Rectal Cancer

First-degree relatives should undergo colonoscopy at an age that is 10 years before the patient's diagnosis, but no later than age 50 [8, 9]. 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 normal, colonoscopy should be repeated in this risk group after 10 years at the latest.

Diagnostics should be carried out in accordance with the guidelines for the diagnosis of genetic predisposition to cancer issued by the German Medical Association (Bundesärztekammer) in Germany, the Austrian Society for Gastroenterology and Hepatology (ÖGGH) in Austria, and the ESMO guidelines [2, 9]. The specific genetic aberration determines the risk of disease and forms the basis for the individualized early detection and prevention plan.

Aminosalicylate can be used for prophylaxis, but results from randomized studies with the primary endpoint of preventing colorectal cancer are not available. 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 a complete colonoscopy with staged biopsies annually. In patients with high-grade dysplasia, restorative proctocolectomy is an effective prophylactic measure.

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

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

• Diameter < 3 cm

• G1 / 2: good or moderate histological differentiation

• L0: no infiltration of lymph vessels

• V0: no infiltration of blood vessels

• R0: complete resection

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

At this stage, neither preoperative nor postoperative radiation therapy or systemic tumor therapy leads to a further reduction in the recurrence rate.

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

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

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

• Upper third of the rectum: partial mesorectal excision with a minimum distal margin of ≥ 5 cm, measured from the macroscopic tumor margin or TME.

In stage I, neither preoperative nor postoperative radiation therapy or systemic tumor therapy leads to a further reduction in the recurrence rate.

The aim of treatment in stages II and III is curative. Relapses may occur locally, but predominantly in the liver and/or lungs. The local relapse rate is 5-12% after TME, the systemic relapse rate is 35-45%, depending on the tumor stage at initial diagnosis and other biological and individual risk factors. Due to the anatomical conditions in the true pelvis, local recurrences of carcinomas in the lower and middle third of the rectum are particularly complicated. This justifies their prevention as a separate, important therapeutic goal. Preoperative radiochemotherapy (RChT) or radiotherapy (RT) and quality-assured surgery can reduce the local recurrence rate to around 5-6% when considering all patients in stages II and III [10]. Perioperative systemic therapy also contributes to reducing the local recurrence rate, but is primarily recommended with the aim of preventing distant metastases [11].

Preoperative RT or RChT has traditionally been recommended for carcinomas in the lower and middle third of the rectum. In carcinomas in the upper third of the rectum, the benefit of RT is very limited; in principle, an approach similar to that for colon cancer is preferred, i.e., primary resection of the tumor or neoadjuvant chemotherapy for locally advanced MSS tumors, see guideline on colon cancer.

Quality-assured imaging can identify patients with a very low risk of local recurrence, so that neoadjuvant RT, which has been uniformly recommended to date, may be omitted for these patients. The previously very conservative criteria for optional omission of radiation (T3 tumor with maximum infiltration of 5 mm into the perirectal fat without clearly affected lymph nodes) can be expanded, based on data from the OCUM and PROSPECT studies in particular [60, 61]. In the PROSPECT study, T3 tumors were included regardless of nodal involvement, provided that the distance to the circular resection margin (CRM) was at least 3 mm and continence-preserving surgery was possible [61]. In this study, neoadjuvant chemotherapy was compared with neoadjuvant RChT. For the patient population described above, the non-inferiority of 3-month neoadjuvant FOLFOX therapy in terms of disease-free survival (DFS) was demonstrated. Local recurrence rates also did not differ between the two arms and were below 2%. In the OCUM study, a large phase II study with a prospectively defined treatment algorithm, only patients whose tumor (i) was located in the middle third of the rectum and had a critically small CRM (≤1 mm) or a T4 situation or (ii) was located in the lower third and had a T3 or T4 stage, received neoadjuvant RChT [60]. In both studies (PROSPECT and OCUM), the local recurrence rate in the defined groups was only 2-3%.

A single standard therapy in stages II and III can therefore no longer be defined. For certain subgroups (such as T3 N1 with free CRM in the middle third), several treatment options are available, so that treatment corridors are defined here (see Table 5).

Patients should be informed about these options. Figure 5 provides a treatment algorithm based on "key questions" and treatment goals, which takes into account various evidence-based treatment options depending on the tumor stage and treatment goal.

In the past, the option of organ preservation was often chosen after complete clinical remission, which was "incidentally" detected in the course of neoadjuvant RChT. In the meantime, however, it has been well demonstrated - not least by the data from the OPRA [57, 62] and OPERA studies [58] - that organ preservation after RChT can also be a primary treatment goal. This fact is also taken into account in the treatment algorithm; different and more or less intensive RChT regimens have been investigated for different tumor stages.

For the approximately 2-3% of patients with locally advanced, MSI-H / dMMR (highly microsatellite instable / mismatch-repair deficient) rectal cancer, the option of primary immune checkpoint inhibitor treatment without RT and / or surgery should be discussed. In an ongoing phase II study, complete clinical remissions were detectable after six months of primary dostarlimab therapy in all patients who were evaluable to date. After a short median follow-up, no case of "local regrowth", i.e., renewed growth of the primary tumor after an initial clinical complete remission (cCR), has occurred [13]. Immunotherapy for MSI-H/dMMR rectal cancer has not yet been approved. A handout from the German DGHO may be helpful when applying for this therapy as an off-label indication (https://www.dgho.de/publikationen/stellungnahmen/gute-aerztliche-praxis/immuncheckpoint-inhibitoren/immuncheckpointinhibitor-20230508).

In the following chapters (6.1.2.2. to 6.1.2.7), the individual treatment modalities and their possible indications are described in more detail in the context of the treatment corridor. Table 5 also provides a further overview of the treatment options according to localization and stage of the primary tumor.

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

• Resection of the regional draining lymph node area with sampling and histological work-up of ≥ 12 lymph nodes

• Adequate safety distance to healthy tissue

• Respecting the integrity of the mesorectal fascia avoiding injuries during surgery

• En-bloc resection of tumor-adherent organs

• Protection of the autonomic pelvic nerves.

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

TME is the standard for the middle and lower third of the rectum. PME is recommended for the upper third of the rectum; results from studies on TME for carcinomas in the upper third of the rectum are pending.

Primary quality-assured surgery for rectal cancer in the middle third can also be performed without neoadjuvant RT/RChT if all criteria for a low risk of local recurrence are met on MRI scans. This applies in particular to tumors that have a reliably free CRM, no detectable EMVI and a tumor that is safely resectable with continence preservation [60]. Furthermore, an N2 situation and lateral lymph node metastases should be excluded. In the ongoing ACO/ARO/AIO 18.2 trial, primary surgery for tumors with a low risk of local recurrence (i.e., tumors in the upper third and tumors in the middle third with free CRM [> 2 mm] and an invasion into the perirectal fat limited to 10 mm, regardless of lymph node status) is compared with neoadjuvant 3-month oxaliplatin-based chemotherapy.

RT and RChT reduce the risk of locoregional recurrence. The target volume includes the region of the primary tumor as well as the mesorectal, presacral, and internal iliac lymphatic drainage pathways.

Due to the particular problem of local relapses in rectal cancer, radiation therapy has been intensively evaluated in preoperative study designs. Alternatives include short-term radiation therapy with high single doses (5 x 5 Gy) or conventionally dosed long-term radiation with single doses of 1.8-2.0 Gy up to a total dose of 45-50.4 Gy.

Preoperative, conventionally fractionated RT can lead to significant tumor reduction, reduces the risk of local recurrence, improves disease-free survival rates, and has led to a significant increase in survival rates in some early randomized studies. With the exception of tumor shrinkage, this also applies to short-term neoadjuvant radiation therapy. In patients with large locally advanced tumors, in whom tumor shrinkage is the treatment goal, combined RChT or TNT is therefore recommended due to its greater local efficacy. In approximately 10-15% of patients, complete remission is achieved after conventional neoadjuvant long-term RChT.

Compared to preoperative conventional fractionated RT alone, combined RChT leads to higher histopathological remission rates and improved locoregional control. In the AIO/ARO/CAO-04 study, it was also superior to postoperative RChT in terms of local recurrence rate. An increase in the rate of patients with disease-free survival or overall survival has not been achieved in the studies published to date.

Fluoropyrimidines are the most effective systemic drugs in combined RChT, with a low rate of side effects. The administration of 5-fluorouracil as a continuous infusion during radiation is more effective than bolus therapy. Modulation of 5-FU metabolism by folinic acid did not improve long-term results. The perioperative administration of capecitabine is not inferior to 5-FU and led to an improvement in disease-free survival in a study. The results of randomized studies on the combination of 5-FU or capecitabine with oxaliplatin during radiation therapy can be summarized as follows according to the results of a meta-analysis: (i) significantly increased gastrointestinal toxicity, comparable hematotoxicity; (ii) Disease-free survival (DFS) slightly but significantly improved (HR 0.90, 95% CI 0.81–0.99); (iii) lower rate of distant metastases. According to data from a meta-analysis, the clinically moderate benefit is particularly evident in younger patients under the age of 60. None of the studies investigating the addition of oxaliplatin to neoadjuvant RChT showed an increase in R0 resection rates or an increase in the chance of sphincter preservation. A combination of fluoropyrimidines with oxaliplatin is therefore not recommended generally for neoadjuvant RChT, but may be considered in younger patients [10]. Details on the dosage and administration of chemotherapy are summarized in the appendix Systemic tumor therapy – protocols.

RT in the middle third can be omitted if defined criteria are met in accordance with the PROSPECT and OCUM studies. The criteria are described in chapter 6.1.2.1. Strict quality assurance of MRI imaging must be ensured if RT is not used.

Adjuvant (postoperative) rRT alone has no significant effect on disease-free survival or overall survival, but reduces local recurrence rates in patients who have not previously received RT. After incomplete anterior wall resection in stage I, RT is an experimental option in clinical trials. Data and recommendations on the procedure following successful primary RChT are summarized in chapter 6.1.2.5.

Until recently, with regard to perioperative chemotherapy in the context of radiation therapy, a distinction was only made between the application of chemotherapy as part of RChT (primarily as a radiosensitizer) and the administration of chemotherapy as adjuvant therapy after RChT and TME surgery. As a further therapeutic principle, especially for tumors with unfavorable tumor stages and/or when organ preservation is intended, so-called "total neoadjuvant therapy" (TNT) should be considered. This refers to the extension of neoadjuvant therapy by chemotherapy, usually lasting 3 to 4.5 months. This can be administered after or before RT or RChT (as induction or consolidation chemotherapy).

In several randomized studies, "total neoadjuvant therapy" (TNT) showed a significant benefit in DFS, especially for patients whose tumors had the following "high-risk characteristics" (criteria from the RAPIDO study): (i) T4 tumors, (ii) tumors with threatened/involved mesorectal resection margins, (iii) EMVI positivity, (iv) N2 status, and (v) enlarged lateral lymph nodes [12, 53, 55].

The optimal design of TNT remains the subject of clinical studies. In particular, the question of which (radiation) regimen should be used when organ preservation is intended is currently being investigated in the ACO/ARO/AIO-18-1 study.

According to multidisciplinary recommendations from working groups of the German Cancer Society, the following principles can be applied in treatment planning [51]: (i) RT can be administered as short-term radiation (5x5 Gy) or long-term RChT. (ii) Chemotherapy should be administered over 3 to 4.5 months, with consolidation chemotherapy being preferred according to data from the CAO/ARO/AIO-12 and OPRA studies if the treatment goal is to achieve the highest possible rate of clinical complete remissions (cCR). FOLFOX or CapOx should be used for chemotherapy; the benefit of additional irinotecan (e.g., in the FOLFIRINOX regimen) has not been demonstrated.

The PROSPECT study included patients with node-positive T2 and T3 adenocarcinomas of the rectum regardless of node involvement, provided that the distance to the circular resection margin (CRM) was at least 3 mm and continence-preserving surgery was possible [54]. Tumors in the middle third were predominantly included. In this study, neoadjuvant chemotherapy with three months of FOLFOX was compared with neoadjuvant RChT. In cases of inadequate response to FOLFOX (defined as tumor shrinkage <20% or < 4 FOLFOX cycles administered), additional RChT could be given. The non-inferiority of neoadjuvant chemotherapy in terms of DFS (primary endpoint) was demonstrated: after a median follow-up of 58 months, the 5-year DFS rate was 80.8% in the FOLFOX arm and 78.6% in the RChT arm (HR 0.92; 90.2% CI 0.74-1.14; non-inferiority test: p=0.005). Overall survival also did not differ (HR 1.04; 95% CI 0.74-1.44; n.s.). Less than 2% of patients in both arms had local recurrence (HR 1.18; 95% CI 0.44-3.16; n.s.). Patient-reported outcomes (PRO) were reported separately in a detailed publication [54]. Side effects and functionality differed between the arms in terms of frequency and timing of onset: during neoadjuvant therapy, patients receiving FOLFOX experienced less diarrhea and better bowel function, whereas patients in the RCHT arm reported less anxiety, loss of appetite, constipation, depression, dysphagia, dyspnea, edema, fatigue, mucositis, nausea, and vomiting, as well as neuropathy. At twelve months postoperatively, however, FOLFOX patients had significantly less fatigue and neuropathy and better sexual function. At no point were there any differences between the arms in terms of bladder function and health-related quality of life.

The results of the PROSPECT study are confirmed by a second randomized study presented at the ESMO Congress in 2023, which was similarly designed and conducted in Asia. This CONVERT study compared neoadjuvant chemotherapy with RChT for patients whose tumors were stage II/III, up to 12 cm from the anus, and did not threaten the mesorectal fascia [56]. Between June 2014 and October 2020, patients were randomized to receive 4 cycles of CapOx or RChT with capecitabine (50Gy in 25 fractions). After surgery, completion with four or six cycles of CapOx was planned. The primary endpoint was locoregional recurrence-free survival. In the standard arm, a 3-year locoregional recurrence-free survival rate of 93% was assumed; the non-inferiority margin was set at an HR of <1.6. N=663 patients were included. The median age was 60 years. The patient population did not only include tumors with a low risk of local recurrence. The number of T4 tumors was 26%, tumors in the lower third accounted for 41% of patients, and EMVI was approximately 20% and lateral lymph nodes were positive in 10% of tumors. Thus, CONVERT included patients with significantly larger tumors, corresponding to a higher risk of recurrence. Although the primary endpoint was not met (3-year local recurrence rates 97.4% versus 96.3% in favor of chemotherapy; HR 1.08, 95% CI 0.46–2.54), the difference is not clinically relevant, especially as the disease-free and overall survival – albeit still preliminary – were almost identical (3-year DFS RChT 87.9% versus chemotherapy 89.2%; HR 0.88, 95% CI 0.54–1.44). Comparing long-term toxicities, 29.2% grade 2–4 toxicities were observed in the RChT arm compared with only 19% in the chemotherapy arm.

In summary, neoadjuvant chemotherapy is a proven alternative to neoadjuvant RChT in two randomized studies for patients who meet the PROSPECT inclusion criteria.

While the value of adjuvant chemotherapy in rectal cancer after rectal resection without preoperative radiation is well established (Cochrane meta-analysis), adjuvant chemotherapy after combined RChT or short-course radiation therapy and TME surgery is controversial. A meta-analysis primarily including studies with 5-FU bolus administration found no evidence of a DFS or overall survival (OS) benefit. However, this meta-analysis is methodologically problematic; at the very least, it demonstrates that bolus regimens should no longer be used. After neoadjuvant RChT, adjuvant chemotherapy with optimal fluoropyrimidine regimens can therefore be offered. Capecitabine, for example, has a good data base. The available study data do not allow definitive differential therapeutic recommendations to be made based on the degree or extent of tumor response to neoadjuvant RChT. Available study results do not justify the general use of oxaliplatin in adjuvant chemotherapy. Younger patients with an increased risk of recurrence (yp stage III) should be advised about the possibility of additional oxaliplatin therapy (as investigated, for example, in the large randomized phase II ADORE study) [10]. The total duration of perioperative chemotherapy should not exceed 6 months, e.g., 5-6 cycles of capecitabine adjuvant or 8 cycles of FOLFOX. According to data from the SCOT study, patients who have undergone primary resection without neoadjuvant RChT can be treated adjuvantly in the same way as colon cancer (i.e., 3 or 6 months depending on the risk profile, see colon cancer).

For patients with carcinomas located in the upper third of the rectum who have not received preoperative radiation or RChT, a procedure analogous to colon cancer is recommended in stages II and III. Criteria for adjuvant chemotherapy in stages II and III are summarized in the colon cancer guideline.

A 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].

In case of complete clinical remission (cCR) after RChT or TNT, confirmed by quality-assured imaging procedures and experienced investigators, surgery can be avoided. The data basis for such an approach is now also good in European patients, although the observation period for the reported patients is generally still short. It is therefore still recommended that these patients be included in studies or registries in order to obtain better long-term data.

At this point in time, foregoing surgery in cases of complete clinical remission documented by experienced examiners (endoscopy, MRI, clinical digital rectal examination) is only recommended for patients who adhere well to closely scheduled follow-up examinations. A blind or staged biopsy of the rectal mucosa to document cCR is not necessary, nor is endosonography.

For patients with locally advanced MSI-H/dMMR rectal cancer, the possibility of immune checkpoint inhibitor therapy without RT and/or surgery should be discussed. In an ongoing phase II study, complete clinical remissions were observed in all evaluable patients after six months of primary dostarlimab therapy [13]. During the median follow-up period, which was short, no cases of local recurrence had occurred. Immune checkpoint inhibitors are not yet approved for the treatment of locally advanced MSI-H rectal cancer. If such an organ preservation concept is used, clinical checks should be performed after 3 and 6 months of therapy. The post-therapeutic watch-and-wait strategy should be carried out as described below.

The patient must be given detailed information and must be willing to undergo close follow-up for at least 5 years. The optimal design of monitoring or the "watch & wait" approach is the subject of studies; the following follow-up procedure can be recommended in accordance with an international commission of experts [17] (see also Table 8): follow-up for 5 years after documentation of cCR; CEA every 3 months for three years, then every six months; digital rectal examination, MRI, and endoscopy every 3 months for two years, then every six months; CT scan of the chest/upper abdomen at months 6, 12, 24, 36, 48, and 60 for 5 years.

Conversion therapy can increase the group of patients with potentially resectable metastases. 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. In randomized and non-randomized phase II studies, dual combinations plus monoclonal antibodies (mAb) or triple combinations ± mAb were used in palliative settings, see chapters 6.2.3 and 6.1.3.3. The PRODIGE-14 study, which randomly tested doublet versus triplet therapy, each + mAb (depending on RAS status), as conversion therapy, found no 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) [24] with clearly defined and stricter inclusion criteria regarding non-resectability, a benefit was found for triple therapy + bevacizumab versus FOLFOX + bevacizumab. In the randomized CAIRO5 study, patients with tumors that were not sensitive to EGFR-directed therapy (i.e., right hemicolonic primary, BRAF V600E MUT or RAS MUT), significantly more R0/R1 resections were achieved with FOLFOXIRI + bevacizumab compared with FOLFOX + bevacizumab (51 versus 37%) [26, 69]. In this respect, a triplet with bevacizumab should be preferred in this patient group.

For EGFR-sensitive tumors, the VOLFI study, a randomized phase II study in younger patients, showed that the addition of panitumumab to a dose-reduced chemotherapy triplet led to high remission rates and consecutively improved resection rates. No improvement in overall survival was demonstrated [27]. However, the phase III TRIPLETE study [28] showed no benefit of triple therapy over doublet therapy (each in combination with panitumumab) in terms of response and resection rates and PFS, so that a chemotherapy doublet should be chosen for patients who are to receive conversion therapy with EGFR-mAb.

In studies with unselected patients, between 5 and 25% of initially unresectable patients were subsequently resectable, with up to 40% in cases of liver metastasis alone. A treatment duration of 2 to 4 months, or up to 6 months if necessary, is recommended depending on the response. Once technical operability has been achieved, surgery should be performed as soon as possible, not postponed after maximum remission has been achieved. This avoids an increase in liver toxicity with a consequent increase in surgical morbidity. In conversion therapy, restaging should be performed every 8–10 weeks with discussion of the CT or MRI images in a multidisciplinary tumor conference. Hepatic surgical expertise should be available in the tumor board or consulted during a referral to a center for hepatic surgery. Surgery should be performed 4 weeks after the end of systemic tumor therapy, or after (4-)6 weeks in the case of bevacizumab-containing therapy. The value of continuing chemotherapy after R0 or R1 resection, in terms of completing chemotherapy over a total treatment period of 6 months, is not established and is the subject of studies. Important factors also include the toxicity of previous therapy and comorbidity, as well as the histopathological response. The additional value of locally effective therapeutic procedures in R1 resection is the subject of clinical studies.

Repeated liver metastasis resections should always be considered if technically (R0 resection) and clinically possible and reasonable.

Despite effective primary therapy and advances in adjuvant treatment, distant metastases occur in approximately 35-45% of patients. The recurrence rate is highest in the first two years after initial diagnosis; after more than 5 years, recurrences are rare. In a subgroup of patients, a cure is possible even in this setting; see chapters 6.1.3.1 and 6.1.3.2. For the treatment algorithm, see Figure 7.

For the majority of patients in stage IV, the therapeutic goal is palliative and includes the treatment of physical and psychological symptoms. Multidisciplinary cooperation is required. The necessity and the possibilities of supportive measures should be discussed early and comprehensively with all affected persons.

The choice of treatment strategy and the most suitable combination of systemic drugs is determined by numerous factors. The following are essential:

• Treatment goals agreed with the patient

• Previous course of the disease

• The biology of the disease, e.g., RAS and BRAF mutation status (in tumor tissue and, if available, in serum) and the location of the primary tumor

• Previous therapy, e.g., preoperative or adjuvant chemotherapy

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

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

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

The standard treatment is mesorectal excision with removal of the regional lymphatic drainage area. The technique depends on the location of the carcinoma:

• Lower third of the rectum: total mesorectal excision (TME) with a minimum distal margin of ≥ 2 cm, measured from the macroscopic tumor margin;

• Middle third of the rectum: total mesorectal excision (TME) with a minimum distal margin of ≥ 5 cm, measured from the macroscopic tumor margin;

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

The standard technique is open surgery. Laparoscopic surgery is an alternative. The advantage of open surgery is the shorter operating time and the shorter learning curve for the surgeon. The main advantages of laparoscopic surgery are the better cosmetic result and the earlier postoperative oral nutrition. In the context of fast-track surgery, which is used for open and laparoscopic rectal surgery, the advantages of laparoscopic surgery, such as faster mobilization and shorter hospital stays, are hardly significant. Laparoscopic surgery can be performed in specialized centers, preferably under study conditions [43].

Special local settings include ileus, tumor perforation, intestinal perforation, or tumor invasion into adjacent organs. In these patients, rectal cancer is usually locally advanced, so resection is part of a multimodal treatment plan. In patients with hereditary disease, the type of genetic predisposition, previous operations, and the overall treatment plan must be taken into account. The type and extent of resection are determined by the location, the supplying vessels, and the lymph drainage area defined by these factors. The surgical technique depends on the location of the primary tumor; see Table 4.

5-Fluorouracil is used in almost all forms of drug therapy for patients with colorectal cancer. The best risk-benefit ratio is achieved with continuous intravenous infusion over 24–48 hours after prior administration of folinic acid. Remission rates are up to 30%. Severe side effects (grade 3 or 4) include 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 ruled out [48].

Aflibercept is a recombinant fusion protein with antiangiogenic activity. In the registration study, the hazard ratio was significantly improved in patients who had previously been treated with oxaliplatin-based therapy by adding aflibercept to FOLFIRI. OS was prolonged by 1.4 months. PFS and response rate were also better in the aflibercept arm. Substance-specific side effects in CTCAE grade 3 or 4 correspond to those of antiangiogenic substances: hypertension (+17.8%), bleeding (+1.3%) (especially epistaxis), arterial (+1.3%) and venous thromboembolism (+1.6%), and proteinuria (+6.6%). Rare critical complications include arterial thromboembolic events and perforations in the gastrointestinal tract.

Bevacizumab is a monoclonal antibody with antiangiogenic activity. In combination with 5-FU/folinic acid, capecitabine, irinotecan, or oxaliplatin, remission rates of around 50% and prolonged PFS are achieved. In combination with irinotecan and 5-FU bolus protocols, an extension of OS was also achieved. Bevacizumab is effective in both first-line and second-line therapy. Continuation of bevacizumab therapy beyond progression resulted in prolonged OS in two randomized clinical trials. In the larger study, a significant improvement in the hazard ratio to 0.81 was achieved. Median OS was prolonged by 1.4 months. Severe side effects (grade 3 or 4) that occurred in more than 5% of patients in the approval studies were hypertension and proteinuria. Less common critical complications include arterial thromboembolic events and perforations in the gastrointestinal tract.

The basic drug in systemic tumor therapy for patients with colorectal cancer is 5-fluorouracil. Capecitabine is an oral fluoropyrimidine that is metabolized enzymatically by the tumor to 5-FU. In comparative clinical studies, it was at least as effective as 5-FU bolus/folinic acid therapy. In monotherapy, remission rates of up to 25% are achieved, and in combination with irinotecan or oxaliplatin, up to 45% of patients. Severe side effects (grade 3 or 4) that occurred in more than 5% of patients in the approval studies were diarrhea and hand-foot syndrome. The combination of proton pump inhibitors with capecitabine-containing therapy should be avoided, as several retrospective studies have shown negative effects on the efficacy of capecitabine. Before starting chemotherapy containing 5-FU, a mutation in the four most important dihydropyrimidine dehydrogenase (DPD) gene loci must be ruled out [48].

Cetuximab is a monoclonal antibody directed against the EGF receptor. The remission rate as monotherapy in second-line treatment is 8%. In first-line therapy in patients with KRAS wild type, remission rates of 55-65% are achieved, each in combination with 5-FU/folinic acid and irinotecan or oxaliplatin. PFS is prolonged. Data on OS are inconsistent. Patients with defined RAS mutations (KRAS gene exons 2-4, NRAS gene exons 2-4) do not benefit from cetuximab therapy and even show a trend toward shorter survival in some chemotherapy combinations. Since there are indications 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. Severe side effects (grade 3 or 4) that occurred in more than 5% of patients in the approval studies were acneiform dermatitis and infusion reactions. Prophylactic therapy for acneiform dermatitis should be given with doxycycline or minocycline. Additional prophylactic local therapy with vitamin K1 cream (Reconval K1) may be considered in women. Medications for the prophylaxis of infusion reactions include corticosteroids and H1 blockers. Biweekly cetuximab administration (500 mg/m2) was equivalent to weekly administration (400/250 mg/m2) in a randomized study.

Dostarlimab is a humanized monoclonal anti-PD1 antibody (IgG4) approved as monotherapy for the treatment of adult patients with recurrent or advanced endometrial cancer with mismatch repair deficiency (dMMR) or high microsatellite instability (MSI-H) that is progressive during or after prior treatment with platinum-based therapy. In the primary treatment of patients with rectal cancer and dMMR, a clinical CR rate of 100% was achieved in 12 published cases. No relapse had occurred after a follow-up period of up to 25 months [13]. In 363 patients in the GARNET study, the most common side effects were hypothyroidism (7%), elevated liver enzymes (6%), and arthralgia (5%) [50].

Encorafenib is an oral, highly selective RAF kinase inhibitor. In combination with cetuximab, it prolongs survival in patients with BRAF V600E-mutated CRC after first-line therapy compared to chemotherapy plus cetuximab. The most common side effects in the approval study were diarrhea, nausea, vomiting, and acneiform dermatitis, including severe (≥ grade 3) fatigue (4%), anemia (4%), and diarrhea (2%). Another typical side effect is palmar-plantar erythrodysesthesia syndrome (PPES; hand-foot syndrome) in 4% of patients (severe in <1%) [49].

Fruquintinib is an oral, selective inhibitor of VEGF receptors 1, 2, and 3. In the FRESCO-2 study [66], a significant prolongation of median survival from 4.8 to 7.4 months was achieved in 691 patients with refractory metastatic colorectal cancer, when compared to placebo. The most common side effects observed in the study were arterial hypertension (14%), weakness (8%), and hand-foot syndrome (6%). Fruquintinib is approved for use after treatment with available standard therapies, including fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapies, anti-VEGF and anti-EGFR mAbs, and after progression or intolerance to TAS-102 or regorafenib.

Ipilimumab, an immune checkpoint inhibitor, is a monoclonal antibody directed against the inhibitory T-cell regulator CTLA-4, thereby enhancing the autologous immune response. It is approved in combination with nivolumab for patients with stage IV MSI-H/dMMR. The overall response rate (ORR) for this combination was 55% in the Checkmate-142 registration study, with survival rates of 87% and 85% after 9 and 12 months. In 32% of patients, treatment-related grade 3 or 4 toxicities occurred: increased liver enzymes AST and/or ALT (11%), increased lipase (4%), anemia (3%) and autoimmune colitis (3%).

Irinotecan is a topoisomerase I inhibitor. In combination with 5-FU/folinic acid, remission rates are 40-50%. PFS and OS are significantly prolonged compared to fluoropyrimidine therapy. Severe side effects (grade 3 or 4) that occurred in more than 5% of patients in the approval studies were diarrhea, nausea/vomiting, neutropenia, and neutropenic fever. The substance can be administered weekly, biweekly, or every three weeks.

Nivolumab is a monoclonal anti-PD1 antibody and belongs to the class of immune checkpoint inhibitors. It is approved in combination with ipilimumab for patients with stage IV MSI-H/dMMR, first-line or after prior treatment with fluoropyrimidines. The overall response rate (ORR) for this combination was 55% in the Checkmate-142 approval study, with survival rates after 9 and 12 months at 87% and 85%. Therapy-related grade 3 or 4 toxicities occurred in 32% of patients: increased AST and/or ALT (11%), increased lipase (4%), anemia (3%) and autoimmune colitis (3%).

Oxaliplatin is a platinum derivative. In colorectal cancer treatment, it is highly effective in combination with fluoropyrimidines (5-FU/folinic acid, capecitabine). In first-line therapy, it increases remission rates to 40-60% and prolongs PFS compared to 5-FU/FA. Severe side effects (grade 3/4) that occurred in more than 5% of patients in the approval studies were nausea/vomiting, diarrhea, mucositis, and polyneuropathy. Intravenous administration of calcium and magnesium does 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. The response to panitumumab depends on mutations in the RAS genes. In the approval study, patients with RASwt showed a statistically significant longer survival time for the combination of panitumumab and chemotherapy compared to the chemotherapy alone arm. In patients who had been treated with panitumumab in the presence of a mutation in one of the RAS genes, PFS and OS were poorer. A severe side effect (grade 3 or 4) that occurred in more than 5% of patients in the approval studies was acneiform dermatitis. Prophylactic treatment of acneiform dermatitis should be given with doxycycline or minocycline. Additional prophylactic local treatment with vitamin K1 cream (Reconval K1) may be considered in women.

Pembrolizumab is a monoclonal anti-PD1 antibody and belongs to the class of immune checkpoint inhibitors. In patients with dMMR/MSI-H CRC, pembrolizumab in first-line therapy led to improved survival with better tolerability compared to doublet chemotherapy with or without anti-VEGFR or -EGFR antibodies. Grade ≥ 3 toxicities occurred in 56% of patients receiving pembrolizumab and 78% in the chemotherapy group. Clinically relevant (≥ 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 in patients with adenocarcinoma of the stomach or gastroesophageal junction. In patients with metastatic colorectal cancer in relapse or refractory to therapy with a fluoropyrimidine, oxaliplatin, and bevacizumab, it was tested in combination with FOLFIRI in a phase III study. The addition of ramucirumab resulted in a statistically significant prolongation of PFS from 4.7 to 5.7 months with a hazard ratio of 0.77 and a prolongation of OS from 11.7 to 13.3 months with a hazard ratio of 0.84. CTCAE grade 3 or 4 adverse events that occurred in more than 5% of patients treated with ramucirumab in combination therapy in the registration study and more frequently than in the control group were neutropenia (28%) and hypertension (11%). Fatigue (12%) and diarrhea (10%) were not significantly more frequent than in the chemotherapy control group. Information on approval status is summarized in Colorectal Cancer Approval.

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 who had failed all established chemotherapy regimens, two phase III studies showed that regorafenib monotherapy significantly improved OS compared with 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 treatment. CTCAE grade 3 or 4 side effects that occurred in more than 5% of patients treated with regorafenib in the approval 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, if necessary, a consistent dose reduction. Information on the approval status is summarized in Colorectal cancer approval.

For cases of intolerance to 5-fluorouracil, the substance S1 has been approved by the EMA since 2022. This approval is based on several studies showing that S1 is not inferior to capecitabine or 5-FU in terms of efficacy and that switching from fluoropyrimidines to S1 because of cardiotoxicity or pronounced hand-foot syndrome is safe. 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 of hand-foot syndrome or cardiovascular toxicity in an adjuvant or metastatic setting.

TAS-102 is an oral cytostatic drug consisting of trifluridine, a thymidine analogue, and tipiracil hydrochloride, a thymidine phosphorylase inhibitor. The cytotoxic component is trifluridine; tipiracil inhibits its rapid degradation. In a phase III study in patients with recurrent or refractory metastatic colorectal cancer after at least two standard chemotherapy regimens, TAS-102 resulted in a statistically significant prolongation of PFS (HR 0.48; median 0.3 months) and prolonged OS (HR 0.68, median 1.7 months). The remission rate was 1.6%. TAS-102 is taken for 5 days in two consecutive weeks, followed by a 2-week break. CTCAE grade 3 or 4 side effects that occurred in more than 5% of patients treated with TAS-102 in the approval study were neutropenia (38%), leukocytopenia (21%), anemia (18%), and thrombocytopenia (5%). Febrile neutropenia occurred in 4% of patients. These complications require close monitoring of blood counts and dose reduction if required. Information on the approval status is summarized in Colorectal Cancer Approval.