Colon Cancer

First-degree relatives should undergo their first colonoscopy at an age 10 years prior to the patient's onset of disease, but no later than 50 years of age [11, 12]. This recommendation also applies to first-degree relatives of patients who were diagnosed with colorectal adenomas before the age of 50. If the findings are unremarkable, colonoscopy should be repeated in this risk group after a maximum of 10 years.

Diagnostic procedures should be carried out in accordance with the guidelines for the diagnosis of genetic predisposition to cancer of the German Medical Association, those of the Austrian Society for Gastroenterology & Hepatology (ÖGGH) in Austria and the ESMO guidelines [2, 12]. The specific genetic aberration determines the risk of disease and is the basis of the individualized early detection and prevention plan.

Aminosalicylate can be used for prophylaxis; results of randomized studies with the primary endpoint of preventing colorectal cancer are not available. The recommendations for early detection depend on the extent of the colitis and the duration of the disease. Patients with pancolitis for more than 8 years or with left-sided colitis for more than 15 years should undergo complete colonoscopy with stepwise biopsies annually. In patients with high-grade dysplasia, restorative proctocolectomy is an effective prophylactic intervention.

No specific recommendation regarding prophylaxis and early detection can currently be given for these patients.

The number of patients with potentially resectable metastases can be increased by means of so-called conversion therapy. The aim of this approach is to achieve technical resectability by downsizing the metastases. Accordingly, treatment protocols with high response rates and the chance of greater volumetric shrinkage of the metastases are recommended. In randomized and non-randomized phase II trials, doublet combinations plus antibodies (mAb) or triplet combinations ± mAb derived from the palliative setting were used, see Chapter 6.2.3 and Chapter 6.1.4.3. The PRODIGE-14 trial, which randomly tested doublet versus triplet, each + mAb (choice depending on RAS status), as conversion therapy, did not find a statistically significant improvement in R0/R1 resection rates; disease-free and overall survival were also not significantly different [52]. However, in the smaller OLIVIA study (80 patients) [22] with more clearly defined and stricter inclusion criteria with regard to irresectability, a benefit was found for triplet therapy + bevacizumab versus FOLFOX + bevacizumab. In the randomized CAIRO-5 study, significantly more R0/R1 resections were also achieved with FOLFOXIRI + bevacizumab compared with FOLFOX + bevacizumab in patients with non-EGFR-sensitive tumors (i.e., primary in the right hemicolon, BRAF V600E MUT or RAS MUT) (51 versus 37%) [54, 55]. In this respect, a triplet plus bevacizumab should be preferred in this patient group.

For EGFR-sensitive tumors in the VOLFI study (a randomized phase II study), the addition of panitumumab to a dose-reduced chemotherapy triplet led to high remission rates and consecutively improved resection rates in patients who tended to be younger. An improvement in overall survival was not shown [23]. However, the phase III TRIPLETE study [53] showed no benefit of a triple over a doublet therapy (each in combination with panitumumab) in terms of response and resection rates as well as PFS, so that a chemotherapy doublet should be chosen for patients who are to receive conversion therapy including an EGFR-mAb.

In studies with unselected patients, between 5 and 25% of initially non-resectable patients were subsequently resectable, up to 40% in the case of liver metastasis only. A treatment duration of 2 to 4, possibly up to 6 months is recommended, depending on clinical response. Once technical resectability has been achieved, surgery should be performed as soon as possible, and not deferred until maximum remission has been achieved. In this way, an increase in liver toxicity with a consecutive increase in surgical morbidity can be avoided. In the case of conversion therapy, restaging should be performed every 8-10 weeks with discussion of the CT or MRI images in an interdisciplinary tumor board. Liver surgery expertise should be available on the tumor board or be consulted as part of a presentation at a liver surgery center. Surgery should be performed 4 weeks after the end of systemic tumor therapy, or after (4-) 6 weeks in the case of a therapy containing bevacizumab. The value of continuing chemotherapy after R0 or R1 resection, i.e., completing chemotherapy over a total of 6 months, is of unclear benefit and therefore the subject of clinical studies. Important factors to be considered in this setting are the toxicity of the previous therapy and comorbidity as well as the histopathological response. The added benefit of local treatment for R1 resection is also the subject of clinical studies.

Repeated liver metastasis resections should always be considered, if technically (R0 resection) and clinically feasible and appropriate.

Despite effective primary therapy and progress in adjuvant treatment, distant metastases emerge in 35-45% of patients. The relapse rate is highest in the first two years after first diagnosis, while recurrence after more than 5 years is rare. In a subgroup of patients, a cure is also possible in this setting, see Chapters 6.1.4.1 and 6.1.4.2. For the treatment algorithm, see Figure 7.

In the majority of patients in stage IV, the therapeutic goal is palliative and includes the treatment of physical and psychological complaints. It requires multidisciplinary cooperation. The necessity and the possibilities of supportive measures should be discussed early and comprehensively with all affected persons.

The selection of the therapeutic strategy and the most favorable drug combinations are determined by numerous factors. Aspects to be considered are:

• Treatment goals set with the patient (and his relatives, if applicable)

• Course of the disease so far

• Biology of the disease, e.g., RAS and BRAF mutation status and localization of the primary tumor

• Prior treatment, e.g., preoperative or adjuvant chemotherapy

• Therapy-related factors, i.e., toxicity, quality of life

• Disease-unrelated factors, such as biological age and comorbidity

Biological test methods for the selection of the optimal therapy, e.g., gene signatures or in vitro sensitivity testing, have not yet been sufficiently validated. Monitoring by serial measurement of circulating tumor cells or circulating DNA is also not a standard procedure.

The basis of treatment for colon cancer is radical surgical resection. The quality of surgery has a direct impact on the long-term survival of patients. For information on the oncological principles of surgical treatment of colon carcinoma, see Chapter 6.1. The type and extent of resection are determined by the localization, the supplying vessels and the lymphatic drainage area defined by these. The surgical technique depends on the location of the primary tumor, see Table 5.

The operation can be performed open, laparoscopically and robotically with the appropriate expertise. The advantage of open surgery is the shorter operating time. The advantages of laparoscopic surgery are the cosmetic outcome, less blood loss and potentially faster postoperative recovery. The long-term oncologic results of the two approaches are presumably equivalent [38].

Special local situations include ileus, tumor perforation, intestinal perforation or infiltration into adjacent organs. For obstructive carcinomas, two-step surgery with creation of a passive anus praeter or one-step subtotal colectomy are feasible. In patients with hereditary disease, the type genetic burden, previous operations, and the overall treatment concept must be considered.

Aflibercept is a recombinant fusion protein with anti-angiogenic activity. In the pivotal study, the addition of aflibercept to FOLFIRI significantly improved the hazard ratio in patients previously treated with oxaliplatin-based therapy. Overall survival was prolonged by 1.4 months. Progression-free survival and response rates were also better in the aflibercept arm. Drug-related adverse events in CTCAE grade 3 / 4 were consistent with other antiangiogenic agents: Hypertension (+17.8%), bleeding (+1.3%) (especially epistaxis), arterial (+1.3%) and venous thromboembolism (+1.6%), and proteinuria (+6.6%). Rare critical complications included arterial, thromboembolic events, and gastrointestinal tract perforations.

Bevacizumab is a monoclonal antibody with anti-angiogenic activity. In combination with 5-FU / folinic acid, capecitabine, irinotecan or oxaliplatin, remission rates of 50% and prolongation of progression-free survival are achieved. In combination with irinotecan and 5-FU bolus protocols, prolongation of overall survival has also been achieved. Bevacizumab is effective in both first-line and second-line therapy. Continuation of bevacizumab therapy beyond progression resulted in prolonged overall survival in two randomized clinical trials. In the larger trial, a significant improvement in hazard ratio to 0.81 was achieved. Median overall survival was prolonged by 1.4 months. Serious adverse events (grade 3 / 4) that occurred in more than 5% of patients in the pivotal studies were hypertension and proteinuria. Less common critical complications included arterial thromboembolic events and gastrointestinal tract perforations.

The basic drug in chemotherapy of patients with colorectal carcinoma is 5-fluorouracil. Capecitabine is an oral fluoropyrimidine that is enzymatically metabolized by the tumor to 5-FU. In comparative clinical trials, it was at least as effective as 5-FU bolus/folinic acid therapy. When used as monotherapy, remission rates are achieved in up to 25%, and in combination with irinotecan or oxaliplatin in up to 45% of patients. Serious adverse events (grade 3 / 4) occurring in more than 5% of patients in the pivotal trials were diarrhea and hand-foot syndrome. The combination of proton pump inhibitors with capecitabine-containing therapy should be avoided, as negative effects on capecitabine efficacy have been demonstrated in several retrospective studies. Mutations among the four major dihydropyrimidine dehydrogenase (DPD) gene loci must be excluded prior to 5-FU-containing chemotherapy [39].

Cetuximab is a monoclonal antibody against the EGF receptor. The remission rate after monotherapy in second-line is 8%. In first-line therapy in patients with KRAS wild-type, remission rates of 55-65% are achieved in combination with 5-FU / folinic acid and irinotecan or oxaliplatin. Progression-free survival is prolonged. Overall survival data are inconsistent. Patients with defined RAS mutations (KRAS genes exon 2-4, NRAS genes exon 2-4) have no benefit from cetuximab therapy, and in some chemotherapy combinations even a trend towards shorter survival was observed. Because there is evidence of a negative interaction with capecitabine and bolus 5-FU protocols, that is not yet understood, the combination of cetuximab with oral fluoropyrimidines and bolus 5-FU protocols is not recommended, see also Approval Status Colorectal Cancer (in German only). Serious adverse events (grade 3 / 4) that occurred in more than 5% of patients in the pivotal studies were acneiform dermatitis and infusion reactions. Prophylactic therapy for acneiform dermatitis should be given with doxycyline or minocycline. Additional prophylactic local therapy with vitamin K1 cream (Reconval K1) may be considered in women. Medications for prophylaxis of infusion reactions are corticosteroids and H1 blockers. Biweekly administration (500 mg/m²) was equivalent to weekly cetuximab administration (400/250 mg/m²) in a randomized trial.

Encorafenib is an oral highly selective RAF kinase inhibitor. In combination with cetuximab, it resulted in prolonged survival in patients with BRAF V600E-mutated CRC after first-line therapy compared with chemotherapy plus cetuximab. The most common adverse events in the pivotal study were diarrhea, nausea, vomiting, and acneiform dermatitis, of which severe (≥ grade 3) were fatigue (4%), anemia (4%), and diarrhea (2%). Another typical side effect is palmar-plantar erythrodysesthesia syndrome (PPES) in 4% of patients (severe in <1%).

5-Fluorouracil is used in almost all forms of medical tumor therapy for patients with colorectal carcinoma. The best risk-benefit ratio is achieved with intravenous continuous infusion over 24-48 hours after previous administration of folinic acid. Remission rates are up to 30%. Severe side effects (grade 3-4) are diarrhea and stomatitis. Patients with functionally relevant polymorphisms of the 5-FU degradation genes have an increased risk of severe side effects including neutropenia, neutropenic fever, severe ulcerative mucositis, and others. Before chemotherapy containing 5-FU, a mutation in the four most important dihydropyrimidine dehydrogenase (DPD) gene loci must be excluded [39].

Fruquintinib is an oral, selective inhibitor of VEGF receptors 1, 2 and 3. In the FRESCO-2 study [50], a significant increase in median survival time from 4.8 to 7.4 months was achieved compared to placebo in 691 patients with refractory metastatic colorectal cancer. The most common adverse events observed in the study were arterial hypertension (14%), weakness (8%) and hand-foot syndrome (6%).

Ipilimumab is a drug from the group of monoclonal antibodies named immune checkpoint inhibitors. It blocks the inhibitory T-cell regulator CTLA-4 and thereby enhances the autologous immune response. It is approved in combination with nivolumab after pretreatment and treatment failure with/under fluoropyrimidine-containing combination chemotherapy for stage IV patients with MSI-H/dMMR. The overall response rate (ORR) for this combination was 55% in the pivotal Checkmate-142 trial, with survival rates at 9 and 12 months of 87% and 85%, respectively. 32% of patients experienced grade 3 / 4 toxicities associated with therapy: elevation of AST and/or ALT (11%), elevation of lipase (4%), anemia (3%), colitis (3%).

Irinotecan is a topoisomerase I inhibitor. In combination with 5-FU / folinic acid, remission rates are 40-50%. Progression-free survival and overall survival are significantly prolonged compared to fluoropyrimidine therapy. Serious adverse events (grade 3 / 4) that occurred in more than 5% of patients in the pivotal studies were diarrhea, nausea/vomiting, neutropenia and neutropenic fever. The substance can be applied weekly, bi-weekly or tri-weekly.

Nivolumab is an anti-PD-1 monoclonal antibody of the immune checkpoint inhibitor class. It is approved in combination with ipilimumab after pretreatment and treatment failure with/under chemotherapy for stage IV patients with MSI-H/dMMR, after pretreatment with fluoropyrimidines. The overall response rate (ORR) for this combination in the pivotal Checkmate-142 trial was 55%, with survival rates at 9 and 12 months of 87% and 85%, respectively. 32% of patients experienced grade 3 / 4 toxicities associated with therapy: elevation of AST and/or ALT (11%), elevation of lipase (4%), anemia (3%), colitis (3%).

Oxaliplatin is a platinum derivative. It is highly effective in combination with fluoropyrimidines (5-FU/folinic acid [FA], capecitabine). In first-line therapy, it increases remission rates to 40-60% and prolongs progression-free survival compared to 5-FU/FA. Serious adverse events (grade 3 / 4) occurring in more than 5% of patients in pivotal trials were nausea/vomiting, diarrhea, mucositis, and polyneuropathy. Intravenous administration of calcium and magnesium do not reduce the risk of polyneuropathy.

Panitumumab is a monoclonal antibody directed against the EGF receptor. In patients with KRASwt tumors, the remission rate in second-line therapy was 10% for monotherapy and 35% for combination with FOLFIRI after failure of oxaliplatin ± bevacizumab. Response to panitumumab is dependent on mutations in the RAS genes. In the pivotal study, patients with RASwt showed statistically significantly longer survival for the panitumumab/chemotherapy combination versus the chemotherapy-only arm. Progression-free and overall survival were worse in patients treated with panitumumab in the presence of a mutation in one of the RAS genes. Serious adverse event (grade 3 / 4) occurring in more than 5% of patients in the pivotal studies was acneiform dermatitis. Prophylactic therapy for acneiform dermatitis should be given with doxycyline or minocycline. Additional prophylactic topical therapy with vitamin K1 cream (Reconval K1) may be considered in women.

Pembrolizumab is an anti-PD-1 monoclonal antibody from the class of immune checkpoint inhibitors. In patients with dMMR/MSI-H CRC, pembrolizumab improved survival in first-line therapy and was better tolerated than doublet chemotherapy with or without VEGFR or EGFR antibodies. Toxicities ≥ grade 3 occurred in 56% of patients receiving pembrolizumab and 78% in the chemotherapy group. More severe (≥ grade 3) were diarrhea (6%) and hypertension (7%), immune-mediated hepatitis (3%), colitis (3%), skin toxicity, and adrenal insufficiency (1% each).

Ramucirumab is a human IgG1 antibody that specifically binds to vascular endothelial growth factor receptor-2 (VEGFR2). It is approved for second-line treatment of patients with adenocarcinoma of the stomach or gastroesophageal junction. In patients with metastatic colorectal cancer recurrent or refractory after therapy with a fluoropyrimidine, oxaliplatin and bevacizumab, it was tested in a phase III trial in combination with FOLFIRI. The addition of ramucirumab resulted in a statistically significant prolongation of progression-free survival from 4.7 to 5.7 months with a hazard ratio of 0.77 and prolongation of overall survival from 11.7 to 13.3 months with a hazard ratio of 0.84. Adverse events CTCAE grade 3 / 4 that occurred in more than 5% of patients treated with ramucirumab in the combination therapy in the pivotal study, and more frequently than in the control group, were neutropenia (28%) and hypertension (11%). Fatigue (12%) and diarrhea (10%) were not significantly more common than in the chemotherapy control arm. Information on approval status is summarized in Colorectal Cancer Approval Status (in German only).

Regorafenib is an oral multikinase inhibitor that blocks the activity of multiple protein kinases, including those involved in the regulation of tumor angiogenesis, oncogenesis and the microenvironment. In patients after failure of all established chemotherapies, regorafenib monotherapy has been shown in two phase III studies to significantly improve overall survival compared to best supportive care in a meta-analysis with a hazard ratio of 0.76. Regorafenib causes symptomatic toxicity in many patients at the start of therapy. CTCAE grade 3 / 4 adverse events that occurred in more than 5% of regorafenib-treated patients in the pivotal study, and significantly more frequently in the treatment arm than in the placebo arm, were fatigue (+6%), diarrhea (+4%), hand-foot syndrome (+17%), and hypertension (+6%). Side effects occur after a median of 14 days and therefore require close monitoring (e.g., weekly) at the start of therapy and dose reduction if necessary. Information on approval status is summarized in Colorectal Cancer Approval Status (in German only).

TAS-102 is an oral cytostatic drug. It consists of trifluridine, a thymidine analog, and tipiracil hydrochloride, a thymidine phosphorylase inhibitor. The cytotoxic component is trifluridine while tipiracil inhibits its rapid degradation. In a phase III study in relapsed or refractory patients with metastatic colorectal cancer after at least two standard chemotherapies, TAS-102 resulted in a statistically significant prolongation of progression-free survival (HR 0.48; median 0.3 months) and overall survival (HR 0.68, median 1.7 months). The remission rate was 1.6%. TAS-102 is taken for 5 days in each of two consecutive weeks, followed by 2 weeks off. Adverse events CTCAE grade 3 / 4 that occurred in > 5% of patients treated with TAS-102 in the pivotal study were neutropenia (38%), leukocytopenia (21%), anemia (18%), and thrombocytopenia (5%). Febrile neutropenia was observed in 4% of patients. These complications require close monitoring of blood counts and dose reduction if necessary. TAS-102 should whenever possible be combined with bevacizumab based on the results of the SUNLIGHT study, showing significantly improved overall survival by the addition of bevacizumab to TAS-102 [56]‚. Information on approval status is summarized in Colorectal Cancer Approval Status (in German only).

For patients with colon cancer who are intolerant of 5-fluouracil, the substance S1 has been approved by EMA in 2022. This approval is based on several studies showing that S1 is non-inferior to capecitabine or 5-FU in terms of efficacy, and that switching from fluoropyrimidines to S-1 due to cardiotoxicity or pronounced hand-foot syndrome is safely feasible. S1 is approved as monotherapy or in combination with oxaliplatin or irinotecan, with or without bevacizumab, for the treatment of patients with metastatic colorectal cancer who cannot continue treatment with another fluoropyrimidine because hand-foot syndrome or cardiovascular toxicity has developed in an adjuvant or metastatic setting.