Rectal Cancer

First-degree relatives should be colonoscoped at an age 10 years prior to the patient's age at diagnosis, but at the latest at the age of 50 years [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 unremarkable, 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 of the German Medical Association, those of the Austrian Society for Gastroenterology & Hepatology (ÖGGH) in Austria and the ESMO guidelines [2, 9]. 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. Recommendations for screening/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 stepwise biopsies every year. In patients with high-grade dysplasia, restorative proctocolectomy is an effective prophylactic intervention.

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

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 a low-risk situation 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 transanal as a microsurgical full-wall excision or as a direct tumor excision.

At this stage, neither preoperative nor postoperative radiotherapy or systemic tumor therapy reduce the recurrence rate.

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

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

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

• Upper third of the rectum: partial mesorectal excision with a minimum 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.

Treatment in stages II and III is curative. Relapse may occur locally, but predominantly in the liver and/or lungs. The local recurrence rate is 5-12% after TME, the systemic recurrence rate is 35-45%, depending on the tumor stage at initial diagnosis and other biological and individual risk factors. Due to the anatomy of the true pelvis, local recurrences of carcinomas in the lower and middle third of the rectum are particularly prone to complications. This justifies their prevention as an important therapeutic goal in its own right. Preoperative radiochemotherapy or radiotherapy and quality-assured surgery can reduce the local recurrence rate - considering all patients in stages II and III - to around 5-6% [10]. Systemic perioperative tumor treatment also contributes to reducing the local recurrence rate, but is primarily recommended with the aim of preventing distant metastases [11].

Preoperative radiotherapy or radiochemotherapy has traditionally been recommended for carcinomas in the lower and middle third of the rectum. For carcinomas in the upper third of the rectum, the benefit of radiotherapy is very limited; in principle, a procedure analogous to colon carcinoma is preferred here, i.e., primary resection of the tumor or neoadjuvant chemotherapy for locally advanced MSS tumors (see Onkopedia guideline Colon cancer).

Quality-assured imaging can identify patients with a very low risk of local recurrence, so that the previously uniformly recommended neoadjuvant radiotherapy can be waived for these patients. The previously very conservative criteria for the optional omission of radiotherapy (T3 tumor with maximum infiltration of 5 mm into the perirectal fat without clearly affected lymph nodes) can be expanded according to data from the OCUM and PROSPECT studies in particular. 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 radiochemotherapy. The non-inferiority of the 3-month neoadjuvant FOLFOX therapy with regard to DFS was demonstrated for the patient cohort described above. The 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 (≤ 1mm) or a T4 situation or (ii) was located in the lower third and had a T3 or T4 stage were treated with neoadjuvant radiochemotherapy [60]. In both studies (PROSPECT and OCUM), the rate of local recurrence in the defined groups was only 2-3%.

A single treatment standard 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 can be considered, 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" or treatment goals, which takes into account various evidence-based treatment options depending on tumor stage and treatment goal.

In the past, the option of organ preservation was often utilized after a complete clinical remission, which was "incidentally" detected in the course of neoadjuvant radiochemotherapy. 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 radiochemotherapy can also be a primary treatment goal. This fact is also taken into account in the treatment algorithm; different and more or less intensive radiochemotherapy 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 radiotherapy 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. During the (still 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 chapter 6.1.2.2. to chapter 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 a 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.

Primary quality-assured surgery for rectal cancer in the middle third can also be performed without neoadjuvant radiotherapy/radiochemotherapy 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 [> 2mm] and an invasion into the perirectal fat limited to 10mm, regardless of lymph node status) is compared with neoadjuvant 3-month oxaliplatin-based chemotherapy.

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

Due to the particular problem of localized relapses in rectal cancer, radiotherapy has been intensively evaluated as part of preoperative study concepts. Available options are short-course radiotherapy with high single doses (5 x 5 Gy) or conventionally dosed 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 radiation can induce significant tumor shrinkage, reduces the local risk of recurrence, improves the disease-free survival rate and led to a significant increase in survival rates in some of the early randomized studies. With the exception of tumor reduction, this also applies to neoadjuvant short-term radiotherapy. In patients with large locally advanced tumors, where tumor shrinkage is the treatment goal, concurrent radiochemotherapy or TNT is therefore recommended due to its higher local efficacy. In about 10-15% of patients, pathohistologic complete remission is achieved after conventional neoadjuvant long-course radiochemotherapy.

Compared to preoperative conventional fractionated radiotherapy alone, combined radiochemotherapy leads to higher pathohistologic remission rates and improved locoregional control. In the AIO/ARO/CAO-04 study, it was also superior to postoperative radiochemotherapy in terms of the local recurrence rate. 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 for combined radiochemotherapy, with a low rate of side effects. The administration of 5-fluorouracil as a continuous infusion during radiotherapy is more effective than bolus therapy. Modulation of the 5-FU metabolism by folinic acid did not improve the long-term results. The perioperative administration of capecitabine is not inferior to 5-FU and led to an improvement in disease-free survival in one study. The results of randomized studies on the combination of 5-FU or capecitabine with oxaliplatin during radiotherapy can be summarized as follows according to the results of a meta-analysis: (i) gastrointestinal toxicity significantly increased, hematotoxicity comparable; (ii) DFS slightly but significantly improved (HR 0.90, 95% CI 0.81 - 0.99); (ii) lower rate of distant metastases. According to data from a meta-analysis, the clinically moderate benefit can be observed particularly in younger patients under 60 years of age. An increase in R0 resection rates or an increase in the chance of sphincter preservation was not found in any of the studies investigating the addition of oxaliplatin to neoadjuvant radiochemotherapy. A combination of fluoropyrimidines with oxaliplatin is therefore not recommended in principle for neoadjuvant radiochemotherapy, but can be considered in younger patients [10]. Details on dosage and application of chemotherapy are summarized in the German appendix Systemic tumor therapy - protocols.

Radiotherapy in rectal cancer of the middle third can be waived if defined criteria are met according to the PROSPECT and OCUM studies. These criteria are described in chapter 6.1.2.1. Stringent quality assurance of MRI imaging must be ensured if radiotherapy is waived.

Adjuvant (postoperative) radiotherapy alone has neither a significant impact on disease-free survival nor on 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 procedure after successful primary radiochemotherapy are summarized in chapter 6.1.2.5.

With regard to perioperative chemotherapy in the context of radiotherapy, until recently a distinction was only made between the application of chemotherapy in the context of radiochemotherapy (primarily as a radiation sensitizer) and the administration of chemotherapy as adjuvant therapy after radiochemotherapy and TME surgery. "Total neoadjuvant therapy" (TNT) is now included as a further therapeutic principle, particularly for tumors with tumor-biologically unfavorable tumor stages and/or where organ preservation is intended. This refers to the supplementation of neoadjuvant therapy by chemotherapy, usually lasting 3 to 4.5 months. This can be administered after or before radio- or radiochemotherapy (as so-called induction or consolidation chemotherapy).

In several randomized studies, TNT showed a significant benefit in disease-free survival, especially for patients whose tumors had defined "high-risk characteristics" (as used in the RAPIDO study): (i) T4 tumors, (ii) tumors with threatened/involved mesorectal resection margin, (iii) EMVI positivity, (iv) N2 status and (v) enlarged lateral lymph nodes [12, 53, 55].

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

According to multidisciplinary recommendations from working groups of the German Cancer Society, the following principles can be applied in treatment planning [51]: (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, whereby according to data from the CAO/ARO/AIO-12 and OPRA trials, consolidation chemotherapy should be preferred if the treatment goal is to achieve the highest possible rate of clinical complete remissions (cCR). Chemotherapy should be carried out using FOLFOX or CapOx; the benefit of additional administration of irinotecan (e.g., in the FOLFIRINOX regimen) has not been proven.

In the PROSPECT study, nodal-positive T2 tumors and T3 adenocarcinomas regardless of nodal involvement were included, provided that the distance to the circular resection margin (CRM) was at least 3 mm and continence-preserving surgery was possible [54]. Mainly tumors in the middle third were included. In this study, neoadjuvant chemotherapy with three months of FOLFOX was compared with neoadjuvant radiochemotherapy. In case of insufficient response to FOLFOX (defined as tumor shrinkage <20% or less than four administered FOLFOX cycles), additional RChT could be given. The non-inferiority of neoadjuvant chemotherapy with regard to DFS - the 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; test for non-inferiority: p=0.005).). There was also no difference in overall survival (HR 1.04; 95% CI 0.74-1.44; n.s.). Less than 2% local recurrences were diagnosed in both arms (HR 1.18; 95% CI 0.44-3.16; n.s.). The patient-reported outcomes (PRO) were reported separately [54]. Side effects and functionality differed between the arms in terms of frequencies and time of occurrence: during neoadjuvant therapy, patients on FOLFOX had less diarrhea and better bowel function, whereas patients in the RChT arm complained of less anxiety, loss of appetite, constipation, depression, dysphagia, dyspnea, edema, fatigue, mucositis, nausea and vomiting, and neuropathy. After 12 months post surgery, however, FOLFOX patients had significantly less fatigue and neuropathy and better sexual function. There were no differences between the arms in terms of bladder function and health-related quality of life at any time point.

The results of the PROSPECT trial were confirmed by another randomized trial presented at the 2023 ESMO congress, which had a similar design and was conducted in Asia. This CONVERT trial compared neoadjuvant chemotherapy to RChT for patients with stage II/III tumors up to 12 cm ab ano that did not threaten the mesorectal fascia [56]. Between June 2014 and October 2020, patients were randomized to 4 cycles of CapOx or to 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. A 3-year locoregional recurrence-free survival of 93% was assumed in the standard arm; the non-inferiority margin was set at an HR of <1.6. A total of 663 patients were included, their 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%, lower third tumors accounted for 41% of patients, EMVI was positive in about 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 missed (3-year local recurrence rates 97.4% versus 96.3% to the disadvantage of chemotherapy; HR 1.08, 95% CI 0.46-2.54), the difference is not clinically relevant. DFS and overall survival - although 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, there were 29.2% grade 2-4 toxicities in the RChT arm compared to only 19% in the chemotherapy arm.

In summary, neoadjuvant chemotherapy was shown to be a valid alternative to neoadjuvant RChT in two randomized trials for patients who meet the inclusion criteria of PROSPECT.

While the value of adjuvant chemotherapy for rectal cancer after rectal resection without preoperative radiotherapy is certain (see Cochrane meta-analysis), adjuvant chemotherapy par principe after combined radiochemotherapy or short-term radiotherapy and TME surgery is controversial. In a meta-analysis, which primarily examined studies with bolus application of 5-FU, no advantage could be demonstrated in either disease-free or overall survival. However, while this meta-analysis is methodologically critical, at least it proves that bolus regimens should no longer be used. After neoadjuvant radiochemotherapy, adjuvant chemotherapy with optimal fluoropyrimidine regimens can therefore be offered. Capecitabine, for example, has a good data basis. The available study data do not allow us to make specific differential therapeutic recommendations based on the degree or extent of the tumor response to neoadjuvant radiochemotherapy. A general use of oxaliplatin in adjuvant chemotherapy cannot be justified on the basis of available study data. Younger patients with an increased risk of recurrence (yp stage III) should be informed about the option of additional oxaliplatin therapy (as investigated, for example, in the large randomized phase II ADORE study) [10]. The duration of perioperative chemotherapy should be extended to a maximum of 6 months, e.g., with a further 5-6 cycles of adjuvant capecitabine or 8 cycles of FOLFOX. Patients after primary resection who have not undergone neoadjuvant radiochemotherapy can, according to data from the SCOT study, be treated in the adjuvant setting as for colon cancer (i.e., 3 or 6 months depending on the risk profile, see Onkopedia Colon cancer)

For patients with localization of the carcinoma in the upper third of the rectum, who have not received preoperative radiotherapy or radiochemotherapy, a procedure as for colon carcinoma is recommended in stages II and III. Criteria for adjuvant chemotherapy in stages II and III are compiled in the Onkopedia guideline on Colon cancer.

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 the presence of a complete clinical remission (cCR) after radiochemotherapy or TNT, confirmed by quality-assured imaging procedures and experienced examiners, surgery can be omitted. The data basis for such a procedure is now also solid in the European patient population, but the follow-up period of the reported patients is generally still short. It is therefore recommended that these patients continue to be included in studies or registries in order to obtain better long-term data.

At present, waiving of surgery is only recommended for patients with good adherence to closely scheduled follow-up examinations if complete clinical remission is documented by experienced examiners (endoscopy, MRI, clinical digital rectal examination). A blind or staged biopsy of the rectal mucosa to document cCR is just as unnecessary as endosonography.

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, cCR was detectable after six months of primary dostarlimab therapy in all patients who have been analyzed to date [13]. During the still short median follow-up, no case of local recurrence has occurred. Immune checkpoint inhibitors have not yet been approved for the treatment of locally advanced MSI-H rectal cancer. If such an organ preservation concept is used, clinical controls should be carried out after 3 and 6 months of therapy. The post-therapeutic watch-and-wait strategy should be carried out as depicted below.

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

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 6.1.3.3. The PRODIGE-14 trial, which randomly tested doublet versus triplet, each + mAb (selected depending on RAS status), as conversion therapy, did not find a statistically significant improvement in R0/R1 resection rates, disease-free and overall survival [24]. However, in the smaller OLIVIA study (80 patients) [25] 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%) [26]. 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 [27]. However, the phase III TRIPLETE study [28] 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. By this, increasing 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 assessment of CT or MRI images by a multidisciplinary 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 chapter 6.1.3.1 and chapter 6.1.3.2. 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 standard procedure is mesorectal excision with removal of the regional lymphatic drainage area, technically depending on the location of the carcinoma:

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

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

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

Open surgery is standard, an alternative is laparoscopic surgery. The advantage of open surgery is the shorter operation time and the shorter learning curve for the surgeon. The main advantages of laparoscopic surgery are the better cosmetic result and the previous postoperative recovery. 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 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. In these patients, the rectal carcinoma is usually locally advanced, so that resection is positioned as part of a multimodal treatment concept. In patients with hereditary disease, the type of genetic burden, previous operations and the overall concept of care must be taken into account.

The type and extent of the resection are determined by the localization, the supplying vessels and the lymph drainage area defined by these. The surgical technique depends on the location 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, see also Approval Status Colorectal Cancer for the German speaking countries. 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.

Dostarlimab is a humanized anti-PD-1 monoclonal 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 has progressed 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. At a follow-up period of up to 25 months, no relapse had occurred [13]. In 363 patients in the GARNET study, the main side effects observed were hypothyroidism (7%), liver enzyme elevations (6%) and arthralgias (5%) [50].

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].

Fruquintinib is an oral, selective inhibitor of VEGF receptors 1, 2 and 3. In the FRESCO-2 study [66], 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%). The marketing authorization application to the EMA was accepted for review in June 2023 and FDA approval was granted in November 2023.

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 humanized 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 for Germany, Austria and Switzerland.

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. Information on approval status is summarized in Colorectal carcinoma approval for Germany, Austria and Switzerland .

For the 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 newer 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 given 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. Information on approval status is summarized in Colorectal carcinoma approval for Germany, Austria and Switzerland .