Rectal Cancer

First-degree relatives should undergo colonoscopy at an age 10 years prior to the patient's disease, but at the latest at the age of 50 years [8, 9]. This recommendation also applies to first-degree relatives of patients 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.

Diagnostics should be performed according to the guidelines for the diagnosis of genetic predisposition to cancer of the German Medical Association, those of the Austrian Society of Gastroenterology & Hepatology (ÖGGH), and the ESMO guidelines [2, 9]. The specific genetic aberration determines the risk of disease and is the basis of the individualized screening and prevention plan.

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

For these patients, no recommendation regarding prophylaxis and early detection can be given at present.

For stage pT1 carcinomas, local surgical tumor excision (full wall excision) is sufficient as the sole therapeutic measure if the following conditions for classification as low-risk are met:

• Diameter < 3 cm

• G1 / 2: good or moderate histological differentiation

• L0: no infiltration of lymphatic vessels

• V0: no infiltration of blood vessels

• R0: complete resection

Excision can be performed transanally as a microsurgical full-wall excision or as a direct tumor excision.

At this stage, neither preoperative nor postoperative radiotherapy or systemic cancer treatment further reduces the recurrence rate.

cT1 carcinomas with gradings G3-4 have a higher risk of recurrence. In this group and in all other T stages, the treatment standard is mesorectal excision with resection of the regional lymphatic drainage area, technically depending on the location of the carcinoma:

• Lower rectal third: total mesorectal excision (TME) with a minimal distal distance of ≥ 2 cm, measured from the macroscopic tumor margin.

• Middle rectal third: total mesorectal excision (TME) with a minimal distal distance of ≥ 5 cm, measured from the macroscopic tumor margin.

• Upper rectal third: partial mesorectal excision with a minimal distal distance ≥ 5 cm measured from the macroscopic tumor margin or TME.

In stage I, neither preoperative nor postoperative radiotherapy or systemic cancer treatment further reduces the recurrence rate.

In stage II and III, the primary therapy depends on the tumor location, see Figure 5. For carcinomas in the lower and middle third of the rectum, preoperative radiation or radiochemotherapy is recommended. For carcinomas in the upper third of the rectum, the benefit of radiotherapy is controversially discussed and treatment in analogy to colon cancer preferred, i.e. primary resection of the tumor, see Guideline Colon Cancer.

Resection of the primary tumor is essential for curative therapy. The quality of the surgical procedure has a significant impact on prognosis. Oncological principles for surgery are:

• Removal of the regional lymphatic drainage area with sampling and histologic workup of ≥ 12 lymph nodes.

• Appropriate safety distance to healthy tissue

• Respecting the intactness of the fascia of the mesorectum avoiding injuries during surgery.

• En-bloc resection of tumor-adherent organs

• Protection of the autonomic pelvic nerves

Standard for the middle and lower rectal thirds is TME. In the upper rectal third, PME is recommended; results of studies on TME for carcinomas in the upper rectal third are pending.

Radiotherapy and radiochemotherapy reduce the locoregional recurrence risk and may increase the cure rate. The target volume includes the region of the primary tumor and the mesorectal, presacral, and iliac-internal lymphatic drainage pathways.

Radiotherapy in the middle third can be omitted if the following findings are present: (i) tumor penetration depth into perirectal fat of 5mm or less (mrT3a and b situation) and lack of contact with circumferential resection margin; (ii) no confirmed extramural vein invasion (EMVI negative); (iii) no evidence of lymph node metastases (for definition see chapter 5.2.1)).

Because of the special problem of local recurrences in rectal cancer, radiotherapy has been intensively evaluated within the framework of preoperative study concepts. Alternatives are short-course radiotherapy with high single doses (5 x 5 Gy) or conventionally fractionated long-course radiotherapy with single doses of 1.8 - 2.0 Gy up to a total dose of 45 - 50.4 Gy.

Preoperative conventionally fractionated irradiation can induce significant tumor shrinkage, reduce local recurrence risk, improve disease-free survival, and increases survival rates according to results from randomized trials. Apart from tumor shrinkage, this also holds true for neoadjuvant short-course radiotherapy. In patients with large locally advanced tumors where tumor shrinkage is the therapeutic goal, combined radiochemotherapy or TNT is therefore recommended because of its higher potential to shrink these tumors. In about 10-15% of patients, complete pathohistological remission is achieved after conventional long-course neoadjuvant radiochemotherapy.

Adjuvant (postoperative) radiotherapy alone has no significant impact on disease-free survival or overall survival, but leads to a reduction in local recurrence rates in previously non-irradiated patients. After incomplete anterior wall resection in stage I, radiotherapy is an experimental option in clinical trials. Data and recommendations on the treatment approach after successful primary radiochemotherapy are summarized in chapter 6.1.2.4.

Compared to preoperative conventional fractionated radiotherapy alone, combined radiochemotherapy leads to higher pathohistological remission rates and improved locoregional control. It was also superior to postoperative radiochemotherapy in terms of local recurrence rates in the AIO/ARO/CAO-04 trial. An increase in the rate of patients with disease-free survival or overall survival was not achieved in the studies published to date.

Fluoropyrimidines are the most effective drugs in combined radiochemotherapy, with a low rate of side effects. Administration of 5-fluorouracil as a continuous infusion during radiotherapy is more effective than bolus therapy. Modulation of 5-FU metabolism by folinic acid did not improve long-term outcomes. Perioperative administration of capecitabine is noninferior to 5-FU and resulted in a significant improvement in disease-free survival in one study. According to results of a meta-analysis, the results of randomized trials combining 5-FU or capecitabine with oxaliplatin during radiotherapy can be summarized as follows: (i) gastrointestinal toxicity significantly increased, hematotoxicity was comparable; (ii) DFS slightly but significantly improved (HR 0.90, 95% CI 0.81 - 0.99); (ii) a lower rate of distant metastases was reported. According to data from another meta-analysis, the clinically moderate benefit is particularly observed in younger patients < 60 years of age. There was no increase in R0 resection rates or chance of sphincter preservation in any of the trials on the addition of oxaliplatin to neoadjuvant radiochemotherapy. Therefore, a combination of fluoropyrimidines with oxaliplatin is not generally recommended for neoadjuvant radiochemotherapy, but may be considered in younger patents [10].

With regard to perioperative chemotherapy, until recently a distinction was only made between the application of chemotherapy in the context of radiochemotherapy (primarily as a radiosensitizer) and the administration of chemotherapy as adjuvant therapy after radiochemotherapy and TME surgery. As a further therapeutic principle, especially for tumors with stages unfavorable from a tumor biology point of view and/or if organ preservation is intended, the so-called "total neoadjuvant therapy" (TNT) should be considered. This means a prolongation of neoadjuvant therapy by usually 3- to 4.5-months of chemotherapy. It can be administered after or before radio- or radiochemotherapy (as so-called induction or consolidation chemotherapy).

In several randomized trials, TNT showed a significant benefit for disease-free survival, especially for patients whose tumors had "high-risk characteristics" (RAPIDO trial criteria): (i) T4 tumors, (ii) tumors with / of mesorectal resection margin, (iii) EMVI positivity, (iv) N2 status, and (v) enlarged lateral lymph nodes [12].

The optimal design of a TNT is still subject to clinical studies. The question of which (radiotherapy) regimen should be used when organ preservation is intended is currently being investigated in the ACO/ARO/AIO-18-1 trial.

According to multidisciplinary recommendations of working groups of the German Cancer Society, the following principles can be applied in therapy planning: (i) Radiotherapy can be given as short-course radiotherapy (5x5 Gy) or long-course radiochemotherapy. (ii) Chemotherapy should be administered over 3 to 4.5 months, with consolidation chemotherapy preferred according to data from the CAO/ARO/AIO-12 and OPRA trials if the therapeutic goal is to achieve the highest possible rate of clinical complete remission (cCR). Chemotherapy should be given using FOLFOX or CapOx; the benefit of adding irinotecan (such as in the FOLFIRINOX regimen) has not been proven.

For patients with locally advanced, MSI-H / dMMR rectal cancer, the possibility of immune checkpoint inhibitor therapy without radiotherapy and / or surgery should be discussed. In an ongoing phase II study, complete clinical remissions were detectable in all 14 patients evaluable to date after six months of primary dostarlimab therapy. During the so far short median follow-up, no case of local recurrence had occurred. Imune checkpoint inhibitors have not yet been approved for the treatment of locally advanced MSI-H rectal cancer. If such an organ preservation approach is used, clinical controls should be scheduled after 3 and 6 months of therapy. The post-treatment watch-and-wait strategy should be performed as follows: 3-4 monthly sigmoidoscopy, digital-rectal examination and quality-assured rectal MRI for the first two years, then (years 3-5) every six months. Distant metastases should be excluded at least once per year by whole-body CT [13].

Data and recommendations on the approach after successful primary radiochemotherapy alone are summarized in chapter 6.1.2.4.

While the beneficial impact of adjuvant chemotherapy for rectal cancer after surgical resection without preoperative radiotherapy is verified (see Cochrane meta-analysis), adjuvant chemotherapy par principe after combined radiochemotherapy or short-term radiotherapy and TME surgery is controversial. A meta-analysis primarily examining trials with bolus application of 5-FU failed to demonstrate a benefit for disease-free or overall survival. While this meta-analysis is methodologically problematic, it provides further evidence that bolus regimens should no longer be used. Adjuvant chemotherapy with optimal fluoropyrimidine regimens should be offered after neoadjuvant radiochemotherapy. Capecitabine, for example, has a good data background in this setting. At present, available study results do not allow us to make firm differential therapeutic recommendations based on the degree or extent of tumor response to neoadjuvant radiochemotherapy. A general use of oxaliplatin in adjuvant chemotherapy cannot be justified from current trial data. Younger patients with an increased risk of recurrence (ypStage III) should be counseled about the possibility of additional oxaliplatin therapy [10]. The duration of perioperative chemotherapy should add up to about 6 months in total, e.g., by an additional 5-6 adjuvant cycles of capecitabine or 8 cycles of FOLFOX. Patients after primary resection, who have not received neoadjuvant radiochemotherapy, can be given adjuvant chemotherapy (i.e., 3 or 6 months depending on the risk profile, see colon cancer) in analogy to colon carcinoma according to data from the SCOT study.

In patients with cancer localization in the upper third of the rectum, who have not received preoperative radiation or radiochemotherapy, a procedure analogous to that for colon carcinoma is recommended in stages II and III. Criteria for adjuvant chemotherapy in stage II and III are compiled in the guideline colon carcinoma.

Combination of proton pump inhibitors with capecitabine-containing therapy, e.g., in the CapOx or XELOX regimen, should be avoided, as several retrospective data sets suggest a possible negative effect on capecitabine efficacy [14, 15, 16].

If a complete clinical remission (cCR), confirmed by quality-assured imaging procedures and experienced investigators, has been achieved after radiochemotherapy or TNT, surgery can be omitted. The database for this approach has been validated for a European patient population, but the follow-up of patients is relatively short. Therefore, the inclusion of these patients in studies or registries is still recommended in order to obtain better long-term data.

At this point in time, the waiver of surgical resection in case of cCR remission documented by experienced investigators (endoscopy, MRI, clinical digital-rectal examination) will be limited to patients with a reliable adherence to close follow-up examinations. A blind or step biopsy of the rectal mucosa to document a cCR is just as unnecessary as the performance of an endosonography.

Detailed patient information and adherence to stringent follow-up over at least 5 years is required. The optimal design of follow-up (or "watch & wait", respectively) is the subject of current studies; the following follow-up procedure can be recommended according to an international expert statement [17]: follow-up for 5 years after documentation of cCR; for three years, 3-monthly CEA, then six-monthly; for two years, 3-monthly digital-rectal examination, MRI, and endoscopy, then six-mothly; for 5 years, CT thorax/upper abdomen at months 6, 12, 24, 36, 48 and 60.

The number of patients with potentially resectable metastases can be increased by a so-called conversion therapy. The aim of this therapy is to achieve technical resectability by downsizing the metastases. Accordingly, treatment protocols with high response rates and the chance of greater volumetric shrinkage of metastases are recommended. Two-drug combinations plus antibodies or three-drug combinations ± antibodies used in the palliative setting have been tested in randomized and non-randomized phase II studies, see chapter 6.2.3 and chapter 6.1.4.3. The UNICANCER PRODIGE 14 trial, which randomized doublet versus triplet, each + mAb (depending on RAS status) as conversion therapy, found no statistically significant improvement of R0/R1 resection rates; disease-free and overall survival were also not significantly different [24] In the smaller OLIVIA trial (80 patients) [25] with more clearly defined and stricter inclusion criteria regarding irreversibility, there was a benefit for triplet therapy + bevacizumab versus FOLFOX + bevacizumab. These results were recently confirmed in a Dutch study presented at ASCO 2022 for the group of RAS or BRAF mutated or right-sided tumors [26]. In this respect, it should be decided on a case-by-case basis in the tumor board whether triplet + mAb or doublet + mAb should be used. In the randomized phase II VOLFI study, the addition of panitumumab to a dose-reduced chemotherapy triplet did lead to high remission rates and improved resection rates, mainly in younger patients [27]. However, the randomized phase III "Triplete" trial first presented at ASCO 2022 showed no benefit in terms of resection rates for FOLFOXIRI + panitumumab therapy compared with a doublet + panitumuab [28].

In studies with non-selected patients, between 5 and 25%, and up to 40% in the case of exclusive liver metastasis, of initially unresectable patients subsequently underwent secondary resection. A preoperative systemic treatment duration of 2 to 4, possibly up to 6 months, depending on tumor response, is recommended. After achieving technical operability, surgery should be performed as soon as possible, not after maximum remission has been achieved. By this, increasing liver toxicity resulting in a higher surgical morbidity can be avoided. In patients undergoing conversion therapy, restaging should be performed every 8-10 weeks with discussion of CT or MRI images in the multidisciplinary tumor board. Surgery should be performed 4 weeks after the end of preoperative drug therapy, and after 6 weeks following bevacizumab-containing therapy. The value of continuing chemotherapy after R0 or R1 resection, in terms of completing chemotherapy for a total of 6 months, is not proven. Important factors also include toxicity of previous therapy and comorbidity, as well as histopathologic response. The additional value of locally effective therapy methods in R1 resection is the subject of clinical studies.

Despite effective primary therapy and progress in adjuvant treatment, distant metastases emerge in about 35-45% of patients. The relapse rate is highest in the first two years after initial diagnosis, while relapses after more than 5 years are rare. In a subgroup of patients, a cure is also possible in this situation, see Chapter 6.1.4.1 "Stage IV with resectable metastases" and chapter 6.1.4.2 "Stage IV with metastases after conversion therapy".

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.

Surgical standard is mesorectal excision with removal of the regional lymphatic drainage area, technically depending on the location of the carcinoma:

• Lower rectal third: total mesorectal excision (TME) with a minimal distal distance of ≥ 2 cm, measured from the macroscopic tumor margin.

• Middle rectal third: total mesorectal excision (TME) with a minimal distal distance of ≥ 5 cm, measured from the macroscopic tumor margin.

• Upper rectal third: partial mesorectal excision (PME) with a minimal distal distance ≥ 5 cm, measured from the macroscopic tumor margin.

The standard is the open surgical technique. An alternative is laparoscopic surgery. The advantage of open surgery is the shorter operating time and the shorter learning curve of surgeons. Significant advantages of laparoscopic surgery are better cosmetic outcome and earlier restorative diet. In the context of fast-track surgery applied to open and laparoscopic rectal surgery, the advantages of laparoscopic surgery such as faster mobilization and shorter hospital stay are hardly significant. Laparoscopic surgery can be performed in specialized centers, preferably under study conditions [43].

Special local situations include ileus, tumor perforation, intestinal perforation or infiltration into adjacent organs. For obstructive carcinomas, two-step surgery can be performed with creation of protective stoma or one-step subtotal colectomy is feasible. In patients with hereditary disease, the nature of the genetic burden, previous operations, and the overall treatment concept must be considered.

The type and extent of resection are determined by the localization, the supplying vessels and the lymphatic drainage area defined by this. The surgical technique depends on the localization of the primary tumor, see Table 4.

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 the medical tumor therapy 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- and capecitabine containing chemotherapy [48].

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. 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%) [49].

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 mucosites, and others.

Mutations among the four major dihydropyrimidine dehydrogenase (DPD) gene loci must be excluded prior to 5-FU- and capecitabine containing chemotherapy [48].

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. This drug 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 (FS), capecitabine). In first-line therapy, it increases remission rates to 40-60% and prolongs progression-free survival compared to 5-FU/FS. 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.

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. 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.

In case of intolerance of 5-fluorouracil, 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.

TAS-102 is a new 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 a 2-week treatment break. Adverse events CTCAE grade 3/4 that occurred in more than 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.