Evidence - Right Hemicolectomy, Robot-Assisted, with Complete Mesocolic Excision (CME) and UFA (Uncinatus First Approach) (Critical View Concept (CV))

Staging Diagnostics:

• Complete Colonoscopy
  • Gold standard in the diagnosis of colorectal carcinoma
  • for localization diagnostics and histological confirmation and to exclude a second carcinoma (approx. 5% of cases)
  • If the entire colon is not visible colonoscopically, a CT or MR colonography can be used
  • After emergency surgery (ileus, tumor perforation, colonoscopically uncontrollable bleeding): postoperative colonoscopy after anastomosis healing and patient recovery to exclude a synchronous double carcinoma
• Histological Confirmation
• Laboratory Examination with Determination of CEA Value

Note: At the time of initial diagnosis, the tumor marker CEA is elevated in about 30% of all colorectal carcinomas and should therefore be determined preoperatively. In tumor follow-up, CEA is a reliable indicator of recurrence in marker-expressing tumors and is also an independent prognostic factor in the case of liver metastases. The significance of CA 125 as a parameter for further treatment of a proven peritoneal carcinomatosis is currently unclear (1, 2). CA 19-9 is repeatedly discussed as another tumor marker, but it does not increase the predictive value regarding the presence of a recurrence compared to a sole CEA value determination.

• Chest X-ray in 2 Planes
• Abdominal Ultrasound
• Possibly CEUS (Contrast-Enhanced Ultrasound) in case of suspected hepatic metastasis
• Possibly MRI Liver in case of suspected hepatic metastasis

Note: Although a CT abdomen or CT thorax-abdomen is not considered necessary in the S3 guideline, it is performed in most clinics. It serves not only to detect hepatic metastases but also to assess the primary tumor, possibly enlarged lymph nodes, and the positional relationship of the tumor-bearing colon to other structures, such as the ureters and their course.

From (3): Körber et al.: S3 Guideline Colorectal Carcinoma, Oncology Guidelines Program of the AWMF, German Cancer Society e.V. and German Cancer Aid. Status: 2019. Retrieved on: 03.07.2019.

Interdisciplinary Tumor Conference:

All patients with colorectal carcinomas should be presented in an interdisciplinary tumor conference after completion of primary therapy (e.g., surgery, chemotherapy). A study from the UK showed that this approach significantly increased patient survival (4).

Patients should be presented pre-therapeutically in the following constellations (3):

• any rectal carcinoma
• any colon carcinoma in stage IV
• distant metastases
• local recurrences
• before any local ablative measure

TNM Classification:

The TNM system for colorectal carcinoma is defined as follows (5):

The UICC stages are then as follows:

Therapy Planning

The therapy of colon carcinoma is derived from the TNM and UICC stages determined in diagnostics (3):

Operative Approach and Surgical Oncological Principles

The progress in the treatment of colon carcinoma over the last 30 years is due to increasing individualization of therapy, consistent implementation of surgical-oncological principles, more aggressive therapy regimens in the metastatic stage, and the use of minimally invasive surgical techniques. Standardized treatment concepts in multimodal tumor therapy have led, among other things, to an increase in the average five-year survival rate from 65% to over 85% and a reduction in the locoregional recurrence rate from an average of over 13% to under 2% in non-metastatic colon carcinoma in UICC stages II and III (6). In the metastatic stage, five-year survival rates of over 40% are now achieved in 20% of patients (7).

Of crucial importance for the prognosis is the en-bloc resection of the tumor-bearing colon segment with systematic locoregional lymphadenectomy. The systematic lymphadenectomy with a high yield of potentially metastatic lymph nodes is the basis for standardized classification of lymph node status, the resulting therapy recommendation, and the prognosis of the patient.

Lymphatic metastasis in carcinomas of the cecum and ascending colon occurs centrally along the supplying vessels A. ileocolica and A. colica dextra or in the area of the right flexure also via the right branch of A. colica media.

Lymph node stations are described from peripheral to central along the arterial vessels as follows (8):

• epicolic and paracolic compartment
• intermediate compartment
• central compartment

The bidirectional longitudinal or paracolic drainage to the sides of the tumor occurs via the paracolic lymph nodes over a lateral spread of a maximum of 10 cm (9).

Spread from the cecum or ascending colon to the terminal ileum does not occur in practice (10).

These details of lymphatic drainage are taken into account when determining the extent of resection in colon carcinomas. It is oriented to the supply area of the radicularly severed main arteries and should also be at least 10 cm on both sides of the tumor. The last lymph node station is located centrally at the origin of the main vessels from the main vessels. The proximal resection plane is located in the terminal ileum 10 cm before the Bauhin valve, the distal between the right lateral and medial transverse third.

The surgical therapy of right-sided colon or cecum carcinoma should include the complete mesocolic excision (CME). This is now widely accepted in the literature as the gold standard (11).

In addition to systematic lymphadenectomy, the CME concept also aims to maximize the reduction of the number of local recurrences by increasing the radicality and quality of the resection. Analogous to the mesorectum, there is a mesocolon in the same way, which as a bilateral sheath contains the lymph nodes at the supplying arteries and is therefore considered anatomical guide structures for oncological surgery. The technique was published by Hohenberger et al. in 2009 (12).

The three basic principles of preparation in CME are:

• adherence to the specified anatomical layers during preparation with preservation of the two mesocolic fascias,
• central severance of the supplying vessels
• sufficient length of the specimen (longitudinal resection distances).

The goal is maximum local radicality with maximum lymph node yield.

Essential for the surgical success of the concept is the largely sharp preparation in the layer between the parietal and mesenteric fascia and strict observance of these structures.

The proximal severance of the supplying colon arteries occurs immediately after the origin from the A. mes. sup. while preserving the nerve plexuses in the central lymph node compartment along the "surgical trunk." This includes the section along the V. mesenterica superior between the ileocolic blood vessels and the Henle trunk (13). These resection boundaries correspond to the anatomically defined area of a D3 lymphadenectomy. The area to be resected

extends medially to the left of the A. mesenterica superior and laterally to the right of the V. mesenterica superior as well as in front of and behind these blood vessels (14, 15). At least 12 or more lymph nodes should be removed and examined.

Study Results

Due to the increasing standardization of en-bloc resection with systematic lymphadenectomy, an improvement in the overall prognosis in the curative situation has been achieved over the last 20 years, also against the background of established chemotherapy (12). Retrospective studies have demonstrated a correlation between the number of lymph nodes examined and the stage-independent prognosis (16, 17).

The CME leads to higher quality specimens without increasing complication rates (12, 18, 19). The previous data also suggest an improvement in survival rates with consistent implementation of CME (12).

Data from Denmark, Sweden, and Germany show that the CME technique in patients with colon carcinoma in UICC stage I – III is associated with better disease-free survival than conventional colon resection (19-21).

A meta-analysis published by Wang et al. in 2018, which compares CME with "conventionally" performed surgery, demonstrates the oncological superiority of CME (22). However, this publication also reveals that CME surgery is technically more demanding and is associated with a higher rate of intraoperative bleeding due to vascular injuries and a higher rate of postoperative complications. This can most likely be attributed to insufficient knowledge of the venous conditions in the area of the Henle trunk (23).

Although the study quality regarding the number of lymph nodes is low, it is considered that patients with a larger number of removed and examined lymph nodes have an improved prognosis in UICC stage II and III. This correlation was shown in 3411 patients in stage II and III as part of the so-called Intergroup Trials and the INTACC study (24, 25).

Not only the number of lymph node metastases is relevant, but also the general number of removed lymph nodes. Thus, a prognostic effect can also be demonstrated in nodal-negative tumors, which correlates with the number of removed or examined lymph nodes (26).

The number of lymph nodes can thus be considered a surrogate marker for the quality of treatment and diagnosis for both surgery and pathology. Finally, the pathologist should categorize the specimen into grade 1 (good, preservation of the mesocolic layer) to grade 3 (poor with tears to the muscularis propria or to the tumor).

Incidentally, the CME concept has significantly sharpened our surgical-anatomical understanding of the right hemicolon: Traditional errors and inaccuracies have been eliminated, such as the regularly given origin of an A. colica dextra from the A. mes. sup. or the outflow via a V. colica dextra with direct entry into the V. mes. sup. instead of into the 90% present truncus gastropancreaticocolicus (Henle trunk).

Special Operative Cases:

· For large polypoid, especially villous tumors and generally possible segmental and tubular resection, where a carcinoma diagnosis could not be secured pre-therapeutically, a dignity assessment in frozen section is often not possible for examination technical reasons (examination of multiple tissue blocks!). Therefore, an oncological operation should be considered primarily (3).

· In case of adherence of the tumor to surrounding structures and neighboring organs, it is not possible to clarify intraoperatively macroscopically in most cases whether it is an infiltration of the carcinoma in the sense of an organ-transcending T4 situation or only a peritumoral inflammatory reaction. In such cases, intraoperative tissue samples and frozen section examinations should be strictly avoided to prevent the risk of tumor cell dissemination, which is associated with a significant deterioration in prognosis (27). Therefore, in these cases, an en-bloc resection including adjacent structures is justified.

· In cases where imaging cannot make a clear diagnostic assignment of unclear liver lesions, histological confirmation should be obtained (3).

Laparoscopic and Robotic Surgery in Colon Carcinoma

Mono- and multicenter RCTs (KOLOR, COST, CLASSIC-Trail) showed no differences between laparoscopic and open techniques in colon carcinoma surgery in terms of surgical-oncological quality indicators (R-status, lymph node count) and long-term results (tumor recurrences, survival) with appropriate expertise of the surgeon (28-30).

As an advantage of minimally invasive surgery, a relatively low perioperative morbidity with unchanged overall morbidity and mortality was shown in the short-term course (31).

In the long-term course, no differences were found between laparoscopic and conventional surgery in terms of the rate of incisional hernias and adhesions-related relaparotomies or tumor recurrences (32, 33). The British CLASSIC study also confirms the oncological safety of laparoscopic surgery in colorectal carcinomas (34).

According to the current S3 guideline "Colorectal Carcinoma," a laparoscopic resection of colon carcinoma can therefore be performed in suitable cases with appropriate experience of the surgeon (3).

Significantly later than laparoscopic oncological colon surgery – around 2010 - robotic oncological colon surgery was implemented in clinics.

Robotic surgery, as an advancement of laparoscopic surgery, offers great optimization potential compared to simple laparoscopy, especially in terms of oncological surgery of the abdomen, with its higher precision of instrument guidance and improved visualization.

Studies show that robotics can be safely applied in colon carcinoma and has advantages in terms of tissue preservation and reduction of postoperative functional disorders (35-39).

The best data on robotic-assisted versus conventionally laparoscopic colorectal oncological surgery with early postoperative results and also oncological long-term results are available for right hemicolectomy and rectal resections.

Solaini et al. compared in a meta-analysis with an RCT among the total of 11 studies considered 869 robot-assisted with 7388 conventionally laparoscopic operated right hemicolectomies (40). For robotic procedures, a significantly longer operation time was found, but with a significantly reduced conversion rate. An intracorporeal anastomosis could be performed significantly more frequently in robot-assisted resected patients compared to conventionally laparoscopic operated patients. The early postoperative course between robot-assisted and conventionally laparoscopic operated patients did not differ with the same morbidity and mortality in the groups.

Lorenzon et al. included in their meta-analysis, in addition to 18 case-control studies, 3 RCTs (41). The aim was to compare the early postoperative results between robot-assisted and conventionally laparoscopic colorectal resections. The results from the RCTs showed no differences between robot-assisted and conventionally laparoscopic resected patients in terms of operation time, hospital stay, or postoperative morbidity. Considering all studies and all colorectal resections, lower costs and shorter operation times were found on the side of laparoscopically operated patients, while robotically operated patients had slightly lower morbidity (odds ratio=0.6-0.9). In isolated consideration of the subgroup of left-sided hemicolectomies, only a significant difference was found: conventionally laparoscopic operated patients showed a shorter operation time.

Regarding oncological radicality, the available studies show heterogeneous results, from which no clear advantage of robotics over laparoscopic procedures can currently be derived. Two studies comparing robotic colon procedures with laparoscopic colon procedures show advantages on the side of robotics in terms of the number of resected lymph nodes (42, 43). However, historical collectives were used as a control group for robotics, which could represent a strong bias, as the radicality and consistency of CME have certainly increased in recent years.

In the above-cited meta-analysis by Soleini from 2018 and also in another study comparing two collectives, no significant difference was found in terms of lymph node count (40, 44).

Regarding 5-year survival after oncological colorectal procedures, Spignoglio et al. found no significant differences in the comparison of robotic with conventionally laparoscopic surgery (44). Long-term results with larger, also multicenter studies are still pending.

In summary, the following advantages arise for robotics:

Due to the technical advantages of robotics compared to conventional laparoscopy, such as higher precision, articulability, and better visualization with zoomable 3-D view, some hurdles that conventional laparoscopic oncological colon surgery faced can be overcome. Another advantage is the tremor filter, which facilitates operating in highly sensitive regions.

Specifically, the Da Vinci system used in the present article makes intracorporeal anastomosis relatively easy, as in open surgery, with minimal access trauma. Central lymph node dissection and central ligation according to the CME concept are also significantly facilitated compared to conventional laparoscopy.

Ultimately, the published results so far show a significant reduction in technical conversions from minimally invasive to open access due to these surgical advantages (40, 43, 45). Also, the learning curve for minimally invasive procedures is shorter with robotic-assisted surgery compared to conventional laparoscopic surgery (46), at least when considering only the development of operation times. In the work of Parisi et al., it was concluded that this is completed after 44 procedures (47).

Despite all the mentioned advantages, at the time of guideline creation, the evidence for robotic surgery still had to be rated as insufficient. At the time of creation, there were no meaningful prospective randomized studies on the value of robotics in colon carcinoma of the sigmoid. Due to the lack of short- and especially oncological long-term results at the time of guideline creation, robotic-assisted surgery in colon carcinoma is currently not recommended outside of studies in the valid S3 guideline (3).

Finally, it can be added here that in intestinal centers that enter into the DGAV register, it is evident in the benchmark that robotics has led to an improvement in perioperative results and contributed to excellent oncological results (48). Furthermore, it is shown that the proportion of successfully minimally invasively operated patients without conversion is higher in robotics than in conventional laparoscopy and that significantly fewer contraindications exist.

Disadvantageously, for right hemicolectomy with CME, a tendentially longer operation time was found when comparing the robotic to the conventional laparoscopic procedure (40, 49).

The cost aspect of robotics also plays a significant role in the discussion (40, 49). For example, in the meta-analysis by Solaini, the robot-assisted procedures were associated with significantly higher costs. However, it should not be neglected that after the successful establishment of the robotic system, there are potential savings beyond acquisition and material costs. In German centers that have established robotics for colorectal carcinoma, it is generally shown that the length of stay of robotically operated patients is reduced compared to conventionally laparoscopic operated patients and that it is generally no longer necessary to provide a monitoring bed, except for multimorbid patients.

Multimodal Tumor Therapy

Numerous studies demonstrate the importance of drug tumor therapy in non-metastatic colon carcinoma. Adjuvant chemotherapy in UICC stage III is associated with a significant improvement in prognosis of about 20% overall survival (50). In stage II, patients with risk factors (T4 tumor, tumor perforation, emergency interventions, number of examined/excised lymph nodes < 12) have a significantly worse prognosis than patients in the same stage without risk factors and should therefore receive adjuvant chemotherapy (3).

Adjuvant Therapy in Right-Sided Colon Carcinoma

Indications

• Adjuvant chemotherapy is not recommended in UICC stage I.
• In UICC stage II, it is a so-called "can situation," i.e., depending on risk factors and microsatellite status, it can certainly be recommended. In the presence of microsatellite instability, no adjuvant chemotherapy is recommended. If risk factors are present, adjuvant chemotherapy should be considered. Selected risk situations include: T4 tumor, tumor perforation/tear, emergency surgery, insufficient number of examined lymph nodes (<12))
• In UICC stage III, adjuvant therapy is always recommended.

Prerequisites

Prerequisite for adjuvant therapy is the R0 resection of the primary tumor. The basis for the indication for adjuvant therapy after quality-assured tumor resection is the pathohistological stage determination, especially the determination of the pN status. To establish pN0, 12 or more regional lymph nodes should be examined (UICC 2002). Immunocytological findings of isolated tumor cells in bone marrow biopsies or lymph nodes as well as cytological tumor cell findings in peritoneal washings are not an indication for adjuvant therapy outside of studies.

Contraindications

• Poor general condition (ECOG >2),
• severe infection
• limited life expectancy due to comorbidities
• liver cirrhosis in Child B or C stage
• severe coronary heart disease or heart failure (NYHA III and IV)
• advanced renal insufficiency ((pre-)terminal)
• blood disorders, impaired bone marrow function
• inability to participate in regular follow-up examinations

Therapy Modalities

• Start: Postoperatively as soon as possible
• In randomized studies, adjuvant chemotherapy was initiated within 8 weeks.

Note: RCTs to determine the ideal timing do not exist. In a retrospective analysis of cohort studies, an inverse correlation between the timing of the start of adjuvant chemotherapy and survival was calculated (51). This was also confirmed in another retrospective analysis of cohort studies (52) and in a retrospective registry analysis (52, 53).

• Duration: 3–6 months, depending on risk-benefit assessment
• UICC stage II: Monotherapy with fluoropyrimidines
• UICC stage III: Combination therapy with Oxaliplatin
• FOLFOX: Folinic acid + 5-FU in combination with Oxaliplatin
• XELOX (CAPOX®): Capecitabine + Oxaliplatin
• In patients >70 years, no therapy with Oxaliplatin should be performed
• In case of contraindications to Oxaliplatin, monotherapy with fluoropyrimidines should be performed

Note: Adjuvant chemotherapy should not be omitted solely due to age. However, there is no sufficient evidence for adjuvant chemotherapy in patients over 75 years.

Neoadjuvant Chemotherapy in Colon Carcinoma

The role of neoadjuvant chemotherapy in the treatment of locally advanced colon carcinomas has been investigated in recent years. A randomized study from the UK showed that combined neoadjuvant/adjuvant chemotherapy (Oxaliplatin, folinic acid, and 5-FU) vs. solely adjuvant chemotherapy in locally advanced colon carcinomas resulted in a lower rate of R1 resections and significant downstaging. Tumor progression under ongoing neoadjuvant chemotherapy was not observed [2, 12]. Studies have shown that computed tomography is suitable for identifying locally advanced colon carcinomas in terms of the T category and thus selecting for neoadjuvant chemotherapy or preoperatively assessing the response to chemotherapy [1, 20]. Oncological long-term results are still pending, and it is currently not recommended in the guidelines.

Multivisceral Resection

In case of adherence of a tumor to neighboring organs, it is not possible for the surgeon to clarify macroscopically whether it is an infiltration of the carcinoma into the neighboring organ or only a peritumoral inflammatory reaction. In such cases, biopsies and frozen section examinations should be strictly avoided, as there is always the risk of local tumor cell dissemination. This is always associated with a significant deterioration in prognosis. Therefore, if technically feasible, an en-bloc resection of the tumor with the infiltrated structures is recommended (multivisceral resection). In the case of rectal carcinoma, this may require, for example, complete pelvic exenteration.

Metastatic Situation

At the time of diagnosis, distant metastases are present in about 25% of patients. In the metastatic situation, there is generally a significant reduction in the five-year survival rate.

If distant metastases are present, it must be clarified whether a purely palliative concept should be pursued or whether healing is possible through primary or secondary resection of metastases (especially liver metastases). With an increased presentation of patients in UICC stage IV in the tumor conference, the rate of metastasis surgery increased (54).

In recent years, the prognosis has also been significantly improved in stage IV through both more radical surgical action and drug tumor therapy (combination of dual therapy and antibodies), so that with a five-year survival rate of up to 50%, the prognosis for about 20% of metastatic patients has been significantly improved (55).

In the literature, response rates of up to 60% and an R0 resection rate of up to 15% are achieved through the application of various chemotherapy protocols (56).

It should generally be distinguished between patients with synchronous and metachronous metastasis (57-59). The synchronous must be considered prognostically unfavorable compared to metachronous metastasis. Furthermore, information on disease dynamics is lacking here. The benefit of primary resection is therefore more uncertain in this patient group than in patients with metachronous metastasis. Other prognostic factors that can be considered in decision-making include the number of metastatic lesions, the presence of extrahepatic metastasis (60).

Simultaneous resection of liver metastases probably does not affect long-term survival compared to a two-stage approach with appropriate patient selection.

Patients in good general condition can be subjected to intensive treatment, i.e., surgery or chemotherapy. For resectable tumor manifestations and favorable risk constellation, primary metastasis resection should be aimed for. Those patients for whom primary surgical intervention is not possible should receive the most effective systemic chemotherapy possible. The primary therapeutic goal is maximum tumor reduction. The choice of chemotherapy regimen depends crucially on the molecular pathological profile of the tumor. In patients with RAS wild-type tumors, the localization of the primary tumor is also an additional decision-making basis.

However, simultaneous liver metastasis resection can lead to higher mortality with corresponding comorbidity or older age (>70 years). Especially in the case of multiple synchronous liver metastases, a two-stage and multimodal approach should be chosen (3).

The assessment should be made by a tumor board involving a surgeon experienced in metastasis surgery. In the case of extensive hepatic metastasis in stage IV and an asymptomatic primary tumor without stenosis and without bleeding, chemotherapy can also be started without resection of the primary (3).

Peritoneal Carcinomatosis

If isolated and limited peritoneal carcinomatosis is present in a colon carcinoma, the indication for cytoreductive surgery followed by hyperthermic intraperitoneal chemotherapy (HIPEC) can be reviewed. The use of this combination therapy has shown a significant survival advantage in terms of extending median survival from 12.6 to 22.3 months (61).

The Peritoneal Cancer Index (PCI) is used to determine the extent of peritoneal carcinomatosis. The following prerequisites should be met for HIPEC in colon carcinoma:

• PCI<20
• No extra-abdominal metastases
• Possibility of macroscopic resection or destruction of all tumor manifestations

If the PCI value is below 20 in patients without additional extra-abdominal metastases, cytoreduction with HIPEC can be performed in specialized centers if R0 resection is possible. The procedure should preferably be performed within the framework of studies (3).

Perioperative Concept

The ERAS concept ("enhanced recovery after surgery") of multimodal postoperative rehabilitation in gastrointestinal surgery is implemented in most clinics in this country in a partially modified form. The goal of the concept is to quickly manage the pathophysiological changes triggered by the surgical intervention, such as fatigue, intestinal atony, and insulin resistance. The concept includes, among other things, early removal of gastric tubes and intra-abdominal drains, early oral nutrition, stimulation of intestinal motility, sufficient analgesia (epi-/peridural), and early mobilization. Numerous studies have shown that the ERAS concept can significantly shorten the length of stay, reduce perioperative morbidity, and accelerate recovery (62, 63).

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