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, 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 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 in marker-expressing tumors is a reliable indication of recurrence 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 confirmed peritoneal carcinomatosis is currently unclear (1, 2). CA 19-9 is recurrently 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 dissemination
- Possibly MRI liver in case of suspected hepatic dissemination
- Possibly contrast-enhanced CT
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 spatial 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 Guideline Program of the AWMF, German Cancer Society e.V. and German Cancer Aid. Status: 2019. Retrieved on: 07/03/2019.
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 United Kingdom showed that this approach significantly increased patient survival (4).
Patients should be presented pre-therapeutically in the following scenarios (3):
- every rectal carcinoma
- every 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):
| T1 | Submucosa
|
| T2 | Muscularis propria |
| T3 | Perirectal tissue: Mesorectum |
| T4 | T4a Visceral peritoneum T4b Other organs/structures
|
| N1/2 | N1a 1 regional lymph node metastasis N1b 2–3 regional lymph node metastases N1c Satellites/tumor nodules in the mesorectum N2a 4–6 regional lymph nodes N2b >6 regional lymph nodes
|
| M1 | M1a Metastases limited to one organ (liver, lung, ovary, non-regional lymph nodes, no peritoneal metastases) M1b Metastases in more than one organ M1c Metastases in the peritoneum with/without metastases in other organs |
The UICC stages are as follows:
| UICC Stage | TNM |
| 0 | Tis (Carcinoma in situ) |
| I | Up to T2, N0, M0 |
| II | |
| IIA | T3, N0, M0 |
| IIB | T4a, N0, M0 |
| IIC | T4b, N0, M0 |
| III | |
| IIIA | Up to T2, N1, M0 or T1, N2a, M0 |
| IIIB | T3/T4, N1, M0 or T2/T3, N2a, M0 or T1/T2, N2b, M0 |
| IIIC | T4a, N2a, M0 or T3/T4a, N2b, M0 or T4b, N1/N2, M0 |
| IV | |
| IVA | Any T, any N, M1a |
| IVB | Any T, any N, M1b |
| IVC | Any T, any N, M1c |
Therapy Planning
The therapy of colon carcinoma is derived from the TNM and UICC stages determined in diagnostics (3):
| UICC Stage | TNM | Therapy Recommendation |
| 0–I | Tis to T1 | Endoscopic resection |
| Further approach based on histopathology: | ||
| - Low-risk situation (G1/G2) and | ||
| Complete resection (R0): No re-resection | ||
| - Low-risk and incomplete resection: Complete endoscopic/local surgical re-resection | ||
| - High-risk situation (G3/G4): Radical surgical resection | ||
| No adjuvant chemotherapy | ||
| I | T2, N0, M0 | Radical surgical resection |
| No adjuvant chemotherapy | ||
| II | Up to T4, N0, M0 | Radical surgical resection |
| Consider adjuvant chemotherapy individually/patient counseling | ||
| III | Any T, N+, M0 | Radical surgical resection |
| Adjuvant chemotherapy | ||
| IV | Any T, N+, M+ | Individual approach depending on findings |
Surgical Approach:
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).
Left-sided colon carcinoma metastasizes via the A. colica media to the trunk of the A. mes. inf. The resection should be performed with sufficient safety margins orally and aborally. Safety margins of at least 10 cm are recommended orally and aborally. The oncological left hemicolectomy includes the removal of the aboral transverse colon, the left flexure, the descending colon, the sigmoid colon up to the proximal rectum. It involves the central transection of the A. mes. inf. about 1 cm distal to its origin from the aorta to spare the neural structures located there (Plexus mesentericus inferior (Ganglion mesentericum inferius) (Autonomic Nervous System) and thus the oncologically necessary removal of the entire lymph node pathway of the inferior mesenteric artery.
CAVE: In at least 2 - 4% of patients, lymph node metastases are located near the origin of the inferior mesenteric artery (8, 9).
When transecting the mesorectum in the upper part, "coning" (thinning) should be avoided.
The surgical therapy of left-sided colon carcinoma should include complete mesocolic excision (CME). 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 also a mesocolon, 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 (10).
The three basic principles of preparation in CME are adherence to the specified anatomical layers during preparation while preserving the two mesocolic fascias, central resection of the supplying vessels, and sufficient length of the specimen. The goal is maximum local radicality with maximum lymph node yield. CME leads to higher quality specimens without increasing complication rates (10-12). The previous data also suggest an improvement in survival rates with consistent implementation of CME (10). 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 (12-14).
At least 12 or more lymph nodes should be removed and examined. Although the study quality on 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 demonstrated in 3411 patients in stage II and III in the so-called Intergroup Trials and in the INTACC study (15, 16).
Not only the number of lymph node metastases is relevant, but also the general number of removed lymph nodes. Thus, even in nodal-negative tumors, a prognostic effect can be demonstrated that correlates with the number of removed or examined lymph nodes (17).
The number of lymph nodes can thus be considered a surrogate marker for the quality of treatment and diagnosis of both surgery and pathology. Finally, the pathologist should categorize the specimen into Grade 1 (good, preservation of the mesocolic layer) through Grade 2 (moderate with surface tears) to Grade 3 (poor with tears to the muscularis propria or to the tumor).
Special Surgical Cases:
- In large polypoid, especially villous tumors and potentially possible segmental and tubular resection, where a carcinoma diagnosis could not be confirmed 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 cases of tumor adherence to surrounding structures and neighboring organs, it is often not possible to determine macroscopically intraoperatively whether it is an infiltration of the carcinoma in the sense of an organ-overlapping T4 situation or just 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 worsening of prognosis (18). 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 performed (3). However, pre-therapeutic confirmation should also be considered to pursue a "liver first" concept.
Laparoscopic Surgery in Colon Carcinoma
Mono- and multicenter RCTs (KOLOR, COST, CLASSIC-Trail) found no differences between laparoscopic and open techniques in colon carcinoma surgery regarding surgical-oncological quality indicators (R-status, number of lymph nodes) and long-term results (tumor recurrences, survival) (19-21).
As an advantage of minimally invasive surgery, a relatively low perioperative morbidity with unchanged overall morbidity and mortality was shown in the short term (22).
In the long term, no differences were found between laparoscopic and conventional surgery in terms of the rate of incisional hernias and adhesion-related relaparotomies or tumor recurrences (23, 24). The British CLASSIC study also confirms the oncological safety of laparoscopic surgery in colorectal carcinomas (25).
According to the current S3 guideline "Colorectal Carcinoma," laparoscopic resection of colon carcinoma can be performed in suitable cases with appropriate experience of the surgeon (3).
The guideline does not address articulating laparoscopic instruments. In the meantime, however, some monocentric studies on articulating ArtiSential instruments in colorectal surgery have been published.
Darwich et al. published a series of 17 patients with TME for rectal carcinomas in 2022 (26).
The TME, which poses high demands on the minimally invasive surgeon due to the narrow space in the small pelvis, was completed laparoscopically in all cases without conversion using articulating ArtiSential instruments despite a relatively high mean BMI of 28. The mean blood loss was very low at an average of 30 milliliters. There were no intraoperative complications and no postoperative anastomotic insufficiency. An average of 15 lymph nodes were removed. In addition, a well-classified TME specimen was confirmed by the pathologist.
From the same working group, 73 cases were also published in 2022, which received a colorectal resection with the help of ArtiSential instruments within 18 months (27). This is the largest series of colorectal resections using ArtiSential instruments to date. The results support the findings of the previous publication. It initially shows the feasibility of operations using the articulating instruments for the entire laparoscopic colorectal surgery. In this series, too, no conversion to laparotomy was necessary in any case. Compared to the literature, very good results are shown in terms of morbidity and mortality.
Although the present single-center results are to be considered excellent, comparative, preferably multicenter studies, ideally with a prospective randomized approach, should be initiated to generate a sufficient evidence base here, comparing articulating instruments with non-articulating laparoscopic instruments and with robotics.
Multimodal Tumor Therapy in Non-Metastatic Colon Carcinoma
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 (28). 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 also receive adjuvant chemotherapy (3).
Adjuvant Therapy in Descending 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 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, number of examined lymph nodes too low (<12))
- In UICC stage III, adjuvant therapy is always recommended.
Prerequisites
The 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 staging, 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 and 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 (29). This was also confirmed in another retrospective analysis of cohort studies (30) and in a retrospective registry analysis (30, 31).
- 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, therapy with oxaliplatin should not be performed
- In case of contraindications to oxaliplatin, monotherapy with fluoropyrimidines should be performed
Note: Adjuvant chemotherapy should not be omitted solely for age reasons. 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 non-metastatic colon carcinomas has been investigated in recent years. A randomized study from the United Kingdom showed that combined neoadjuvant/adjuvant chemotherapy (oxaliplatin, folinic acid, and 5-FU) vs. adjuvant chemotherapy alone in locally advanced colon carcinomas resulted in a lower rate of R1 resections and significant downstaging. Tumor progression during 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 them 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 cases of tumor adherence to neighboring organs, it is not possible for the surgeon to determine macroscopically whether it is an infiltration of the carcinoma into the neighboring organ or just a peritumoral inflammatory reaction. In such cases, biopsies and frozen section examinations should be strictly avoided, as there is always a risk of local tumor cell dissemination. This is always associated with a significant worsening of 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, a complete pelvic exenteration may be required.
Metastatic Situation
At the time of diagnosis, about 25% of patients have distant metastases. The primary organ affected by distant metastases in left-sided colon carcinoma is the liver. Secondarily, colon carcinoma metastasizes to the lungs. 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 a cure 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 (32).
In recent years, the prognosis in stage IV has also been significantly improved by 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 (33).
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 (34).
It should generally be distinguished between patients with synchronous and metachronous metastasis (35-37). The synchronous must be considered prognostically unfavorable compared to metachronous metastasis. In addition, 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 and the presence of extrahepatic metastasis (38).
The simultaneous resection of liver metastases probably does not affect long-term survival compared to a two-stage approach with appropriate patient selection.
Patients with hepatic dissemination should be presented in the interdisciplinary tumor board of a liver center after guideline-compliant staging to decide on the basic concept of curative, potentially curative, or palliative.
The assessment should be carried out by a tumor board with the participation of a surgeon experienced in metastasis surgery. In the case of extensive hepatic dissemination in stage IV and an asymptomatic primary tumor without stenosis and without bleeding, chemotherapy can also be started without resection of the primary tumor ("Chemo first") (3).
As part of restaging after initial liver-specific chemotherapy, the initial concept should then be reevaluated. In addition, in addition to one-stage atypical and anatomical resection, two-stage concepts involving hypertrophy procedures (ALPPS, portal vein ligation, hepatic vein occlusion) can be applied, which are only performed in centers.
Patients in good general condition can be subjected to intensive treatment, i.e., surgery or chemotherapy. In the case of resectable tumor manifestations and favorable risk constellation, primary metastasis resection after liver-specific chemotherapy should be aimed for ("liver first approach" or "Chemo first approach"). 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).
Peritoneal Carcinomatosis
If isolated and limited peritoneal carcinomatosis is present in 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 (39).
The Peritoneal Cancer Index (PCI) is used to determine the extent of peritoneal carcinomatosis. The following prerequisites should be met:
- 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, and if R0 resection is possible, operative cytoreduction with HIPEC can be performed in specialized centers. Here, implementation within the framework of studies should be preferred (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 aim 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, the 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 (40, 41).