorrhea, lymphocele, lymphatic ascites, and particular types (chylous leakage), labeled in line with the Lv classification [19].

2. 2.

   Anastomotic leakage: A defect of the intestinal wall on the anastomotic website resulting in a communication between intra- and extraluminal compartments. The severity is graded based mostly on medical administration affect. Grade A anastomotic leakage ends in no change in sufferers’ administration, whereas grade B leakage requires lively therapeutic intervention however is manageable with out re-laparotomy. Grade C anastomotic leakage requires re-laparotomy [20].

3. 3.

   Postoperative diarrhea is unfastened stool, watery stool, or mucous stool thrice or extra a day inside 6 months after the operation.

The aggregation methodology for all postoperative morbidities will contain calculating the proportion of sufferers who expertise problems inside the first 30 days post-operation relative to the whole variety of sufferers. Group comparisons will probably be carried out utilizing the chi-square or Fisher’s actual check.

Postoperative mortality

Postoperative mortality is outlined as loss of life from any trigger inside the first 30 days following the operation. Will probably be measured by the proportion of deceased sufferers relative to the whole variety of sufferers. Group comparisons will probably be carried out utilizing the chi-square or Fisher’s actual check.

Pattern measurement calculation

In keeping with the SEER database (2004–2012) and AJCC fifth, sixth, and seventh editions, the 5-year general survival for stage II proper colon most cancers was 68–84%, and for stage III, it was roughly 57 to 60% [21,22,23]. Within the JCOG0404 trial, the 5-year general survival for stage II-III was 91% [24]. Literature knowledge means that the baseline survival for D2 lymph node dissection group is estimated to be 75% for stage II-III of the illness, and for D3 group, it’s 90%, respectively. An anticipated distinction of 15% in 5-year general survival between D2 and D3 LND teams is anticipated. The log-rank check (Lacatos, proportion of surviving) was utilized within the PASS 11 program for pattern measurement calculation. The facility of the research is about at 80%, with a kind I error 5%. An anticipated lack of follow-up is estimated at 15% for sufferers in every group. The enrollment interval for sufferers is 3 years, and the whole length of the research will probably be 8 years. Based mostly on aforementioned circumstances, 239 sufferers needs to be included within the research (Desk 1). Finally, 120 sufferers will probably be included in D3 group, and 119 sufferers in D2 group. The anticipated variety of deaths within the D2 group is 24, and within the D3 group, it’s 10.

Knowledge evaluation

Upon recruiting the final affected person, a 5-year follow-up will start. Intention-to-treat and per-protocol evaluation will probably be carried out. Lacking knowledge will probably be imputed utilizing Multivariate Imputation by Chained Equations (MICE bundle in R), aside from survival knowledge [25]. All collected knowledge will probably be meticulously saved within the eCRF, and subsequent statistical evaluation will probably be carried out. The info evaluation course of will probably be carried out in an anonymized method, managed by members of the college’s analysis group, who will solely deal with the collected knowledge. Knowledge evaluation will probably be solely carried out by the statisticians, additionally in an anonymized method. The numeric variables will probably be offered as imply and commonplace deviation or median and vary. For categorical variables, numbers and percentages will probably be expressed. T-test or Mann–Whitney U check will probably be employed for comparability between numeric variables, and chi-square or Fisher’s actual check will probably be used to match categorical variables. A subgroup evaluation by stage of the illness will probably be carried out. The survival evaluation will probably be estimated utilizing Kaplan–Meier curves, and comparisons will probably be made utilizing the log-rank check. Cox regression will probably be utilized to investigate the danger elements of survival. The occasion for general survival will probably be outlined as loss of life from any trigger, and for disease-free survival, it is going to be native or distant recurrence or loss of life. Sufferers misplaced to the 5-year follow-up will probably be censored. All statistical exams are two-sided, and statistical significance is outlined as p < 0.05. The statistical evaluation will probably be carried out in R Studio underneath the Affero Common Public License model 3.

Knowledge monitoring

An unbiased knowledge monitoring committee (DMC) has been established, comprising skilled colorectal surgeons, biostatisticians, analysis contractors, and ethicists. A particularly assigned unbiased specialist will run the evaluation of intraoperative discipline and re-evaluation course of and deal with the post-operative specimens in line with the research design and protocol necessities. After surgical procedure, all post-operative problems and occasions will probably be monitored by a particular doctor and recorded within the eCRF. For knowledge assortment, further specialists will probably be assigned who is not going to be concerned within the perioperative administration. Confidentiality agreements have been signed by all investigators concerned to guard the private info of the individuals. All study-related info will probably be saved securely on the research website. The DMC members will convene earlier than the graduation of the research and at common intervals all through its length. The committee will assess numerous features of the research, together with adversarial occasions, participant withdrawals, and endpoints. The finial dataset will probably be assessed by all concerned investigators and all members of DMC. The auditing will probably be carried out as soon as per yr and the method will probably be unbiased from investigators and the sponsor. Within the occasion that any main adjustments come up throughout the conduct of the trial, all concerned events will convene a gathering to handle potential considerations. The concerned knowledge will probably be saved securely for a interval of 5 years after enrollment of the final participant.

Reporting of postoperative complication

All potential harms will probably be collected systematically. MedDRA will probably be used to categorise any potential harms, and all harms will probably be reported in line with the Clavien-Dindo classification [26].

Ethics and analysis registration

Comparability of D2 vs D3 lymph node dissection for proper colon most cancers (RICON NCT03200834) was authorised by the Native Ethics Committee of Donetsk Nationwide Medical College underneath reference No. 24/1 dated 01/20/2017.

Interim evaluation and monitoring

An interim evaluation will probably be carried out as soon as, contemplating multiplicity utilizing the Lan–DeMets methodology with O’Brien and Fleming sort boundaries. The DMC will independently evaluation the interim evaluation report and prematurely terminate the research within the curiosity of affected person security and well-being if obligatory.