A few decades ago, patients with PM from colorectal cancer (CRC) had a poor prognosis and seemed incurable [43]. Over recent years, the management and treatment of PM has undergone major developments [44]. The introduction of cytoreductive surgery (CRS), together with hyperthermic intraperitoneal chemotherapy (HIPEC), gave hope to patients with PM [45,46]. During CRS/HIPEC, to eradicate residual microscopic cancer cells, a heated solution with chemotherapeutic agents is applied perioperative directly into the peritoneum after macroscopically visible tumor nodules have been surgically removed. Historically, extensive debulking surgery started in around 1930 by J.V. Meigs for ovarian cancers, and the importance of cytoreductive surgery and, subsequently, of adjuvant chemotherapy became more evident over the next decades, not only for ovarian cancer, but also for pseudomyxoma peritonei [47,48,49,50]. With the increasing use of adjuvant chemotherapy, the idea of intraperitoneal application emerged to increase the therapeutic index [51]. In the following years, several trials with CRS/HIPEC and optimization attempts with different chemotherapeutic agents, depending on histological origin, were conducted [44]. To date, two main surgical intraperitoneal delivery techniques of hyperthermic intraperitoneal chemotherapy have been described: the open coliseum technique and closed administration [52]. In the 1990s, Sugarbaker and his team proposed the peritoneal cancer index (PCI) as a standardized scoring system to quantify peritoneal tumor burden during an operation, and the completeness of cytoreduction score (CC score) to determine how radical the surgery was [53]. The introduction of these scores is relevant for the selection of patients for CRS/HIPEC or to compare results among centers [54]. The contemporary staging of PM is performed with the peritoneal cancer index (PCI), a staging system ranging from 0 to 39 points, which adequately describes the distribution and the size of PM in a patient [55]. The comparison of PM with other metastatic sites is often problematic. Imaging modalities (e.g., computed tomography or magnetic resonance imaging) are more sensitive for metastasis in the lung or liver. Nevertheless, a review article on imaging diagnoses of PM from gastrointestinal and ovarian cancer showed an adequate pooled sensitivity and specificity of 80% and 90%, respectively, for PET-CT, and 92% and 85% for MRI. The authors claim that MRI could become the imaging modality of choice in staging PM, because MRI is already widely available [56]. In a clinical trial (NCT03314649), the role of mutated DNA of cancer cells in the abdominal cavity of gastric cancer patients is assessed, with the goal of increasing sensitivity in the diagnosis of micrometastasis. Another interesting approach is the detection of peritoneal implants from CRC with near-infrared fluorescence imaging after the i.v. administration of indocyane green (ICG) (NCT02032485). Even though many new strategies in the diagnostic procedure are currently being investigated, current clinical practice still relies on the surgical staging of PM by either laparoscopy or laparotomy [57].

Patient selection for CRS/HIPEC is key. Negative predictive factors after CRS/HIPEC are the extent of the disease (PCI), nodal stage, tumor biology, response systemic therapy or major complications after CRS/HIPEC. Some of these prognostic factors can be summarized by clinical scores (e.g., PDSS or BIOSCOPE). For example, BIOSCOPE includes the PCI, the nodal stage, tumor grading and the RAS/RAF mutational status, and helps to discriminate prognostic groups [66]. In clinical practice, these scores are usually not exclusive, but may help in the clinical decision process. After CRS/HIPEC, a major complication (Clavien-Dindo classification IIIB or higher) rate of 8.3% to 24% has been published in recent series [67,68].

HIPEC can also be performed as an adjuvant treatment to prevent peritoneal spread. In their trial, Virzi et al. demonstrated the feasibility and safety of HIPEC in an adjuvant setting, even though 16% of patients experienced major complications [69]. The COLOPEC trial could not prove any benefit in peritoneal-free survival after adjuvant HIPEC compared with the control arm [70].

Since the use of 5FU, the field of medical oncology has evolved dramatically and new systemic regimens and targeted agents have significantly improved the survival of patients with advanced stages of CRC [71]. Today, the choice of a systemic chemotherapy regimen depends decisively on the molecular pathological profile of the tumor. Frequently used systemic first-line regimens include combinations of 5FU or capecitabine with oxaliplatin or irinotecan [18]. Triple therapy with 5FU, oxaliplatin and irinotecan (FOLFOXIR) is a very effective regimen and has demonstrated superior response rates [72]. However, due to its side effects, it is usually given to patients in a good health condition [73]. Targeted therapies, e.g., cetuximab, an EGFR-antibody, or bevacizumab, a humanized IgG monoclonal antibody targeting VEGF-A, are often added, depending on the molecular profile of the tumor. Multiple trials, including the phase III CRYSTAL and PRIME study, showed that adding an anti-EGFR to FOLFIRI and FOLFOX4, respectively, is beneficial for patients with RAS wild-type tumors [20]. Overall, median overall survival has dramatically improved to nearly 30 months in the context of aggressive chemotherapy, which often enables secondary surgery of metastasis [72] (Table 1). The majority of patients included in these trials, however, have hematogenous metastasis, which has a significantly better prognosis than peritoneal metastasis [4,5]. Nevertheless, response to neoadjuvant systemic treatment is also a prognostic factor in patients with PM [74]. Thus, progress in this field is likely to enable more aggressive surgery in the future.

PM—CRC Outcome after Different Treatment Approaches
	mOS (Months)
	CRS/HIPEC	Systemic Chemotherapy	PIPAC	Amount of Disease	Used Drug
Vervaal V. et al., 2003 [60]	22.2	12.6	-	+++	5FU
Elias D. et al., 2009 [58]	67.7	23.9	-	++	FOLFOX/FOLFIRI
Franko J. et al., 2016 [5]	16.3	-	-	NA	FOLFOX/FOLFIRI +/−ab
Cremolini Ch. et al., 2020 [75]	-	28.9	-	NA	FOLFOXIRI
Quenet F. et al., 2021 [59]	41	-	-	++	FOLFOX/FOLFIRI
Breuer E. et al., 2021 [4]	51	-	-	++	FOLFOX/FOLFIRI
Demtröder C. et al., 2015 [76]	-	-	15.7	+++	FOLFOX/FOLFIRI +/−ab
Goére D. et al., 2020 [77]	mOS not reached during 50.8 months of follow-up	-		+	FOLFOX/XELOX

3. Novel Concepts and New Treatment Strategies for the Treatment of PM